DE102004046012A1 - New D-glucopyranosylphenyl-substituted cyclic compounds useful as sodium-dependent glucose cotransporter inhibitors for treating metabolic diseases, e.g. diabetes - Google Patents

Abstract

D-glucopyranosylphenyl-substituted cyclic compounds (I) are new. D-glucopyranosylphenyl-substituted cyclic compounds of formula (I) and their tautomers, stereoisomers and salts, other than 3-(3-beta -D-glucopyranosyl-4,5-dimethoxybenzyl)-4-(3,4-dimethoxybenzyl)-dihydro-2(3H)-furanone (Ia), are new: Cy : a 5- or 6-membered saturated or monounsaturated ring containing 0-3 heteroatoms (N, O, S) in which 1-2 CH 2groups can be replaced by CO, S, SO or SO 2and C-bonded H atoms can be replaced by F; Z : O, CH 2, CH, NR, CO, S, SO or SO 2, where CH 2and CH are optionally substituted with Me or F; R 1>e.g. H, halo, 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, 3-7C cycloalkyl, (3-7C)cycloalkyl(1-3C)alkyl, 5-7C cycloalkenyl, (5-7C)cycloalkenyl(1-3C)alkyl, 1-4C alkylcarbonyl, aroyl; R 2>H, F, Cl, Br, OH, 1-4C (fluoro)alkyl, 1-4C alkoxy, CN or NO 2; R 1>+R 2>3-5C alkylene, 3-5C alkenylene or butadienylene, optionally substituted with F or 1-2 of Cl, OH, 1-3C alkoxy and 1-3C alkyl, where 1-2 CH 2groups can be replaced by O, S, CO, SO, SO 2or NR and 1-2 CH groups can be replaced by N; R 3>R 1>(but not iodo) or Y; R 4>H, F, Cl, CN, NO 2, NH 2, mono- or di(1-3C alkyl)amino, 1-3C alkylcarbonylamino, 1-3C alkyl, 1-3C alkoxy, COOH, 1-3C alkoxycarbonyl, fluoromethyl or fluoromethoxy; R 3>+R 4>2-6C alkylene or 4-6C alkenylene optionally substituted with F or 1-2 of Cl, OH, 1-3C alkoxy and 1-3C alkyl, where 1-2CH 2groups can be replaced by O, S, CO, SO, SO 2or NR; or R 3>+R 4>forms a fused 5- or 6-membered ring optionally substituted with F or 1-2 of Cl, OH, 1-3C alkoxy and 1-3C alkyl, where 1-2 CH 2groups can be replaced by O, S, CO, SO, SO 2or NR and 1-2 CH groups can be replaced by N or a fused aromatic ring can be substituted with 1-2 of L; R 5>H, F, Cl, CN, 1-3C alkyl, 1-3C alkoxy, fluoromethyl or fluoromethoxy; R 4>+R 5>1-4C alkylene or 2-4C alkenylene, optionally substituted with F or 1-2 of Cl, OH, 1-3C alkoxy and 1-3C alkyl, where 1-2 CH 2groups can be replaced by O, S, CO, SO, SO 2or NR; R 6>H, 1-3C alkyl or F; R 4>+R 5>+R 6>3-6C alkanetriyl optionally substituted with F or 1-2 of Cl, OH, 1-3C alkoxy and 1-3C alkyl, where 1-2 CH 2groups can be replaced by O, S, CO, SO, SO 2or NR; Y : e.g. O, CH 2(optionally substituted with F, Cl, 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, 3-7C cycloalkyl, 5-7C cycloalkenyl or Y is =C(Ry)DBRb; D : CO or SO 2; Ry : H, F, Cl, CN, CF 3or 1-3C alkyl; B : a bond, O or NR; Rb : e.g. H, 1-6C alkyl, 3-6C alkenyl, 3-6C alkynyl, 3-7C cycloalkyl, 5-7C cycloalkenyl, (3-7C)cycloalkyl(1-3C)alkyl; Rb+B : pyrrolidine, morpholine, piperidine, piperazine of 4-(1-4C alkyl)piperazine; R : H or 1-4C alkyl; L : halo, 1-3C alkyl, CHF 2, CF 3, 1-3C alkoxy, OCHF 2, OCF 3, CN; R7a, R7b, R7c, R7d : H, (1-18C alkyl)carbonyl, (1-18C alkoxy)carbonyl, arylcarbonyl or aryl(1-3C)alkylcarbonyl; aryl : phenyl or naphthyl substituted with 0-2 of L; heteroaryl : e.g. pyrrolyl, furyl, thienyl, imidazolyl or pyridyl. [Image] ACTIVITY : Antidiabetic; Antilipemic; Antiarteriosclerotic; Anorectic; Hypotensive; Cardiant; Antiinflammatory; Antigout. MECHANISM OF ACTION : Sodium-dependent glucose cotransporter (SGLT) inhibitor. Test details are described but no results given.

Description

wobei die Reste R¹ bis R⁶, Z, Cy sowie R^7a, R^7b, R^7c und R^7d 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 D-glucopyranosyl-phenyl-substituted cyclen of the general formula I.

wherein the radicals R ¹ to R ⁶ , Z, Cy and R ^7a , R ^7b , R ^7c and R ^7d 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 cotransporter SGLT possess, for the treatment of diseases, especially suggested by diabetes.

Out International Publication WO 98/31697, WO 01/27128, WO 02/083066 and WO 03/099836 are glucopyranosyl-substituted Aromatics and their production and their possible activity as SGLT2 inhibitors known.

Object of the invention

Of the present invention is based on the object, new pyranosyl-substituted Phenyle show, especially those that have activity in the sodium-dependent Glucose cotransporters SGLT, in particular SGLT2 possess. Another The object of the present invention is to show pyranosyl-substituted Phenylene in vitro and / or in vivo in comparison 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

Cy einen 5- oder 6-gliedrigen gesättigten oder einfach ungesättigten Carbocyclus bedeutet, der im Ring ein, zwei oder drei Heteroatome unabhängig voneinander ausgewählt aus N, O und S aufweisen kann, und
der mit R⁴, R⁵ und R⁶ über eine Einfachbindung und mit R³ über eine Einfach- oder eine Doppelbindung substituiert ist, und
in dem eine oder zwei Methylengruppen durch CO oder eine Sulfanylgruppe durch SO oder SO₂ ersetzt sein kann, und
in dem zusätzlich ein oder mehrere an Kohlenstoff gebundene H-Atome durch Fluor ersetzt sein können,
Z -O-, -CH₂-, -CH=, -NR^N-, -CO-, -S-, -SO- oder -SO₂- bedeutet, wobei H-Atome der Methylen- oder Methanylyliden-Brücke unabhängig voneinander durch CH₃ oder F substituiert sein können;
R¹ Wasserstoff, Fluor, Chlor, Brom, Iod, C_1-6-Alkyl, C_2-6-Alkinyl, C_2-6-Alkenyl, C_3-10-Cycloalkyl, C_3-10-Cycloalkyl-C_1-3-alkyl, C_5-10-Cycloalkenyl, C_5-10-Cycloalkenyl-C_1-3-alkyl, 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, C_1-4-Alkoxycarbonyl, Amino, C_1-4-Alkylamino, Di-(C_1-3-alkyl)amino, Pyrrolidin-1-yl, Piperidin-1-yl, Morpholin-4-yl, Piperazin-1-yl, 4-(C_1-4-Alkyl)piperazin-1-yl, C_1-4-Alkylcarbonylamino, C_1-6-Alkyloxy, C_3-10-Cycloalkyloxy, C_5-10-Cycloalkenyloxy, Aryloxy, C_1-4-Alkylsulfanyl, C_1-4-Alkylsulfinyl, C_1-4-Alkylsulfonyl, 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, Arylsulfonyl, Hydroxy, Cyan und Nitro,
wobei Alkyl-, Alkenyl-, Alkinyl-, Cycloalkyl- und Cycloalkenyl-Reste teilweise oder vollständig fluoriert oder ein- oder zweifach mit gleichen oder verschiedenen Substituenten ausgewählt aus Chlor, Hydroxy, C_1-3-Alkoxy und C_1-3-Alkyl substituiert sein können, und
wobei in Cycloalkyl- und Cycloalkenyl-Resten ein oder zwei Methylengruppen unabhängig voneinander durch O, S, CO, SO oder SO₂ substituiert sein können, und
wobei in N-Heterocycloalkyl-Resten eine Methylengruppe durch CO oder SO₂ substituiert sein kann, und
R² Wasserstoff, Fluor, Chlor, Brom, Hydroxy, C_1-4-Alkyl, C_1-4-Alkoxy, Cyan oder Nitro, wobei Alkyl-Reste ein- oder mehrfach mit Fluor substituiert sein können, oder
für den Fall, dass R¹ und R² an zwei miteinander benachbarte C-Atome des Phenylrings gebunden sind, können R¹ und R² derart miteinander verbunden sein, dass R¹ und R² zusammen eine C_3-5-Alkylen-, C_3-5-Alkenylen- oder Butadienylen-Brücke bilden, die teilweise oder vollständig fluoriert oder ein- oder zweifach mit gleichen oder verschiedenen Substituenten ausgewählt aus Chlor, Hydroxy, C_1-3-Alkoxy und C_1-3-Alkyl substituiert sein kann, und in der eine oder zwei Methylengruppen unabhängig voneinander durch O, S, CO, SO, SO₂ oder NR^N ersetzt sein können, und in der im Falle einer Butadienylen-Brücke eine oder zwei Methingruppen durch ein N-Atom ersetzt sein können,
R³ Wasserstoff, Fluor, Chlor, Brom, C_1-6-Alkyl, C_2-6-Alkinyl, C_2-6-Alkenyl, C_3-10-Cycloalkyl, C_3-10-Cycloalkyl-C_1-3-alkyl, C_5-10-Cycloalkenyl, C_5-10-Cycloalkenyl-C_1-3-alkyl, Aryl, Heteroaryl, Aryl-C_1-3-alkyl, Heteroaryl-C_1-3-alkyl, 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, Hydroxycarbonyl, C_1-4-Alkoxycarbonyl, C_1-4-Alkylamino, Di-(C_1-3-alkyl)amino, Pyrrolidin-1-yl, Piperidin-1-yl, Morpholin-4-yl, Piperazin-1-yl, 4-(C_1-4-Alkyl)piperazin-1-yl, C_1-4-Alkylcarbonylamino, Arylcarbonylamino, Heteroarylcarbonylamino, C_1-4-Alkylsulfonylamino, Arylsulfonylamino, C_1-6-Alkoxy, C_3-10-Cycloalkyloxy, C_5-10-Cycloalkenyloxy, Aryloxy, Heteroaryloxy, C_1-4-Alkylsulfanyl, C_1-4-Alkylsulfinyl, C_1-4-Alkylsulfonyl, 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, Arylsulfonyl, Amino, Hydroxy, Cyan oder Nitro bedeutet, und
wobei Alkyl-, Alkenyl-, Alkinyl-, Cycloalkyl- und Cycloalkenyl-Reste teilweise oder vollständig fluoriert oder ein- oder zweifach mit gleichen oder verschiedenen Substituenten ausgewählt aus Chlor, Hydroxy, C_1-3-Alkoxy und C_1-3-Alkyl substituiert sein können, und
wobei in Cycloalkyl- und Cycloalkenyl-Resten ein oder zwei Methylengruppen unabhängig voneinander durch O, S, CO, SO oder SO₂ substituiert sein können, und
wobei in N-Heterocycloalkyl-Resten eine Methylengruppe durch CO oder SO₂ substituiert sein kann, oder
R³ bedeutet eine über eine Doppelbindung mit Cy verbundene Gruppe Y,
R⁴ Wasserstoff, Fluor, Chlor, Cyan, Nitro, Amino, C_1-3-Alkyl-amino, Di-(C_1-3-Alkyl)amino, C_1-3-Alkylcarbonylamino, C_1-3-Alkyl, C_1-3-Alkoxy, Hydroxycarbonyl, C_1-3-Alkoxycarbonyl oder durch 1 bis 3 Fluoratome substituiertes Methyl- oder Methoxy bedeutet, und
für den Fall, dass R³ und R⁴ an dem selben C-Atom des Cyclus Cy gebunden sind, können R³ und R⁴ derart miteinander verbunden sein, dass R³ und R⁴ zusammen eine C_2-6-Alkylen- oder C_4-6-Alkenylen-Brücke bilden, die teilweise oder vollständig fluoriert oder ein- oder zweifach mit gleichen oder verschiedenen Substituenten ausgewählt aus Chlor, Hydroxy, C_1-3-Alkoxy und C_1-3-Alkyl substituiert sein kann und in der eine oder zwei Methylengruppen unabhängig voneinander durch O, S, CO, SO, SO₂ oder NR^N substituiert sein können, oder
für den Fall, dass R³ und R⁴ an zwei benachbarte Atome des Cyclus Cy bebunden sind, können R³ und R⁴ derart miteinander verbunden sein, dass R³ und R⁴ zusammen mit den beiden benachbarten Atomen des Cyclus Cy einen anellierten gesättigten oder ein- oder mehrfach ungesättigten 5- oder 6-gliedrigen Carbocyclus bilden, in dem eine oder zwei Methylengruppen unabhängig voneinander durch O, S, CO, SO, SO₂ oder NR^N und/oder eine oder zwei Methingruppen durch N ersetzt sein können, und der ein- oder mehrfach fluoriert oder ein- oder zweifach mit gleichen oder verschiedenen Substituenten ausgewählt aus Chlor, Hydroxy, C_1-3-Alkoxy und C_1-3-Alkyl oder im Falle eines aromatischen anellierten Cyclus ein- oder zweifach mit gleichen oder verschiedenen Substituenten L substituiert sein kann,
R⁵ Wasserstoff, Fluor, Chlor, Cyan, C_1-3-Alkyl, C_1-3-Alkoxy oder durch 1 bis 3 Fluoratome substituiertes Methyl- oder Methoxy bedeutet, und
R⁴ und R⁵ sind derart miteinander verbunden, dass R⁴ und R⁵ zusammen eine C_1-4-Alkylen- oder C_2-4-Alkenylen-Brücke bilden, die mit 2, 3 oder 4 Atomen des Cyclus Cy einen anellierten oder verbrückten Cyclus bildet und die teilweise oder vollständig fluoriert oder ein- oder zweifach mit gleichen oder verschiedenen Substituenten ausgewählt aus Chlor, Hydroxy, C_1-3-Alkoxy und C_1-3-Alkyl substituiert sein kann, und in der ein oder zwei Methylengruppen unabhängig voneinander durch O, S, CO, SO, SO₂ oder NR^N substituiert sein können, und
R⁶ Wasserstoff, C_1-3-Alkyl oder Fluor bedeutet, oder
R⁴, R⁵ und R⁶ sind derart miteinander verbunden, dass R⁴, R⁵ und R⁶ zusammen eine C_3-6-Alkantriyl-Brücke bilden, die zuammen mit dem Cyclus Cy ein verbrücktes bicyclisches oder ein tricyclisches System bildet, wobei die Alkantriyl-Brücke ein- oder mehrfach fluoriert oder ein- oder zweifach mit gleichen oder verschiedenen Substituenten ausgewählt aus Chlor, Hydroxy, C_1-3-Alkoxy und C_1-3-Alkyl substituiert sein kann, und in der ein oder zwei Methylengruppen unabhängig voneinander durch O, CO, SO₂ oder NR^N substituiert sein können, und
Y Sauerstoff, oder
Methyliden, Fluormethyliden, Chlormethyliden, C_1-6-Alkyl-methyliden, C_2-6-Alkenyl-methyliden, C_2-6-Alkinyl-methyliden, C_3-10-Cycloalkyl-methyliden, C_5-10-Cycloalkenyl-methyliden, C_3-10-Cycloalkyliden, C_5-10-Cycloalkenyliden, C_3-10-Cycloalkyl-C_1-3-alkyl-methyliden, C_5-10-Cycloalkenyl-C_1-3-alkyl-methyliden, Arylmethyliden, Heteroarylmethyliden, Aryl-C_1-3-alkyl-methyliden oder Heteroaryl-C_1-3-alkyl-methyliden bedeutet,
wobei Alkyl-, Alkenyl-, Alkinyl-, Cycloalkyl-, Cycloalkenyl-, Cycloalkyliden- und Cycloalkenyliden-Reste teilweise oder vollständig fluoriert oder ein- oder zweifach mit gleichen oder verschiedenen Substituenten ausgewählt aus Chlor, Cyan, Hydroxy, C_1-3-Alkoxy, C_1-3-Alkylsulfanyl und C_1-3-Alkyl substituiert sein können, und
wobei die zuvor angeführte unsubstituierte Methylidengruppe oder die zuvor angeführten einfach substituierten Methylidengruppen zusätzlich einfach mit Fluor, Chlor, C_1-3-Alkyl, Trifluormethyl, C_1-4-Alkoxy, Cyan oder Nitro substituiert sein können, und
wobei in Cycloalkyl-, Cycloalkenyl-, Cycloalkyliden- und Cycloalkenyliden-Resten ein oder zwei Methylengruppen unabhängig voneinander durch O, S, CO, SO, SO₂ oder NR^N substituiert sein können, oder
Y bedeutet eine Gruppe gemäß der Teilformel

in der
D Carbonyl oder Sulfonyl,
R^Y Wasserstoff, Fluor, Chlor, Cyan, Trifluormethyl oder C_1-3-Alkyl bedeutet,
B eine Einfachbindung, -O- oder -NR^N- bedeutet,
R^B Wasserstoff, C_1-6-Alkyl-, C_3-6-Alkenyl-, C_3-6-Alkinyl-, C_3-10-Cycloalkyl-, C_5-10-Cycloalkenyl-, C_3-10-Cycloalkyl-C_1-3-alkyl-, C_5-10-Cycloalkenyl-C_1-3-alkyl-, Aryl, Heteroaryl, Aryl-C_1-3-alkyl- oder Heteroaryl-C_1-3-alkyl- bedeutet,
wobei Alkyl-, Cycloalkyl- und Cycloalkenyl-Reste teilweise oder vollständig fluoriert oder ein- oder zweifach mit gleichen oder verschiedenen Substituenten ausgewählt aus Chlor, Cyan, Hydroxy, C_1-3-Alkoxy und C_1-3-Alkyl substituiert sein können, oder
R^B und B miteinander unter Ausbildung eines heterocyclischen Rings ausgewählt aus Pyrrolidin, Morpholin, Piperidin, Piperazin und 4-(C_1-4-Alkyl)piperazin verbunden sind, wobei der heterocyclische Ring über die Iminogruppe an die Gruppe D gebunden ist,
R^N unabhängig voneinander H oder C_1-4-Alkyl,
L 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,
R^7a, R^7b, R^7c, R^7d 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 L substituiert sein können; und
unter den bei der Definition der vorstehend erwähnten Reste erwähnten Heteroarylgruppen eine Pyrrolyl-, Furanyl-, Thienyl-, Imidazolyl-, Pyridyl-, Indolyl-, Benzofuranyl-Benzothiophenyl-, Chinolinyl- oder Isochinolinylgruppe zu verstehen ist,
oder eine Pyrrolyl-, Furanyl-, Thienyl-, Imidazolyl- 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 L substituiert sein können;
wobei unter dem bei der Definition der vorstehend erwähnten Reste erwähnten N-Heterocycloalkyl-Rest ein gesättigter carbocyclischer Ring, der eine Imino-Gruppe im Ring aufweist, zu verstehen ist, der eine weitere Imino-Gruppe oder ein O- oder S-Atom im Ring aufweisen kann, und
wobei, soweit nichts anderes erwähnt wurde, die vorstehend erwähnten Alkylgruppen geradkettig oder verzweigt sein können,
deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze, insbesondere deren physiologisch verträglichen Salze,
wobei, folgende Verbindung (D1) nicht mit umfasst ist:
(D1) 3-[(3-β-D-glucopyranosyl-4,5-dimethoxyphenyl)methyl]-4-[(3,4-dimethoxyphenyl)methyl]-dihydro-2(3H)-furanon.A first subject of the present invention are D-glucopyranosyl-phenyl-substituted cyclen of the general formula I.

Cy is a 5- or 6-membered saturated or monounsaturated carbocycle which in the ring may have one, two or three heteroatoms independently selected from N, O and S, and
which is substituted with R ⁴ , R ⁵ and R ⁶ via a single bond and with R ³ via a single or a double bond, and
in which one or two methylene groups may be replaced by CO or a sulfanyl group by SO or SO ₂ , and
in which additionally one or more carbon-bonded hydrogen atoms may be replaced by fluorine,
Z is -O-, -CH ₂ -, -CH =, -NR ^N -, -CO-, -S-, -SO- or -SO ₂ -, where H atoms of the methylene or methanylylidene bridge independently of one another may be substituted by CH ₃ or F;
R ^{1 is} hydrogen, fluorine, chlorine, bromine, iodine, C _1-6 -alkyl, C _2-6 -alkynyl, C _2-6 -alkenyl, C _3-10 -cycloalkyl, C _3-10 -cycloalkyl-C _{1- 3} -alkyl, C _5-10 -cycloalkenyl, C _5-10 -cycloalkenyl-C _1-3 -alkyl, 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, C _{1 4} alkoxycarbonyl, amino, C _1-4 alkylamino, di (C _1-3 alkyl) amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4 (C _1-4 alkyl) piperazin-1-yl, C _1-4 alkylcarbonylamino, C _1-6 alkyloxy, C _3-10 cycloalkyloxy, C _5-10 cycloalkenyloxy, aryloxy, C _1-4 Alkylsulfanyl, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, 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, arylsulfine yl, arylsulfonyl, hydroxy, cyano and nitro,
wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl radicals are partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C _1-3 alkoxy and C _1-3 alkyl substituted can be, and
wherein in cycloalkyl and cycloalkenyl radicals one or two methylene groups can be substituted independently of one another by O, S, CO, SO or SO ₂ , and
wherein in N-heterocycloalkyl radicals a methylene group may be substituted by CO or SO ₂ , and
R ^{2 is} hydrogen, fluorine, chlorine, bromine, hydroxyl, C _1-4 -alkyl, C _1-4 -alkoxy, cyano or nitro, where alkyl radicals may be mono- or polysubstituted by fluorine, or
in the event that R ¹ and R ² are bonded to two adjacent C atoms of the phenyl ring, R ¹ and R ^{2 may} be linked together such that R ¹ and R ² together form a C _3-5 alkylene, C _3-5 alkenylene or butadienylene bridge which may be partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C _1-3 alkoxy and C _1-3 alkyl, and in which one or two methylene groups can be replaced independently of one another by O, S, CO, SO, SO ₂ or NR ^N , and in which in the case of a butadienylene bridge one or two methine groups can be replaced by an N atom,
R ^{3 is} hydrogen, fluorine, chlorine, bromine, C _1-6 -alkyl, C _2-6 -alkynyl, C _2-6 -alkenyl, C _3-10 -cycloalkyl, C _3-10 -cycloalkyl-C _1-3 alkyl, C _5-10 -cycloalkenyl, C _5-10 -cycloalkenyl-C _1-3 -alkyl, aryl, heteroaryl, arylC _1-3 -alkyl, heteroarylC _1-3 -alkyl, 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, hydroxycarbonyl, C _1-4 -alkoxycarbonyl, C _1-4 -alkylamino, di- (C _1-3 -alkyl) -amino, pyrrolidin-1-yl , Piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4- (C _1-4 alkyl) piperazin-1-yl, C _1-4 alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C _1-4 Alkylsulfonylamino, arylsulfonylamino, C _1-6 alkoxy, C _3-10 cycloalkyloxy, C _5-10 cycloalkenyloxy, aryloxy, heteroaryloxy, C _1-4 alkylsulfanyl, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl , 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, arylsulfonyl, amino, hydroxy, cyano or nitro, and
wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl radicals are partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C _1-3 alkoxy and C _1-3 alkyl substituted can be, and
wherein in cycloalkyl and cycloalkenyl radicals one or two methylene groups can be substituted independently of one another by O, S, CO, SO or SO ₂ , and
wherein in N-heterocycloalkyl radicals a methylene group may be substituted by CO or SO ₂ , or
R ^{3 represents} a group Y connected via a double bond with Cy,
R ^{4 is} hydrogen, fluorine, chlorine, cyano, nitro, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, C _1-3 alkylcarbonylamino, C _1-3 alkyl, C _1-3 denotes alkoxy, hydroxycarbonyl, C _1-3 -alkoxycarbonyl or methyl or methoxy substituted by 1 to 3 fluorine atoms, and
in the event that R ³ and R ⁴ are bonded to the same C-atom of the Cy cycle, R ³ and R ^{4 may} be linked together such that R ³ and R ⁴ together form a C _2-6 alkylene or C Form _4-6 alkenylene bridge which may be partially or fully fluorinated or mono- or disubstituted by identical or different substituents selected from chloro, hydroxy, C _1-3 alkoxy and C _1-3 alkyl and in which one or two methylene groups may be independently substituted by O, S, CO, SO, SO ₂ or NR ^N , or
in the event that R ³ and R ^{4 are} attached to two adjacent atoms of the Cy cycle, R ³ and R ^{4 may} be linked together such that R ³ and R ⁴ together with the two adjacent atoms of the Cy cycle form a fused saturated or unsaturated group form a mono- or polyunsaturated 5- or 6-membered carbocycle in which one or two methylene groups can be replaced independently by O, S, CO, SO, SO ₂ or NR ^N and / or one or two methine groups by N, and which is mono- or polyfluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxyl, C _1-3 -alkoxy and C _1-3 -alkyl or in the case of an aromatic fused cycle, once or twice with identical or different substituents Substituents L may be substituted,
R ^{5 is} hydrogen, fluorine, chlorine, cyano, C _1-3 -alkyl, C _1-3 -alkoxy or methyl or methoxy substituted by 1 to 3 fluorine atoms, and
R ⁴ and R ⁵ are bonded together such that R ⁴ and R ⁵ together form a C _1-4 alkylene or C _2-4 alkenylene bridge fused with 2, 3 or 4 atoms of the Cy cycle forms bridged Cyclus and which may be partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C _1-3 alkoxy and C _1-3 alkyl, and in the one or two methylene groups independently may be substituted by O, S, CO, SO, SO ₂ or NR ^N , and
R ^{6 is} hydrogen, C _1-3 -alkyl or fluorine, or
R ⁴ , R ⁵ and R ⁶ are joined together such that R ⁴ , R ⁵ and R ⁶ together form a C _3-6 alkanetriyl bridge which together with the Cy cycle forms a bridged bicyclic or tricyclic system, wherein the alkanetriyl bridge may be mono- or polyfluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C _1-3 -alkoxy and C _1-3 -alkyl, and in which one or two methylene groups are independent may be substituted by O, CO, SO ₂ or NR ^N , and
Y oxygen, or
Methylidene, fluoromethylidene, chloromethylidene, C _1-6 alkylmethylidene, C _2-6 alkenylmethylidene, C _2-6 alkynylmethylidene, C _3-10 cycloalkylmethylidene, C _5-10 cycloalkenylmethylidene , C _3-10 cycloalkylidene, C _5-10 cycloalkenylidene, C _3-10 cycloalkyl C _1-3 alkylmethylidene, C _5-10 cycloalkenyl C _1-3 alkylmethylidene, arylmethylidene, heteroarylmethylidene , Aryl-C _1-3 -alkyl-methylidene or heteroaryl-C _1-3 -alkyl-methylidene,
wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylidene and cycloalkenylidene radicals are partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, cyano, hydroxy, C _1-3 -alkoxy , C _1-3 -alkylsulfanyl and C _1-3 -alkyl, and
in addition, the above-mentioned unsubstituted methylidene group or the above-mentioned monosubstituted methylidene groups may be easily substituted with fluorine, chlorine, C _1-3 alkyl, trifluoromethyl, C _1-4 alkoxy, cyano or nitro, and
wherein in cycloalkyl, cycloalkenyl, cycloalkylidene and cycloalkenylidene radicals one or two methylene groups may be independently substituted by O, S, CO, SO, SO ₂ or NR ^N , or
Y represents a group according to the sub-formula

in the
D is carbonyl or sulfonyl,
R ^{Y is} hydrogen, fluorine, chlorine, cyano, trifluoromethyl or C _1-3 -alkyl,
B is a single bond, -O- or -NR ^N -,
R ^{B is} hydrogen, C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-10 cycloalkyl, C _5-10 cycloalkenyl, C _3-10 cycloalkyl C _1-3 alkyl, C _5-10 cycloalkenyl C _1-3 alkyl, aryl, heteroaryl, arylC _1-3 alkyl or heteroarylC _1-3 alkyl,
wherein alkyl, cycloalkyl and cycloalkenyl radicals may be partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, cyano, hydroxy, C _1-3 alkoxy and C _1-3 alkyl, or
R ^B and B are joined together to form a heterocyclic ring selected from pyrrolidine, morpholine, piperidine, piperazine and 4- (C _1-4 alkyl) piperazine, wherein the heterocyclic ring is bonded to the group D via the imino group,
R ^N independently of one another are H or C _1-4 -alkyl,
L is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, C _1-3 -alkyl, difluoromethyl, trifluoromethyl, C _1-3 -alkoxy, difluoromethoxy, trifluoromethoxy and cyano,
R ^7a , R ^7b , R ^7c , R ^7d 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; and
the heteroaryl groups mentioned in the definition of the abovementioned radicals are pyrrolyl, furanyl, thienyl, imidazolyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl groups,
or a pyrrolyl, furanyl, thienyl, imidazolyl or pyridyl group in which one or two methine groups are replaced by nitrogen atoms,
or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group in which one to three methine groups are replaced by nitrogen atoms,
wherein the above-mentioned heteroaryl groups may be independently substituted one or two times with the same or different L groups;
wherein the N-heterocycloalkyl radical mentioned in the definition of the abovementioned radicals is to be understood as meaning a saturated carbocyclic ring which has an imino group in the ring which contains a further imino group or an O or S atom in the ring can have, and
Unless otherwise stated, the abovementioned alkyl groups may be straight-chain or branched,
their tautomers, their stereoisomers, their mixtures and their salts, in particular their physiologically tolerated salts,
wherein, the following compound (D1) is not included:
(D1) 3 - [(3-.beta.-D-glucopyranosyl-4,5-dimethoxyphenyl) methyl] -4 - [(3,4-dimethoxyphenyl) methyl] -dihydro-2 (3H) -furanone.

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, can erfindunsgemäße connections 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.

The Compound (D1) 3 - [(3, β-D-glucopyranosyl-4,5-dimethoxyphenyl) methyl] -4 - [(3,4-dimethoxyphenyl) methyl] dihydro-2 (3H) -furanone (Chemical Abstracts Registry No. 106678-86-8) is in Abe, Fumiko; Yamauchi, Tatsuo; Lignans from Trachelospermum asiaticum, Chemical & Pharmaceutical Bulletin (1986), 34 (19), 4340-5, but without a link with an inhibitory effect on SGLT.

Therefore is the use of the compounds of the invention, including physiologically compatible Salts, including the above explicitly excluded compound (D1) or a its physiologically tolerable Salts, as a medicament also an object of this invention.

Another object of this invention are pharmaceutical compositions containing at least one compound of the invention or a physiologically acceptable salt according to the invention, including the vorste explicitly excluded compound (D1) or one of its physiologically acceptable salts, in addition 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, including the above explicitly excluded compound (D1) or one of its physiological acceptable Salts for the manufacture of a medicament for the treatment or Prophylaxis of diseases or conditions suitable by Inhibition of the sodium-dependent Glucose cotransporter SGLT, in particular SGLT2 can be influenced.

One Another object of this invention is the use of at least a compound of the invention or one of its physiologically acceptable salts, including the explicitly excluded compound (D1) or a its physiologically tolerable Salts for the manufacture of a medicament for the treatment of Metabolic disorders is suitable.

One Another object of this invention is the use of at least a compound of the invention or one of its physiologically acceptable salts, including the explicitly excluded compound (D1) or a its physiologically tolerable Salts, for the manufacture of a medicament 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, including the above explicitly excluded compound (D1) or a its physiologically tolerable 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 oder 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 R^7a, R^7b, R^7c, R^7d angegebenen Bedeutungen aufweisen oder eine R^aR^bR^cSi-Gruppe oder eine Ketal- oder Acetalgruppe bedeuten, wobei jeweils zwei benachbarte Reste R^8a, R^8b, R^8c, R^8d eine cyclische Ketal- oder Acetalgruppe bilden können, und wobei Alkyl- und/oder Arylgruppen ein- oder mehrfach halogeniert sein können; und R^a, R^b, R^c unabhängig voneinander C_1-4-Alkyl, Aryl oder Aryl-C_1-3-alkyl bedeuten, 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 R⁶ und die Brücke Z sowie der Cyclus Cy wie vor- und nachstehend definiert sind; mit einem Reduktionsmittel in Gegenwart einer 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 R^7a, R^7b, R^7c und R^7d Wasserstoff bedeuten, in einer Verbindung der allgemeinen Formel III
  
  in der Z, Cy, R^8a, R^8b, R^8c, R^8d sowie R¹ bis R⁶ wie zuvor und nachstehend definiert sind, wobei mindestens einer der Reste R^8a, R^8b, R^8c und R^8d nicht Wasserstoff bedeutet, die nicht Wasserstoff bedeutenden Reste R^8a, R^8b, R^8c bzw. R^8d entfernt werden, insbesondere hydrolysiert werden; und erforderlichenfalls ein bei den vorstehend beschriebenen Umsetzungen gemäß Verfahren a) oder b) verwendeter Schutzrest wieder abgespalten wird und/oder gewünschtenfalls eine so erhaltene Verbindung der allgemeinen Formel I selektiv an einer Hydroxygruppe derivatisiert oder diese substituiert 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 or 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 meanings given previously and below for the radicals R ^7a , R ^7b , R ^7c , R ^7d or a R ^a R ^b R ^c Si group or a ketal or Each of two adjacent radicals R ^8a , R ^8b , R ^8c , R ^{8d can form} a cyclic ketal or acetal group, and wherein alkyl and / or aryl groups may be mono- or polyhalogenated; and R ^a , R ^b , R ^c independently of one another are C _1-4 -alkyl, aryl or arylC _1-3 -alkyl, in which 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 in which the radicals R ¹ to R ⁶ and the bridge Z and the cycle Cy are as defined above and below; is reacted with a reducing agent in the presence of an 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 ^7a , R ^7b , R ^7c and R ^{7d are} hydrogen, in a compound of general formula III
  
  in which Z, Cy, R ^8a , R ^8b , R ^8c , R ^8d and R ¹ to R ^{6 are} as defined above and below, where at least one of the radicals R ^8a , R ^8b , R ^8c and R ^{8d is} not hydrogen, the radicals R ^8a , R ^8b , R ^8c or R ^8d which are not hydrogen-significant are removed, in particular hydrolyzed; and, if necessary, a protective moiety used in the reactions described above according to process a) or b) is cleaved off again and / or, if desired, a compound of general formula I thus obtained is selectively derivatized or substituted on a hydroxy group and / or, if desired, a compound of this type general formula I is separated into its stereoisomers and / or, if desired, a compound of the general formula I thus obtained in its salts, in particular for the pharmaceutical application into their physiologically acceptable salts, is transferred.

Detailed description the invention

Unless otherwise stated, the groups, radicals and substituents, in particular R ¹ to R ⁶ , Y, Z, Cy, L, R ^N , R ^7a , R ^7b , R ^7c , R ^7d , R ^Y , D, B, R have ^B , the meanings given above and below.

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

The term aryl used above and below, for example in the groups Y, R ¹ and R ³ , preferably denotes phenyl. In accordance with the general definition and unless stated otherwise, the aryl group, in particular the phenyl group, may be monosubstituted or disubstituted by identical or different radicals L.

The term heteroaryl used above and below, for example in the groups Y, R ¹ and R ³ , preferably denotes pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl. In accordance with the general definition and unless stated otherwise, the heteroaryl group may be monosubstituted or disubstituted by identical or different radicals L.

Preferred meanings of the Cy cycle are cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, tetrahydropyran, 1,3-dioxane, 1,4-dioxane, tetrahydrothiophene, dithiolane and 1,3-dithiane in which a methylene group is replaced by CO may be substituted, and which are substituted as previously indicated with R ³ , R ⁴ , R ⁵ and R ⁶ , and in which one or more carbon-bonded H atoms may be replaced by fluorine.

is in the previously given cyclic groups, a methylene group replaced by CO, so are preferred meanings of the group Cy selected from tetrahydrofuranone, tetrahydropyranone, piperidinone, piperazinone and morpholinone.

Furthermore, in each case one double bond may be present in the groups previously indicated as being preferred for Cy. Preferred meanings of such monounsaturated Cy are cyclopentene and cyclohexene. In the event that substituents R ³ , R ⁴ , R ⁵ and / or R ⁶ are bonded together, this double bond may also be part of a fused cyclic system.

Particularly preferred meanings of the Cy cycle are cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, tetrahydrofuran and 1,3-dioxane, which are substituted as previously indicated by R ³ , R ⁴ , R ⁵ and R ⁶ , and in which one or more carbon atoms bound to carbon may be replaced by fluorine.

Corresponding the number of ring atoms of the Cy cycle can be the compounds of the invention of the formula I in two embodiments be articulated.

According to a first embodiment, those compounds of the formula I according to the invention are preferred in which the group Cy is a 6-membered saturated or monounsaturated carbocycle having in the ring one, two or three, preferably one or two heteroatoms independently selected from N, O. and S, and
which is substituted with R ⁴ , R ⁵ and R ⁶ via a single bond and with R ³ via a single or a double bond, and
in which a methylene group may be replaced by CO or a sulfanyl group by SO or SO ₂ , and
in which one or more carbon-bonded hydrogen atoms may be replaced by fluorine, and
in which the other substituents and groups have the meanings given above and below.

Cyclones Cy preferred according to this embodiment are cyclohexane, piperidine, piperazine, morpholine, tetrahydropyran, 1,3-dioxane, 1,4-dioxane and 1,3-dithiane, in which a methylene group may be replaced by CO, and which are as indicated above with R ³ , R ⁴ , R ⁵ and R ^{6 are} substituted, and in which one or more carbon-bonded H atoms may be replaced by fluorine.

is in the previously given cyclic groups, a methylene group replaced by CO, so are preferred meanings of the group Cy selected from tetrahydropyranone, piperidinone, piperazinone and morpholinone.

Furthermore, in each case one double bond may be present in the groups previously indicated as being preferred for Cy. A preferred meaning of such monounsaturated Cy cycles is cyclohexene. In the event that substituents R ³ , R ⁴ , R ⁵ and / or R ⁶ are bonded together, this double bond may also be part of a fused cyclic system.

Particularly preferred Cy are here cyclohexane, cyclohexene, piperidine, piperazine and 1,3-dioxane, which are substituted as previously indicated with R ³ , R ⁴ , R ⁵ and R ⁶ , and in which one or more carbon atoms bonded to carbon atoms may be replaced by fluorine.

According to a second embodiment, those compounds of the formula I according to the invention are preferred in which the group Cy is a 5-membered saturated or monounsaturated carbocycle having in the ring one, two or three, preferably one or two heteroatoms independently selected from N, O and S, and
which is substituted with R ⁴ , R ⁵ and R ⁶ via a single bond and with R ³ via a single or a double bond, and
in which a methylene group may be replaced by CO or a sulfanyl group by SO or SO ₂ , and
in which one or more carbon-bonded hydrogen atoms may be replaced by fluorine, and
in which the other substituents and groups have the meanings given above and below.

According to this embodiment, preferred Cy's are cyclopentane, pyrrolidine, tetrahydrofuran, dithiolane and tetrahydrothiophene, in which a methylene group may be replaced by CO and which are substituted with R ³ , R ⁴ , R ⁵ and R ⁶ as indicated above, and in which one or more carbon atoms bound to carbon may be replaced by fluorine.

is in the previously given cyclic groups, a methylene group replaced by CO, a preferred meaning of the group Cy Tetrahydrofuranone.

Furthermore, in each case one double bond may be present in the groups previously indicated as being preferred for Cy. A preferred meaning of such monounsaturated Cy cycles is cyclopentene. In the event that substituents R ³ , R ⁴ , R ⁵ and / or R ⁶ are bonded together, this double bond may also be part of a fused cyclic system.

Particularly preferred Cy here are cyclopentane, pyrrolidine and tetrahydrofuran, which are substituted as previously indicated with R ³ , R ⁴ , R ⁵ and R ⁶ , and in which one or more carbon-bonded hydrogen atoms may be replaced by fluorine.

In the event that Cy is a 6-membered cycle, the radical R ^{3 is} preferably in the 3- or 4-position to the bridge Z, more preferably in the 4-position to the bridge Z.

In the event that Cy represents a 5-membered cycle, the radical R ^{3 is} preferably in the 3-position to the bridge Z.

in denen
V1, V2 unabhängig voneinander C oder N bedeuten,
U1, U2, U3, U4 unabhängig voneinander C, N, O, CO oder SO₂ bedeuten,
mit der Maßgabe, dass in dem durch U und V gebildeten Ring maximal 2 Heteroatome ausgewählt aus N und O vorhanden sind, wobei diese Heteroatome nicht unmittelbar miteinander verbunden sind, und maximal eine Gruppe ausgewählt aus CO und SO₂ vorhanden ist, und verbleibende freie chemische Bindungen an C- und N-Atomen mit Wasserstoff abgesättigt sind; und
in denen die übrigen Gruppen und Substituenten eine der zuvor oder nachfolgend angegebenen Bedeutungen aufweisen.Therefore, preferred compounds according to the first embodiment, in which Cy is a 6-membered cycle, are described by the formulas I.1 and I.1 ':

in which
V1, V2 independently of one another denote C or N,
U1, U2, U3, U4 independently of one another denote C, N, O, CO or SO ₂ ,
with the proviso that in the ring formed by U and V at most 2 heteroatoms selected from N and O are present, these heteroatoms are not directly connected to each other, and at most one group selected from CO and SO _{2 is} present, and remaining free chemical Bonds to C and N atoms are saturated with hydrogen; and
in which the remaining groups and substituents have one of the meanings given above or below.

in denen
V1, V2 unabhängig voneinander C oder N bedeuten,
U1, U2, U3 unabhängig voneinander C, N, O, CO oder SO₂ bedeuten,
mit der Maßgabe, dass in dem durch U und V gebildeten Ring maximal 2 Heteroatome ausgewählt aus N und O vorhanden sind, wobei diese Heteroatome nicht unmittelbar miteinander verbunden sind, und maximal eine Gruppe ausgewählt aus CO und SO₂ vorhanden ist, und verbleibende freie chemische Bindungen an C- und N-Atomen mit Wasserstoff abgesättigt sind; und
in denen die übrigen Gruppen und Substituenten eine der zuvor oder nachfolgend angegebenen Bedeutungen aufweisen.Furthermore, preferred compounds according to the second embodiment, in which Cy is a 5-membered cycle, can be described by the formula I.2:

in which
V1, V2 independently of one another denote C or N,
U1, U2, U3 independently of one another denote C, N, O, CO or SO ₂ ,
with the proviso that in the ring formed by U and V at most 2 heteroatoms selected from N and O are present, these heteroatoms are not directly connected to each other, and at most one group selected from CO and SO _{2 is} present, and remaining free chemical Bonds to C and N atoms are saturated with hydrogen; and
in which the remaining groups and substituents have one of the meanings given above or below.

The following are preferred meanings of the other groups and substituents in the compounds of the general formula I, in particular the formulas I.1, I.1 'and I.2, given:
R ^{1 is} preferably hydrogen, fluorine, chlorine, bromine, iodine, C _1-6 -alkyl, C _2-6 -alkynyl, C _2-6 -alkenyl, C _3-10 -cycloalkyl, C _3-10 -cycloalkenyl, C _1-4 alkylcarbonyl, aminocarbonyl, C _1-4 -alkylaminocarbonyl, di- (C _1-3 alkyl) aminocarbonyl, C _1-4 alkoxycarbonyl, C _1-4 alkylamino, di- (C _1-3 alkyl ) amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, C _1-4 -alkylcarbonylamino, C _1-6 -alkyloxy, C _3-10 -cycloalkyloxy, C _5-10 -cycloalkenyloxy, C _1-4 alkylsulfanyl, C _1-4 alkylsulfonyl, C _3-10 cycloalkylsulfanyl, C _3-10 cycloalkylsulfonyl, C _3-10 cycloalkenylsulfanyl, C _5-10 cycloalkenylsulfonyl, hydroxy and cyano,
wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl radicals are partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C _1-3 alkoxy and C _1-3 alkyl substituted can be, and
wherein in cycloalkyl and cycloalkenyl radicals one or two methylene groups can be substituted independently of one another by O, S, CO, SO or SO ₂ , and
where in N-heterocycloalkyl radicals a methylene group may be substituted by CO or SO ₂ .

If the group R ^{1 is} a cycloalkyl or cycloalkenyl radical in which one or two methylene groups are independently of each other substituted by O, S, CO, SO or SO ₂ , preferred meanings of the radical R ^{1 are} selected from the group consisting of tetrahydrofuranyl , Tetrahydrofuranonyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydropyranonyl, dioxanyl and trioxanyl.

If the group R ^{1 is} an N-heterocycloalkyl radical in which a methylene group is substituted by CO or SO ₂ , preferred meanings of the radical R ^{1 are} selected from the group consisting of pyrrolidinone, piperidinone, piperazinone and morpholinone.

R ¹ particularly preferably denotes hydrogen, fluorine, chlorine, bromine, iodine, C _1-6 -alkyl, C _2-6 -alkynyl, C _2-6 -alkenyl, C _3-10 -cycloalkyl, C _5-10 -cycloalkenyl, C _1-6 alkyloxy, C _3-10 cycloalkyloxy or cyano, wherein in cycloalkyl and cycloalkenyl groups one or two methylene units independently of one another can be replaced by O or CO and alkyl, alkenyl and alkynyl radicals can be partially or completely fluorinated.

Examples of the most preferred R ¹ are hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, ethynyl, methoxy, cyclopentyloxy and cyano.

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.

In the event that R ¹ and R ² are bonded to two adjacent C atoms of the phenyl ring, R ¹ and R ^{2 may} be linked together such that R ¹ and R ² together preferably a C _3-4 alkylene or Butadienylene bridge in which one or two methylene units may be replaced independently of one another by O, NR ^N or CO, and in which in the case of a butadienylene bridge a methine group may be replaced by an N atom. Preferably, the interconnected radicals R ¹ and R ² together with the phenyl ring to which they are attached form a bicyclic ring system selected from indane, dihydroindole, dihydrobenzofuran, tetrahydroquinoline, dihydroquinolinone, tetrahydroisoquinoline, dihydroisoquinolinone, tetrahydronaphthalene, naphthalene, quinoline or isoquinoline.

The substituent R ³ has the meanings listed above. In the event that R ³ is bonded to an N atom, R ^{3 is} preferably not halogen or alkyl, cycloalkyl, cycloalkenyl or arylsulfanyl.

If the radical R ^{3 is} bonded to Cy via a single bond, R ^{3 is} preferably hydrogen, fluorine, chlorine, C _1-6 -alkyl, C _2-6 -alkynyl, C _2-6 -alkenyl, C _3-10 -cycloalkyl , C _3-10 -cycloalkyl-methyl, C _5-10 -cycloalkenyl, C _3-10 -cycloalkenyl-methyl, aryl, heteroaryl, C _1-4 -alkylcarbonyl, aminocarbonyl, C _1-4 -alkylaminocarbonyl, di- (C _1-3 alkyl) aminocarbonyl, C _1-4 alkoxycarbonyl, di (C _1-3 alkyl) amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, C _1-4 alkylcarbonylamino, C ₁ _ ₆ alkoxy, C _3-10 cycloalkyloxy, C _5-10 cycloalkenyloxy, aryloxy, heteroaryloxy, C _1-4 alkylsulfanyl, C _1-4 alkylsulfonyl, C _3-10 -Cycloalkylsulfanyl, C _{3 -10-} cycloalkylsulfonyl, C _5-10 -cycloalkenylsulfanyl, C _5-10 -cycloalkenylsulfonyl, hydroxy and cyano, and
in the case where R ³ is bonded to an N atom, R ^{3 is} preferably hydrogen, cyano, C _1-4 -alkyl, C _2-6 -alkynyl, C _2-6 -alkenyl, C _3-6 -cycloalkyl , C _3-6 cycloalkylC _1-3 alkyl, C _5-6 cycloalkenyl, C _5-6 cycloalkenylC _1-3 alkyl, aryl, heteroaryl, arylC _1-3 alkyl, heteroaryl C _1-3 alkyl, C _1-4 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C _1-4 alkylsulfonyl, arylsulfonyl or heteroarylsulfonyl,
wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl radicals are partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C _1-3 alkoxy and C _1-3 alkyl substituted can be, and
wherein in cycloalkyl and cycloalkenyl radicals one or two methylene groups can be substituted independently of one another by O, S, CO, SO or SO ₂ , and
where in N-heterocycloalkyl radicals a methylene group may be substituted by CO or SO ₂ ,
wherein the terms aryl and heteroaryl are as defined above and aryl and heteroaryl groups may be independently of one another mono- or disubstituted by identical or different radicals L substituted.

If the group R ^{3 is} a cycloalkyl or cycloalkenyl radical in which one or two methylene groups are independently of each other substituted by O, S, CO, SO or SO ₂ , preferred meanings of the group R ^{3 are} selected from the group consisting of tetrahydrofuranyl , Tetrahydrofuranonyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydropyranonyl and dioxanyl.

If the group R ^{3 is} an N-heterocycloalkyl radical in which a methylene group is substituted by CO or SO ₂ , preferred meanings of the radical R ^{3 are} selected from the group consisting of pyrrolidinone, piperidinone, piperazinone and morpholinone.

Particularly preferred meanings of R ³ are hydrogen, cyano, hydroxy, C _1-6 -alkyl, C _2-6 -alkynyl, C _1-4 -alkyloxy, C _3-10 -cycloalkyl, C _3-10 -cycloalkyloxy, phenyl, C _1-4 alkylcarbonyl, C _1-4 alkyloxycarbonyl, pyrrolidinone-N-yl, pyrazolyl, tetrazolyl and hydroxy, and
in the case where R ³ is bonded to an N atom, R ³ particularly preferably denotes hydrogen, cyano, C _1-4 -alkyl, C _3-6 -cycloalkyl, aryl, C _1-4 -alkylcarbonyl or C _{1 4-} alkylsulfonyl,
wherein in the cycloalkyl groups one or two methylene units are independently replaced by O or CO and alkyl radicals may be mono- or polyfluorinated, and wherein a phenyl, pyrazolyl or tetrazolyl radical may be mono- or disubstituted by identical or different substituents L. ,

Very particularly preferred radicals R ³ are hydrogen, cyano, hydroxyl, methyl, ethyl, isopropyl, tert-butyl, 2-methylpropyl, phenyl, methoxy, ethoxy, isopropyloxy, cyclopentyloxy, methoxycarbonyl; N-pyrrolidinonyl, 1H-pyrazol-1-yl, 2H-tetrazol-5-yl and 2-methyl-2H-tetrazol-5-yl, and
in the event that R ³ is bonded to an N atom, R ^{3 is} very particularly preferably hydrogen, methyl, ethyl, isopropyl, tert-butyl, 2-methylpropyl or methylcarbonyl.

If the radical R ^{3 is} bonded to Cy via a double bond, then R ^{3 has} a meaning selected from the group Y.

The group Y is preferably oxygen, C _1-6 -alkyl-methylidene, C _2-6 -alkynylmethylidene, C _2-6 -alkenyl-methylidene, C _3-7 -cycloalkyl-methylidene or C _3-7 -cycloalkylidene,
wherein the abovementioned alkyl, alkenyl and alkynyl radicals can be partially or fully fluorinated and independently of one another mono- or disubstituted by substituents selected from chlorine, hydroxyl, C _1-3 -alkoxy and C _1-3 -alkyl, and
in addition, the above-mentioned unsubstituted methylidene group or the above-mentioned monosubstituted methylidene groups may be easily substituted with fluorine, C _1-3 alkyl, trifluoromethyl or cyano, and
wherein in a cycloalkylidene group a methylene group may be replaced by O, S or NR ^N or an ethylene group may be replaced by -NR ^N -CO-, -CO-NR ^N -, -O-CO- or -CO-O-.

In the case where in a cycloalkylidene group, a methylene group is replaced by O, S or NR ^N or an ethylene group by -NR ^N -CO-, -CO-NR ^N -, -O-CO- or -CO-O- , is the meaning of such a sub substituted cycloalkylidene group preferably selected from the group consisting of dihydrofuranylidene, dihydropyranylidene, dihydrothiophenylidene, pyrrolidinylidene, piperidinylidene, dihydrofuranonylidene, dihydropyranonylidene, pyrrolidinonylidene, N-methylpyrrolidinonylidene, piperidinonylidene and N-methylpiperidinonylidene.

Very particularly preferred meanings of the group Y are oxygen, C _1-6 -alkyl-methylidene, C _3-7 -cycloalkyl-methylidene and C _3-7 -cycloalkylidene.

Examples the most preferred meanings of the group Y are oxygen, Ethylidene, isobutylidene, cyclopentylmethylidene and cyclopentylidene.

in der
R^Y Wasserstoff, Fluor, Cyan, Trifluormethyl oder C_1-3-Alkyl bedeutet,
D Carbonyl oder Sulfonyl bedeutet,
B eine Einfachbindung, -O- oder -NR^N- bedeutet,
R^B C_1-6-Alkyl-, C_3-7-Cycloalkyl-, C_5-7-Cycloalkenyl-, C_3-7-Cycloalkyl-C_1-3-alkyl-, C_5-7-Cycloalkenyl-C_1-3-alkyl-, Aryl, Heteroaryl, Aryl-C_1-3-alkyl- oder Heteroaryl-C_1-3-alkyl- bedeutet,
wobei Alkyl-, Cycloalkyl- und Cycloalkenyl-Reste teilweise oder vollständig fluoriert oder ein- oder zweifach mit gleichen oder verschiedenen Substituenten ausgewählt aus Cyan, Hydroxy, C_1-3-Alkoxy und C_1-3-Alkyl substituiert sein können, oder
R^B und B miteinander unter Ausbildung eines heterocyclischen Rings ausgewählt aus Pyrrolidin, Morpholin, Piperidin, Piperazin und 4-(C_1-4-Alkyl)piperazin verbunden sind, wobei der heterocyclische Ring über die Iminogruppe an die Gruppe D gebunden ist.According to a further preferred variant, Y preferably denotes a group according to the partial formula T.

in the
R ^{Y is} hydrogen, fluorine, cyano, trifluoromethyl or C _1-3 -alkyl,
D is carbonyl or sulfonyl,
B is a single bond, -O- or -NR ^N -,
R ^{B is} C _1-6 alkyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, C _3-7 cycloalkyl C _1-3 alkyl, C _5-7 cycloalkenyl C _{1 3-} alkyl, aryl, heteroaryl, arylC _1-3 -alkyl or heteroarylC _1-3 -alkyl-,
wherein alkyl, cycloalkyl and cycloalkenyl radicals may be partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from cyano, hydroxy, C _1-3 alkoxy and C _1-3 alkyl, or
R ^B and B are joined together to form a heterocyclic ring selected from pyrrolidine, morpholine, piperidine, piperazine and 4- (C _1-4 alkyl) piperazine, wherein the heterocyclic ring is bonded to the group D via the imino group.

If cycloalkyl or cycloalkenyl rings in the radicals or groups Y, R ¹ or R ³ are present in which two methylene groups have been replaced by O or S or have been replaced by CO, SO or SO ₂ , these methylene groups are preferably not directly adjacent to one another connected. However, when two methylene groups are replaced by O and CO, they may be directly linked together to form a carboxy group. In the event that Y, R ¹ or R ^{3 is} a cycloalkyl or cycloalkenyl group having one or two methylene groups replaced according to the invention, the relevant group Y, R ¹ or R ^{3 is} preferably a cycloalkyl or cycloalkenyl group, in which a methylene group is substituted by O, S, CO, SO or SO ₂ or an ethylene group is substituted by -O-CO- or -CO-O-.

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 ⁴ are hydrogen, methyl and fluorine, in particular hydrogen. In the event that R ⁴ is bonded to an N atom, R ^{4 is} preferably hydrogen or methyl.

In the event that R ³ and R ⁴ are bonded to the same C atom of Cy, R ³ and R ^{4 may} be linked together such that R ³ and R ⁴ together preferably form a C _4-5 alkylene bridge in which one or two methylene units can be substituted independently of one another by O, NR ^N or CO. Preferably, the interconnected radicals R ³ and R ⁴ together with the carbon atom of Cy to which they are attached form a ring selected from cyclopentane, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidinone, dioxolane, dithiolane, cyclohexane, piperidine, piperidinone, tetrahydropyran , Tetrahydropyranone, dithiane and dioxane, especially dioxolane.

In the event that R ³ and R ^{4 are} attached to two adjacent C atoms of the Cy cycle, R ³ and R ^{4 may} be linked together in such a way that R ³ and R ⁴ together with the two mentioned adjacent atoms of the Cy cycle are preferably form a fused cyclohexane, benzene or cyclopentadiene ring in which one or two methylene groups independently of one another may be replaced by ^N , S or NR ^N and / or one or two methine groups by N, and the one or more fluorinated or a - or doubly with identical or different substituents selected from chlorine, hydroxy, C _1-3 alkoxy and C _1-3 alkyl or in the case of an aromatic fused ring, it may be monosubstituted or disubstituted by identical or different substituents L.

Preferably, the interconnected radicals R ³ and R ⁴ together with the two said adjacent atoms of the Cy cycle form a fused cyclohexane, benzene, furan, thiophene or pyrrole ring, in particular cyclohexane or benzene ring, the one - or polyfluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C _1-3 alkoxy and C _1-3 alkyl or in the case of an aromatic fused ring selected from benzene, furan, thiophene or pyrrole - or may be substituted twice with identical or different substituents L.

Preferred meanings of the radical R ⁵ are hydrogen, methyl and fluorine, in particular hydrogen. In the case where R ⁵ is bonded to an N atom, R ^{5 is} preferably hydrogen or methyl.

In the case where R ⁴ and R ⁵ are bonded together and form a fused or bridged cycle with 2, 3 or 4 atoms of the Cy cycle, R ⁴ and R ⁵ together are preferably a C _2-4 -alkylene bridge, in the one or two methylene units may be independently substituted by O, NR ^N or CO. Preferably, the interconnected radicals R ⁴ and R ⁵ together with Cy form a bicyclic ring selected from bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.1] octane, octahydroindene and decalin, in which one or two methylene units may be independently substituted by O, NR ^N or CO. Particularly preferably, the interconnected radicals R ⁴ and R ⁵ together with Cy form a bicyclo [3.2.1] octane system.

Are replaced in the above-mentioned bicyclic rings one or two methylene units are independently replaced by O, NR ^N or CO, as are in this case preferred meanings decahydroquinoline, decahydroisoquinoline, Octahydrochinolinon, Octahydroisochinolinon, Decahydrochinoxalin, Octahydrochinoxalinon, Octahydrobenzoxazin.

Preferred meanings of the radical R ⁶ are hydrogen, methyl and fluorine, in particular hydrogen. In the event that R ⁶ is bonded to an N atom, R ^{6 is} preferably hydrogen or methyl.

In the event that the radicals R ⁴ , R ⁵ and R ⁶ are joined together, these together preferably form a C _4-5 alkanetriyl bridge, which forms a tricyclic system together with the Cy cycle, the alkanetriyl bridge - or polyfluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C _1-3 alkoxy and C _1-3 alkyl may be substituted, and in the one or two methylene groups independently of each other by O, CO , SO ₂ or NR ^N may be substituted. Preferably, in this case, the C _4-5 alkanetriyl bridge together with the Cy cycle forms a tricyclic system selected from tricyclononane, tricyclodecane and tricycloundekane, particularly preferably adamantane, which is unsubstituted or monofluorinated or polysubstituted or mono- or di-identical or various substituents selected from chlorine, hydroxy, C _1-3 alkoxy, and C _1-3 alkyl.

Preferred meanings of the radical Z are -O-, -CH ₂ -, -CF ₂ -, -C (CH ₃ ) ₂ -, -CH =, -NR ^N -, and -CO-, in particular -O-, -CH ₂ - and -CH =, most preferably -CH ₂ - and -O-.

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

The compounds of the formula I in which R ^7a , R ^7b , R ^7c and R ^{7d 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 , R ^7c and R ^{7d are} hydrogen.

The substituents L are, independently of one another, preferably selected from the group consisting of fluorine, chlorine, bromine, C _1-3 -alkyl, difluoromethyl, trifluoromethyl, C _1-3 -alkoxy, difluoromethoxy, trifluoromethoxy and cyano, particularly preferably from the group consisting of Fluorine, chlorine, methyl, trifluoromethyl, methoxy and difluoromethoxy. If the substituent L is connected to an N atom, preferred meanings L are selected from C _1-3 -alkyl, difluoromethyl and trifluoromethyl.

in denen
V1, V2 unabhängig voneinander C oder N bedeuten,
U1, U2, U3, U4 unabhängig voneinander C, N, O, CO oder SO₂ bedeuten,
mit der Maßgabe, dass in dem durch U und V gebildeten Ring maximal 2 Heteroatome ausgewählt aus N und O vorhanden sind, wobei diese Heteroatome nicht unmittelbar miteinander verbunden sind, und maximal eine Gruppe ausgewählt aus CO und SO₂ vorhanden ist, und verbleibende freie chemische Bindungen an C- und N-Atomen mit Wasserstoff abgesättigt sind; und
in denen R¹ bis R⁶, Z, R^7a, R^7b, R^7c, R^7d wie zuvor definiert sind.Particularly preferred compounds of the general formula I are selected from the group of the formulas I.1a to I.1d and 1.2a to 1.2d, in particular of the formulas I.1c and I.2c:

in which
V1, V2 independently of one another denote C or N,
U1, U2, U3, U4 independently of one another denote C, N, O, CO or SO ₂ ,
with the proviso that in the ring formed by U and V at most 2 heteroatoms selected from N and O are present, these heteroatoms are not directly connected to each other, and at most one group selected from CO and SO _{2 is} present, and remaining free chemical Bonds to C and N atoms are saturated with hydrogen; and
in which R ¹ to R ⁶ , Z, R ^7a , R ^7b , R ^7c , R ^{7d are} as defined ^above .

All Particular preference is given to those compounds of the formulas I.1a, I.1b, I.1c and I.1d, in particular of the formula I.1c, in which the Groups U1, U2, U3, U4, V1 and V2 represent carbon, i. of the By the groups U and V formed cycle cyclohexane means.

bedeutet, und
Y (1) Sauerstoff bedeutet; oder
(2) C_1-6-Alkyl-methyliden, C_2-6-Alkinyl-methyliden, C_2-6-Alkenyl-methyliden, C_3-7-Cycloalkyl-methyliden oder C_3-7-Cycloalkyliden bedeutet, wobei die vorstehend genannten Alkyl-, Alkenyl- und Alkinyl-Reste teilweise oder vollständig fluoriert und unabhängig voneinander ein- oder zweifach mit Substituenten ausgewählt aus Chlor, Hydroxy, C_1-3-Alkoxy und C_1-3-Alkyl substituiert sein können,
wobei die zuvor angeführte unsubstituierte Methylidengruppe oder die zuvor angeführten einfach substituierten Methylidengruppen zusätzlich einfach mit Fluor, C_1-3-Alkyl, Trifluormethyl oder Cyan substituiert sein können, und
wobei in einer Cycloalkyliden-Gruppe eine Methylengruppe durch O, S oder NR^N oder eine Ethylengruppe durch -NR^N-CO-, -CO-NR^N-, -O-CO- oder -CO-O- ersetzt sein kann;
besonders bevorzugt bedeutet X hierbei C_1-6-Alkyl-methyliden, C_3-6-Cycloalkyl-methyliden oder C_3-7-Cycloalkyliden; oder
(3) eine Gruppe gemäß der Teilformel T

bedeutet, in der
R^Y Wasserstoff, Fluor, Cyan, Trifluormethyl oder C_1-3-Alkyl bedeutet,
D Carbonyl oder Sulfonyl bedeutet,
B eine Einfachbindung, -O- oder -NR^N- bedeutet,
R^B C_1-6-Alkyl-, C_3-7-Cycloalkyl-, C_5-7-Cycloalkenyl-, C_3-7-Cycloalkyl-C_1-3-alkyl-, C_5-7-Cycloalkenyl-C_1-3-alkyl-, Aryl, Heteroaryl, Aryl-C_1-3-alkyl- oder Heteroaryl-C_1-3-alkyl- bedeutet,
wobei Alkyl-, Cycloalkyl- und Cycloalkenyl-Reste teilweise oder vollständig fluoriert oder ein- oder zweifach mit gleichen oder verschiedenen Substituenten ausgewählt aus Cyan, Hydroxy, C_1-3-Alkoxy und C_1-3-Alkyl substituiert sein können, oder
R^B und B miteinander unter Ausbildung eines heterocyclischen Rings ausgewählt aus Pyrrolidin, Morpholin, Piperidin, Piperazin und 4-(C_1-4-Alkyl)-piperazin verbunden sind, wobei der heterocyclische Ring über die Iminogruppe an die C=O-Gruppe gebunden ist;
R² Wasserstoff, Fluor, Chlor, Brom, Methyl, Hydroxy, Methoxy, Ethoxy, Trifluormethoxy, Cyan, Nitro oder durch 1 bis 3 Fluoratome substituiertes Methyl bedeutet, besonders bevorzugt Wasserstoff, Fluor, Hydroxy, Methoxy, Ethoxy oder Methyl, insbesondere Wasserstoff oder Methyl bedeutet, und
R⁴, R⁵, R⁶ jeweils unabhängig voneinander Wasserstoff, Methyl oder Fluor, insbesondere Wasserstoff bedeutet, und für den Fall, dass der Substituent an ein N-Atom gebunden ist, jeweils unabhängig Wasserstoff oder Methyl bedeutet; oder
die Reste R⁴, R⁵ und R⁶ sind miteinander unter Bildung einer C_4-5-Alkantriyl-Brücke verbunden und bilden zuammen mit dem Cyclus Cy ein tricyclisches System ausgewählt aus Tricyclononan, Tricyclodekan und Tricycloundekan, besonders bevorzugt Adamantan, das unsubstituiert ist oder ein- oder mehrfach fluoriert oder ein- oder zweifach mit gleichen oder verschiedenen Substituenten ausgewählt aus Chlor, Hydroxy, C_1-3-Alkoxy und C_1-3-Alkyl substituiert sein kann;
Z Sauerstoff, Methyliden oder Methylen, besonders bevorzugt Methylen, und
R^7a, R^7b, R^7c, R^7d unabhängig voneinander Wasserstoff, (C_1-8-Alkyl)oxycarbonyl-, (C_1-18-Alkyl)carbonyl oder Benzoyl, insbesondere Wasserstoff oder (C_1-6-Alkyl)oxycarbonyl-, (C_1-8-Alkyl)carbonyl bedeuten, besonders bevorzugt Wasserstoff, Methoxycarbonyl, Ethoxycarbonyl, Methylcarbonyl oder Ethylcarbonyl, ganz besonders bevorzugt Wasserstoff bedeuten, und
L unabhängig voneinander Fluor, Chlor, Brom, C_1-3-Alkyl, Difluormethyl, Trifluormethyl, C_1-3-Alkoxy, Difluormethoxy, Trifluormethoxy und Cyan bedeuten; und falls L an ein N-Atom gebunden ist, unabhängig voneinander C_1-3-Alkyl, Difluormethyl oder Trifluormethyl;
einschließlich deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze, insbesondere deren physiologisch verträglichen Salze.Very particular preference is given to those compounds of the formulas I.1a to I.1d or 1.2a to 1.2d, in particular of the formulas I.1c and 1.2c, in which the radicals R ¹ to R ⁶ , Z, R ^7a , R ^7b , R ^7c , R ^{7d have} the meanings given above as preferred, in particular in which
R ^{1 is} hydrogen, fluorine, chlorine, bromine, C _1-6 -alkyl, C _2-6 -alkynyl, C _2-6 -alkenyl, C _3-7 -cycloalkyl, C _5-7 -cycloalkenyl, C _1-6 - Alkyloxy, C _3-7 cycloalkyloxy or cyano, wherein in cycloalkyl and cycloalkenyl groups one or two methylene units independently replaced by O or CO and alkyl, alkenyl and alkynyl radicals may be partially or completely fluorinated; particularly preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, ethynyl, methoxy, cyclopentyloxy or cyano means; and
R ^{3 is} (1) hydrogen, cyano, hydroxy, C _1-6 alkyl, C _2-6 alkynyl, C _1-4 alkyloxy, C _3-7 cycloalkyl, C _3-7 cycloalkyloxy, phenyl, C _{1 -4-} alkylcarbonyl, C _1-4 -alkyloxycarbonyl, pyrrolidinon-N-yl, pyrazolyl, tetrazolyl and hydroxy, and in the case where R ^{3 is} attached to an N-atom, R ^{3 is} preferably hydrogen, cyano, C _{1 -4} alkyl, C _3-6 cycloalkyl, aryl, C _1-4 alkylcarbonyl or C _1-4 alkylsulfonyl, wherein in the cycloalkyl groups one or two methylene units are independently replaced by O or CO and alkyl radicals are partially or completely fluorinated and wherein the phenyl radical may be mono- or disubstituted by identical or different substituents L; most preferably, R ^{3 is} hydrogen, cyano, hydroxy, methyl, ethyl, isopropyl, tert -butyl, 2-methylpropyl, phenyl, methoxy, ethoxy, isopropyloxy, cyclopentyloxy, methoxycarbonyl, N-pyrrolidinonyl, 1H-pyrazol-1-yl, 2H-tetrazole -5-yl and 2-methyl-2H-tetrazol-5-yl, and in the case where R ³ is bonded to an N atom, R ³ particularly preferably denotes hydrogen, methyl, ethyl, isopropyl, tert-butyl, 2-methylpropyl or methylcarbonyl; or

means, and
Y (1) is oxygen; or
(2) C _1-6 alkyl-methylidene, C _2-6 -alkynyl-methylidene, C _2-6 -alkenyl-methylidene, C _3-7 -cycloalkyl-methylidene or C _3-7 -cycloalkylidene, wherein the above mentioned alkyl, alkenyl and alkynyl radicals may be partially or completely fluorinated and independently of one another mono- or disubstituted by substituents selected from chlorine, hydroxyl, C _1-3 -alkoxy and C _1-3 -alkyl,
in addition, the above-mentioned unsubstituted methylidene group or the above-mentioned monosubstituted methylidene groups may be easily substituted with fluorine, C _1-3 alkyl, trifluoromethyl or cyano, and
wherein in a cycloalkylidene group a methylene group may be replaced by O, S or NR ^N or an ethylene group may be replaced by -NR ^N -CO-, -CO-NR ^N -, -O-CO- or -CO-O-;
X is particularly preferably C _1-6 -alkyl-methylidene, C _3-6 -cycloalkyl-methylidene or C _3-7 -cycloalkylidene; or
(3) a group according to sub-formula T

means in the
R ^{Y is} hydrogen, fluorine, cyano, trifluoromethyl or C _1-3 -alkyl,
D is carbonyl or sulfonyl,
B is a single bond, -O- or -NR ^N -,
R ^{B is} C _1-6 alkyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, C _3-7 cycloalkyl C _1-3 alkyl, C _5-7 cycloalkenyl C _{1 3-} alkyl, aryl, heteroaryl, arylC _1-3 -alkyl or heteroarylC _1-3 -alkyl-,
wherein alkyl, cycloalkyl and cycloalkenyl radicals may be partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from cyano, hydroxy, C _1-3 alkoxy and C _1-3 alkyl, or
R ^B and B are joined together to form a heterocyclic ring selected from pyrrolidine, morpholine, piperidine, piperazine, and 4- (C _1-4 alkyl) piperazine, wherein the heterocyclic ring is bonded to the C = O group via the imino group is;
R ^{2 is} hydrogen, fluorine, chlorine, bromine, methyl, hydroxyl, methoxy, ethoxy, trifluoromethoxy, cyano, nitro or methyl substituted by 1 to 3 fluorine atoms, particularly preferably hydrogen, fluorine, hydroxyl, methoxy, ethoxy or methyl, in particular hydrogen or Methyl means, and
R ⁴ , R ⁵ , R ^{6 are} each independently of one another hydrogen, methyl or fluoro, in particular hydrogen, and in the event that the substituent is bonded to an N atom, each independently is hydrogen or methyl; or
R ⁴ , R ⁵ and R ⁶ are joined together to form a C _4-5 alkanetriyl bridge and together with the Cy cycle form a tricyclic system selected from tricyclononane, tricyclodecane and tricycloundekane, more preferably adamantane which is unsubstituted or mono- or polyfluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C _1-3 alkoxy and C _1-3 alkyl may be substituted;
Z is oxygen, methylidene or methylene, more preferably methylene, and
R ^7a , R ^7b , R ^7c , R ^{7d are} independently hydrogen, (C _1-8 alkyl) oxycarbonyl, (C _1-18 alkyl) carbonyl or benzoyl, in particular hydrogen or (C _1-6 alkyl) oxycarbonyl -, (C _1-8 alkyl) carbonyl, particularly preferably hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl or ethylcarbonyl, very particularly preferably hydrogen, and
L independently of one another are fluorine, chlorine, bromine, C _1-3 -alkyl, difluoromethyl, trifluoromethyl, C _1-3 -alkoxy, difluoromethoxy, trifluoromethoxy and cyano; and when L is attached to an N atom, independently of one another, C _1-3 alkyl, difluoromethyl or trifluoromethyl;
including their tautomers, their stereoisomers, their mixtures and their salts, in particular their physiologically acceptable salts.

According to a variant of the abovementioned embodiments, those compounds are also preferred in which the cyclic group Cy carrying the substituent R ^{3 has} at least one further substituent R ⁴ , R ⁵ and / or R ^{6 which is} different from hydrogen. According to this variant, those compounds are also preferred which have a substituent R ⁴ meaning methyl or fluorine.

• (a) 1-Chlor-2-(4-methoxy-cyclohexyloxy)-4-β-D-glucopyranos-1-yl-benzol,
• (b) 1-Chlor-2-(cyclohexylmethyl)-4-β-D-glucopyranos-1-yl-benzol,
• (c) 1-Chlor-2-(4-methoxy-cyclohexylmethyl)-4-β-D-glucopyranos-1-yl-benzol,
• (d) 1-Chlor-4-β-D-glucopyranos-1-yl-2-(cis-4-methoxy-cyclohexyloxy)-benzol
• (e) 1-Chlor-4-β-D-glucopyranos-1-yl-2-(trans-4-methoxy-cyclohexyloxy)-benzol
• (f) 1-β-D-glucopyranos-1-yl-3-(4-methoxy-cyclohexylmethyl)-benzol
• (g) 1-β-D-glucopyranos-1-yl-3-(4-hydroxy-cyclohexylidenmethyl)-benzol
• (h) 1-β-D-glucopyranos-1-yl-3-(4-hydroxy-cyclohexylmethyl)-bnzol

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

• (a) 1-chloro-2- (4-methoxycyclohexyloxy) -4-β-D-glucopyranos-1-yl-benzene,
• (b) 1-chloro-2- (cyclohexylmethyl) -4-β-D-glucopyranos-1-yl-benzene,
• (c) 1-chloro-2- (4-methoxycyclohexylmethyl) -4-β-D-glucopyranos-1-yl-benzene,
• (d) 1-Chloro-4-β-D-glucopyranos-1-yl-2- (cis-4-methoxycyclohexyloxy) benzene
• (e) 1-Chloro-4-β-D-glucopyranos-1-yl-2- (trans-4-methoxycyclohexyloxy) benzene
• (f) 1-β-D-glucopyranos-1-yl-3- (4-methoxycyclohexylmethyl) benzene
• (g) 1-β-D-glucopyranos-1-yl-3- (4-hydroxycyclohexylidenemethyl) benzene
• (h) 1-β-D-glucopyranos-1-yl-3- (4-hydroxycyclohexylmethyl) benzene

including their tautomers, their stereoisomers and mixtures thereof.

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 interchangeably used terms "partially or completely fluorinated can be "and" one or more times fluorinated "can mean that the group so designated is not fluorinated or one or more Having fluorine substituents, which also includes the complete fluorination the designated group includes.

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 methylene means a -CH ₂ group and the term methine means a CH group.

The term methylidene means a radical of the partial formula linked via a double bond

The term C _1-n -alkylmethylidene means a methylidene group in which one hydrogen atom is substituted by a C _1-n -alkyl group.

The term methanylyliden means a CH-bridge of the partial formula connected via a single bond and a double bond

The term "butadienylene" means the group

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, isopropynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.

The term C _1-n -alkoxy 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, cyclododecyl, bicyclo [3.2.1.] Octyl, spiro [4.5] decyl, norpinyl, norbornyl, norcaryl, adamantyl, etc. Preferably, the term C includes _3-7 cycloalkyl saturated monocyclic groups.

The term C _3-n -cycloalkyloxy refers to a C _3-n -cycloalkyl-O-group wherein C _3-n -cycloalkyl is as defined above. Examples of such groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.

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.

Of the Term N-heterocycloalkyl refers to a saturated carbocyclic ring, which has an imino group in the ring, and in addition a another imino group or may have an O or S atom in the ring. Examples of such N-heterocycloalkyl groups are pyrrolidine, piperidine, piperazine and morpholine.

If in groups, for example in X, R ¹ or R ³ , occurring alkyl radicals substituted, for example fluorinated, may be, this includes not only alkyl radicals in the groups which are directly alkyl, but also in other, alkyl radicals For example, X, R ¹ and R ³ in the meaning alkoxy, wherein alkyl radicals may be partially or fully fluorinated, also difluoromethoxy and trifluoromethoxy.

The spelling used above and below, in which in one cyclic group, for example, a phenyl group or in the Group Cy, a bond of a substituent to the center of the cyclic Group is indicated, unless otherwise stated, that this substituent at any free, carrying a H atom position the cyclic group may be bonded. So can to a methylene group the cyclic group may also be bonded to two substituents.

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 described below may be prepared from D-gluconolactone or a derivative thereof by addition of the desired aryl group in the form an organometallic compound (Scheme 1).

Scheme 1: Addition of an organometallic compound to a gluconolactone

The reaction according to Scheme 1 is best carried out starting from chloro, bromo or iodo substituted aromatics. From this, the corresponding organometallic compound 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 can be carried out for example with an organolithium compound such as n-, sec- or tert-butyllithium and thereby provides the corresponding lithiated flavor The analogous magnesium compound can also be generated via a halogen-metal exchange with a suitable Grginard compound such as isopropylmagnesium bromide or diisopropylmagnesium. The reactions are preferably carried out between 0 and -100 ° C, more preferably between -30 and -80 ° C in solvents such as ether, tetrahydrofuran, toluene, hexane or methylene chloride. The magnesium or lithium compounds thus obtained can be metalated with metal salts, such as cerium trichloride, to form further organometallic compounds suitable for addition. Alternatively, the organometallic compounds may also be prepared by insertion of a metal into the carbon-halogen bond of an aryl chloride, bromide or iodide. For this purpose, metals such as lithium or magnesium are suitable. The addition of the organometallic compounds to the gluconolactone or derivatives thereof is preferably carried out at temperatures between 0 and -100 ° C, more preferably at -30 to -80 ° C. Suitable solvents are, for example, ethers, toluene, methylene chloride, hexane, tetrahydrofuran or mixtures thereof (see M. Schlosser, Organometallics in Synthesis, John Wiley & Sons, Chichester / New York / Brisbane / Toronto / Singapore, 1994).

The Synthesis of aromatic residues are standard transformations in of organic chemistry and belong to general expertise or are at least from the specialist literature as methods in organic synthesis and known to those skilled in the art in view of the compounds of the invention readily applicable (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 literature cited therein and Synthesis Examples I-IX, XI-XIV and 2).

in der Z, Cy und R', R¹ bis R⁶ wie zuvor definiert sind und
R^8a, R^8b, R^8c und R^8d wie zuvor definiert sind und beispielsweise unabhängig voneinander Acetyl, Pivaloyl, Benzoyl, tert-Butoxycarbonyl, Benzyloxycarbonyl, Trialkylsilyl, Benzyl oder substituiertes Benzyl bedeuten,
mit einem Reduktionsmittel in Gegenwart einer 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 Z, Cy and R ', R ¹ to R ^{6 are} as previously defined and
R ^8a , R ^8b , R ^8c and 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,
reacted with a reducing agent in the presence of an 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 preferably in the presence of a suitable acid, e.g. Hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid, acetic acid, boron trifluoride etherate, Trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate or zinc iodide instead. 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 Cy, Z und R¹ bis R⁶ 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, 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 Cy, Z and R ¹ to R ^{6 are} as previously defined 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, the protective groups are split off.

The Cleavage of a used acyl, acetal or ketal protecting group For example, it is carried out 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 in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C. The cleavage of a trifluoroacetyl radical is preferably carried out by Treatment with an acid like hydrochloric acid optionally in the presence of a solvent such as acetic acid Temperatures between 50 and 120 ° C or by treatment with caustic soda optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C.

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-dimethoxy-benzyl radical takes place however, preferably 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 comes as a protective rest for an ethynyl group is the trimethylsilyl group.

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

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

Furthermore, the compounds of the general formula I thus obtained can be obtained selectively on a Hy droxygruppe derivatized or the hydroxy group itself be substituted.

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) into their optical antipodes and compounds of the general Formula I with at least 2 asymmetric carbon atoms due their physicochemical differences according to known Methods, e.g. by chromatography and / or fractional crystallisation, into their diastereomers, which, if they are in racemic Form incurred, then as mentioned above can be separated into the enantiomers.

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

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 for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic into consideration.

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

The used as starting materials compounds of the general formulas II and III are partly known from the literature or can after in literature known methods and in analogy to the in Examples described in the examples, optionally with additional introduction of protective residues.

The Compounds of the invention are also advantageous according to those described in the following examples Method accessible, this also with the expert, for example, from the literature known methods, in particular those described in WO 98/31697, WO 01/27128, WO 02/083066 and WO 03/099836, combined can be.

As already mentioned at the beginning, have the compounds of the invention the general formula I and their physiologically acceptable Salts have valuable pharmacological properties, in particular an inhibitory effect on the sodium-dependent glucose cotransporter SGLT, 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 . Cells are washed twice with 250μl assay buffer (Hanks Balanced Salt Solutioni, 137mM NaCl, 5.4mM KCl, 2.8mM CaCl ₂ , 1.2mM MgSO ₄ and 10mM HEPES (pH 7.4), 50μg / 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 250 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.

Alternatively, for hSGLT1 and hSGLT2, the measurement of cellular membrane potential can also be used for the biological testing of substances. For this purpose, the cell models described above can be used. For the assay, 10,000 cells per well of a poly-D-lysine coated 384-well black plate with clear bottom are seeded in culture medium and incubated for 16 hours at 37 ° C, 5% CO ₂ . The cells are then washed twice with glucose-free HBSS buffer (12.67 mol / l CaCl ₂ , 4.93 mmol / l MgCl ₂ , 4.07 mmol / l MgSO ₄ , 4.41 mmol / l KH ₂ PO ₄ , pH 7 , 4) and overlaid with 20 μl of HBSS. After addition of 20 .mu.l loading buffer (Membrane Potential Assay Kit Explorer R8126, Molecular Devices GmbH, Ismaning) and 20 .mu.l of the substance to be tested in a suitable concentration is for a further 30 min. incubated at 37 ° C, 5% CO ₂ . The measurement takes place in the Fluorescent Imaging Plate Reader (Molecular Devices GmbH, Ismaning) at 485 nm excitation wavelength and is started by adding 20 μl stimulation buffer (140 mM NaCl and 120 mM glucose). The depolarization of the cell caused by the glucose-induced Na ⁺ influx can be measured and quantified as a change in fluorescence.

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. Apoptosis or To prevent necrosis of pancreatic beta cells. The substances are more suitable for the functionality of pancreatic cells To improve or restore, in addition, the number and size of pancreatic increase beta cells. The compounds of the invention are also useful as diuretics or antihypertensives and 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 dosage required to achieve a corresponding effect in the treatment or prophylaxis usually depends on the compound to be administered, on the patient, on the type and Severity of the disease or condition, and the nature and frequency of administration, and is at the discretion of the physician to be treated. Conveniently, the dosage with intravenous administration in the range of 1 to 100 mg, preferably 1 to 30 mg, and in oral administration in the range of 1 to 1000 mg, preferably 1 to 100 mg, each 1 to 4 times a day. For this purpose, the compounds of the formula I according to the invention, optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, Water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their suitable mixtures in common pharmaceutical preparations such as tablets, dragees, capsules, powders, solutions, suspensions or Incorporate suppositories.

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 those into consideration, for example, the therapeutic efficacy of a SGLT antagonist according to the invention in terms of to reinforce one of the indicated indications and / or a reduction allow the dosage of a SGLT antagonist of the invention. Therapeutics suitable for such combination include e.g. Antidiabetics, such as metformin, sulfonylureas (e.g., glibenclamide, Tolbutamide, glimepiride), nateglinides, repaglinide, thiazolidinediones (e.g., rosiglitazone, pioglitazone), PPAR gamma agonists (e.g., GI 262570) and antagonists, PPAR-gamma / alpha modulators (e.g., KRP 297), alpha-glucosidase inhibitors (e.g., acarbose, voglibose), DPPIV Inhibitors (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, 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 acting antihypertensives, antagonists of the alpha-2-adrenergic receptor, Inhibitors of neutral endopeptidase, platelet aggregation inhibitors and others or combinations thereof. Examples of angiotensin II receptor antagonists are candesartan cilexetil, potassium losartan, Eprosartan Mesylate, Valsartan, Telmisartan, Irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, etc. Angiotensin II receptor antagonists are preferably used for the treatment or prophylaxis of hypertension and diabetic complications, often in combination with a diuretic such as hydrochlorothiazide.

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 this expediently 1/5 of the usual recommended lowest dosage up to 1/1 of the normally recommended Dosage.

Therefore, another object of this invention relates to the use of a compound of the invention or a physiologically acceptable salt of such a compound in combination with at least one of the active ingredients previously described as combination partners for the preparation of a medicament, which is suitable for the treatment or prophylaxis of diseases or conditions which can be influenced by inhibition of the sodium-dependent glucose cotransporter SGLT. This is preferably a metabolic disorder, in particular one of the previously mentioned diseases or conditions, 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-phenol

5-bromo-2-chloro-phenol

To an ice-cooled solution of 20 g of 5-bromo-2-chloroanisole in 300 ml of dichloromethane are added 96 ml of a 1 M solution of boron tribromide in dichloromethane. The reaction solution is stirred for 14 h at room temperature and then cooled in an ice bath. The cooled solution is treated with aqueous saturated potassium carbonate solution, the aqueous phase acidified with 1 M hydrochloric acid and extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and the solvent is completely removed.
Yield: 17.9 g (96% of theory)
Mass spectrum (ESI ⁺ ): m / z = 205/207/209 (bromine + chlorine) [M + H] ⁺

Example II

1-Brom-4-chlor-3-(tri-isopropyl-silyloxy)-benzol

1-bromo-4-chloro-3- (tri-isopropyl-silyloxy) benzene

To an ice-cooled solution of 9.2 g of 5-bromo-2-chloro-phenol and 9.4 ml of triethylamine in 120 ml of dichloromethane are added 9.2 g of triisopropylsilyl chloride in 20 ml of dichloromethane and finally 0.5 g of 4-dimethylaminopyridine. The reaction is stirred for 18 h at room temperature and then diluted with 100 ml of dichloromethane. The diluted solution is washed with 1 M hydrochloric acid and with aqueous sodium bicarbonate solution, dried over sodium sulfate and the solvent removed. The residue is purified over silica gel (cyclohexane / ethyl acetate 9: 1 → 1: 1).
Yield: 9.4 g (59% of theory)
Mass spectrum (ESI ⁺ ): m / z = 363/365/367 (bromine + chlorine) [M + H] ⁺

Example III

cis-4-(tert-Butyl-diphenylsilyloxy)-cyclohexanol und trans-4-(tert-Butyl-diphenylsilyloxy)-cyclohexanol

cis-4- (tert-butyl-diphenylsilyloxy) -cyclohexanol and trans-4- (tert-butyl-diphenylsilyloxy) -cyclohexanol

To an ice-cold one solution of 10.0 g of 1,4-cyclohexanediol (cis / trans mixture about 1: 1) and 14.6 g Imidazole in 15 ml dry dimethylformamide and 20 ml dry Tetrahydrofuran becomes a solution of 29.4 g of tert-butyldiphenylsilyl chloride in 20 ml of dimethylformamide dripped. The reaction solution is stirred for 1 h in an ice bath and then with 100 ml of aq Sodium chloride solution added. The organic phase is separated and the aqueous with Extracted ethyl acetate. The combined organic phases are over sodium sulfate dried, and the solvent will be complete away. The residue is purified by chromatography and in the two isomeric products separated (ethyl acetate / cyclohexane 1: 1).

cis-4- (tert-Butyl-diphenylsilyloxy) cyclohexanol:

• Yield: 4.9 g (16% of theory)
• Mass spectrum (ESI ⁺ ): m / z = 355 [M + H] ⁺

trans-4- (tert-Butyl-diphenylsilyloxy) cyclohexanol:

• Yield: 4.8 g (16% of theory)
• Mass spectrum (ESI ⁺ ): m / z = 355 [M + H] ⁺

Example IV

1-Brom-3-[cis-4-(tert-butyl-diphenylsilyloxyl-cyclohexyloxyl-4-chlor-benzol

1-Bromo-3- [cis-4- (tert-butyl-diphenylsilyloxyl-cyclohexyloxyl-4-chloro-benzene

To a solution of 1.85 g of trans-4- (tert-butyl-diphenylsilyloxy) -cyclohexanol in 20 ml of dry tetrahydrofuran are added in the order mentioned 4.8 g of 5-bromo-2-chloro-phenol, 4.5 g of triphenylphosphine and 3.3 ml of diisopropyl azodicarboxylate. The solution is stirred for 48 h at 55 ° C and then treated with aqueous potassium carbonate solution. It is then extracted with ethyl acetate, dried over sodium sulfate and the solvent removed. The residue is purified over silica gel (cyclohexane / ethyl acetate 4: 1).
Yield: 3.5 g (72% of theory)
Mass spectrum (ESI ⁺ ): m / z = 543/545/547 (bromine and chlorine) [M + H] ⁺

Massenspektrum (ESI⁺): m/z = 543/545/547 (Brom und Chlor) [M+H]⁺ The following compound is obtained analogously to Example IV: (1) 1-bromo-3- [trans-4- (tert-butyl-diphenylsilyloxy) -cyclohexyloxy] -4-chlorobenzene

Mass spectrum (ESI ⁺ ): m / z = 543/545/547 (bromine and chlorine) [M + H] ⁺

Example V

1-Brom-4-chlor-3-(cis-4-hydroxy-cyclohexyloxy)-benzol

1-bromo-4-chloro-3- (cis-4-hydroxy-cyclohexyloxy) benzene

To an ice-cooled solution of 4.8 g of 1-bromo-3- [cis-4- (tert-butyl-diphenylsilyloxy) cyclohexyloxy] -4-chlorobenzene in 25 ml of dry tetrahydrofuran is added 8.8 ml of a 1 M solution of Added tetrabutylammonium fluoride in tetrahydrofuran. The solution is stirred for 14 h at room temperature and then treated with water. It is then extracted with ethyl acetate, dried over sodium sulfate and the solvent removed. The residue is purified on silica gel (cyclohexane / ethyl acetate 1: 0 → 3: 2).
Yield: 2.1 g (79% of theory)
Mass spectrum (ESI ⁺ ): m / z = 327/329/331 (bromine and chlorine) [M + Na] ⁺

Massenspektrum (ESI⁺): m/z = 327/329/331 (Brom und Chlor) [M+Na]⁺ Analogously to Example V, the following compound is obtained: (1) 1-Bromo-4-chloro-3- (trans-4-hydroxycyclohexyloxy) benzene

Mass spectrum (ESI ⁺ ): m / z = 327/329/331 (bromine and chlorine) [M + Na] ⁺

Example VI

1-Brom-4-chlor-3-(cis-4-methoxy-cyclohexyloxy)-benzol

1-bromo-4-chloro-3- (cis-4-methoxy-cyclohexyloxy) benzene

Under an argon atmosphere, 0.28 g of sodium hydride (60% in mineral oil) is added to an ice-cooled solution of 2.1 g of 1-bromo-4-chloro-3- (cis-4-hydroxycyclohexyloxy) benzene in 10 ml of dry tetrahydrofuran , The solution is stirred for 30 minutes in an ice bath and then 0.44 ml of methyl iodide are added. The reaction solution is stirred for 6 h at room temperature and then treated with water. It is then extracted with ethyl acetate, dried over sodium sulfate and the solvent removed. The residue is purified over silica gel (cyclohexane / ethyl acetate 1: 0 → 1: 1).
Yield: 1.8 g (80% of theory)
Mass spectrum (ESI ⁺ ): m / z = 319/321/323 (bromine and chlorine) [M + H] ⁺

Massenspektrum (ESI⁺): m/z = 319/321/323 (Brom und Chlor) [M+H]⁺ The following compound is obtained analogously to Example VI: (1) 1-bromo-4-chloro-3- (trans-4-methoxy-cyclohexyloxy) -benzene

Mass spectrum (ESI ⁺ ): m / z = 319/321/323 (bromine and chlorine) [M + H] ⁺

Example VII

5-Brom-2-chlor-benzaldehyd

5-bromo-2-chloro-benzaldehyde

To a -60 ° C cold solution of 4.4 ml of oxalyl chloride in 125 ml of dichloromethane 7 ml of dimethyl sulfoxide are added dropwise in 25 ml of dichloromethane. After stirring for 5 minutes, a solution of 10.0 g of 5-bromo-2-chloro-benzyl alcohol in 50 ml of tetrahydrofuran is added and the mixture is stirred at -60 ° C. for a further 15 min. Then 31.5 ml Triethylamine added and the reaction solution allowed to warm to room temperature in a cooling bath. At room temperature, water is added, the organic phase, separated and washed with 1 M hydrochloric acid. After drying over sodium sulfate, the solvent is completely removed.
Yield: 9.7 g (98% of theory)
Mass spectrum (ESI ⁺ ): m / z = 218/220/222 (bromine + chlorine) [M + H] ⁺

Example VIII

1-Brom-4-chlor-3-cyclohexylidenmethyl-benzol

1-bromo-4-chloro-3-cyclohexylidenemethyl-benzene

3.55 ml of a 1.9 M solution of phenyl lithium in diethyl ether / cyclohexane (70/30) are added dropwise to an ice-cooled solution of 2.9 g of cyclohexyltriphenylphosphonium bromide in 5 ml of tetrahydrofuran. The solution is stirred for 1 h in an ice bath. Then, a solution of 1.5 g of 5-bromo-2-chloro-benzaldehyde in 5 ml of tetrahydrofuran is added and the reaction solution is stirred for 4 h at room temperature. Thereafter, water is added, extracted with ethyl acetate and the organic phase dried over sodium sulfate. After removal of the solvent, the residue is purified on silica gel (cyclohexane / ethyl acetate 1: 1).
Yield: 0.66 g (34% of theory)
Mass spectrum (ESI ⁺ ): m / z = 284/286/288 (bromine + chlorine) [M] ⁺

Example IX

8-(3-Brom-benzyliden)-1,4-dioxo-spiro[4.5]dekan

8- (3-bromo-benzylidene) -1,4-dioxo-spiro [4.5] dean

A solution of 8.0 g of 3-bromobenzyl bromide and 8.4 g of triphenylphosphine in 100 ml of toluene is stirred for 12 hours under reflux. Thereafter, the resulting precipitate is filtered off, washed with toluene and dried at 50 ° C. The dried 3-bromobenzyl-triphenylphosphonium bromide is added to an ice-cooled suspension of 1.64 g of sodium hydride (60% in mineral oil) in 50 ml of dry tetrahydrofuran and the resulting reaction mixture is stirred for 1 h at 45 ° C. 5.4 g of 1,4-dioxo-spiro [4.5] decane-8-one are then added at room temperature and the reaction solution is stirred at room temperature for 12 h. Thereafter, water is added, the organic phase is separated, the aqueous extracted with dichloromethane, and the combined organic phases are dried over sodium sulfate. After removal of the solvent, the residue is purified on silica gel (cyclohexane / ethyl acetate 1: 0 → 7: 3).
Yield: 3.35 g (31% of theory)
Mass spectrum (ESI ⁺ ): m / z = 308/310 (bromine) [M] ⁺

Example X

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 XI

1-Chlor-4-(2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl)-2-(tri-isopropylsilyloxy)-benzol

1-chloro-4- (2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl) -2- (tri-isopropylsilyloxy) benzene

A solution of 5.0 g of 4-bromo-1-chloro-2- (triisopropylsilyloxy) benzene in 60 ml of dry diethyl ether is cooled to -80 ° C under argon. To the cooled solution, 17.7 ml of a 1.7 M solution of tert-butyllithium in pentane are added dropwise. The solution is stirred for 30 min at -80 ° C and then via a transfer needle to a -80 ° C-cold solution of 7.3 g of 2,3,4,6-tetrakis-O- (trimethylsilyl) -D-glucopyranon in 40 ml of diethyl ether added dropwise. The resulting solution is stirred for 4 h at -78 ° C. Thereafter, a solution of 3 ml of methanesulfonic acid in 80 ml of methanol is added and the solution is stirred for 16 h at room temperature. The solution is then neutralized with ethyldiisopropylamine and concentrated. The residue is taken up in toluene and concentrated again. Then the residue is dissolved in 36 ml of toluene and 3.4 ml of ethyldiisopropylamine are added to the solution. The solution is cooled in an ice bath and then 6.3 ml of acetic anhydride and 0.17 g of dimethylaminopyridine are added. The solution is stirred for 6 h at room temperature and then treated with aqueous sodium bicarbonate solution. The organic phase is separated and the aqueous extracted with ethyl acetate. After drying the combined organic extracts over sodium sulfate and removing the solvent, the residue is chromatographed on silica gel (cyclohexane / ethyl acetate 6: 1 → 1: 1).
Yield: 5.8 g (65% of theory)
Mass spectrum (ESI ⁺ ): m / z = 662/664 (chlorine) [M + NH ₄ ] ⁺

Massenspektrum (ESI⁺): m/z = 618/620 (Chlor) [M+NH₄]⁺ (2) 1-Chlor-4-(2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl)-2-(trans-4-methoxy-cyclohexyloxy)-benzol

Massenspektrum (ESI⁺): m/z = 618/620 (Chlor) [M+NH₄]⁺ (3) 1-Chlor-4-(2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl)-2-cyclohexylidenmethyl-benzol

Massenspektrum (ESI⁺): m/z = 584/586 (Chlor) [M+NH₄]⁺ (4) 1-(2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl)-3-(4,4-dimethoxycyclohexylidenmethyl)-benzol ausgehend von 8-(3-Brom-benzyliden)-1,4-dioxospiro[4.5]dekan

Massenspektrum (ESI⁺): m/z = 610 [M+NH₄]⁺ The following compounds are obtained analogously to Example XI: (1) 1-Chloro-4- (2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl) -2- (cis-4-methoxycyclohexyloxy) benzene

Mass spectrum (ESI ⁺ ): m / z = 618/620 (chlorine) [M + NH ₄ ] ⁺ (2) 1-chloro-4- (2,3,4,6-tetra-O-acetyl-1-methoxy -D-glucopyranos-1-yl) -2- (trans-4-methoxy-cyclohexyloxy) benzene

Mass spectrum (ESI ⁺ ): m / z = 618/620 (chlorine) [M + NH ₄ ] ⁺ (3) 1-chloro-4- (2,3,4,6-tetra-O-acetyl-1-methoxy -D-glucopyranos-1-yl) -2-cyclohexylidenemethyl-benzene

Mass spectrum (ESI ⁺ ): m / z = 584/586 (chlorine) [M + NH ₄ ] ⁺ (4) 1- (2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl) -3- (4,4-dimethoxycyclohexylidenemethyl) benzene starting from 8- (3 bromo-benzylidene) -1,4-dioxospiro [4.5] dean

Mass spectrum (ESI ⁺ ): m / z = 610 [M + NH ₄ ] ⁺

Example XII

1-Chlor-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(tri-isopropyl-silyloxy)-benzol

1-chloro-4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -2- (tri-isopropyl-silyloxy) benzene

A solution of 5.83 g of 1-chloro-4- (2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl) -2- (tri-isopropyl-silyloxy) benzene in 100 ml of acetonitrile and 0.22 ml of water is cooled in an ice bath. Then, 7 ml of triethylsilane and 1.5 ml of boron trifluoride etherate are added. The solution is stirred for 1 h in an ice bath and then at room temperature. After 5 h, a further 6 ml of triethylsilane and 1.2 ml of boron trifluoride etherate are added. After stirring at room temperature for a further 5 h, aqueous sodium bicarbonate solution is added, stirred for 0.5 h and then extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated to dryness.
Yield: 4.80 g (86% of theory)
Mass spectrum (ESI ⁺ ): m / z = 637/639 (chlorine) [M + Na] ⁺

Massenspektrum (ESI⁺): m/z = 589/591 (Chlor) [M+NH₄]⁺ (2) 1-Chlor-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(trans-4-methoxycyclohexyloxy)-benzol

Massenspektrum (ESI⁺): m/z = 589/591 (Chlor) [M+NH₄]⁺ (3) 1-Chlor-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-cyclohexylidenmethylbenzol

Massenspektrum (ESI⁺): m/z = 559/561 (Chlor) [M+Na]⁺ (4) 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-methoxycyclohexylidenmethyl)-benzol ausgehend von 1-(2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl)-3-(4,4-dimethoxy-cyclohexylidenmethyl)-benzol

Massenspektrum (ESI⁺): m/z = 550 [M+NH₄]⁺ (5) 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-hydroxycyclohexylidenmethyl)-benzol als Nebenprodukt bei der Synthese von Beispiel XII (4) ausgehend von 1-(2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl)-3-(4,4-dimethoxy-cyclohexylidenmethyl)-benzol

Massenspektrum (ESI⁺): m/z = 566 (Chlor) [M+NH₄]⁺ The following compounds are obtained analogously to Example XII: (1) 1-Chloro-4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -2- (cis-4-methoxycyclohexyloxy) benzene

Mass spectrum (ESI ⁺ ): m / z = 589/591 (chlorine) [M + NH ₄ ] ⁺ (2) 1-chloro-4- (2,3,4,6-tetra-O-acetyl-β-D -glucopyranos-1-yl) -2- (trans-4-methoxycyclohexyloxy) benzene

Mass spectrum (ESI ⁺ ): m / z = 589/591 (chlorine) [M + NH ₄ ] ⁺ (3) 1-chloro-4- (2,3,4,6-tetra-O-acetyl-β-D -glucopyranos-1-yl) -2-cyclohexylidenmethylbenzol

Mass spectrum (ESI ⁺ ): m / z = 559/561 (chlorine) [M + Na] ⁺ (4) 1- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -2- (4-methoxycyclohexylidenemethyl) benzene starting from 1- (2,3,4 , 6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl) -3- (4,4-dimethoxy-cyclohexylidenemethyl) benzene

Mass Spectrum (ESI ⁺ ): m / z = 550 [M + NH ₄ ] ⁺ (5) 1- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -2 - (4-hydroxycyclohexylidenemethyl) -benzene as a by-product in the synthesis of Example XII (4) starting from 1- (2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl) -3- (4,4-dimethoxy-cyclohexylidenemethyl) benzene

Mass spectrum (ESI ⁺ ): m / z = 566 (chlorine) [M + NH ₄ ] ⁺

Example XIII

1-Chlor-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-hydroxy-benzol

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

To an ice-cooled solution of 4.80 g of 1-chloro-4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -2- (tri-isopropyl-silyloxy) -benzene in 25 ml of dry tetrahydrofuran are added 5 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. The solution is stirred for 14 h at room temperature and then treated with water. It is extracted with ethyl acetate, dried over sodium sulfate and the Solvent removed. The residue is stirred in cyclohexane / ethyl acetate (5: 1) and then dried.
Yield: 1.70 g (86% of theory)
Mass spectrum (ESI ⁺ ): m / z = 476/478 (chlorine) [M + NH ₄ ] ⁺

Example XIV

1-Chlor-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-methoxy-cyclohexyloxy)-benzol

1-chloro-4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -2- (4-methoxy-cyclohexyloxy) benzene

To a solution of 0.25 g of 1-chloro-4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -2-hydroxybenzene in 3 ml of tetrahydrofuran 0.08 g of 4-methoxycyclohexanol, 0.16 g of triphenylphosphine and 0.12 ml of diisopropyl azodicarboxylate are added in the order named. The solution is stirred for 14 h at room temperature and then treated with aqueous potassium carbonate solution. It is then extracted with ethyl acetate, dried over sodium sulfate and the solvent removed. The residue is purified over silica gel (cyclohexane / ethyl acetate 7: 3 → 1: 1).
Yield: 0.05 g (16% of theory)

Preparation of the end compounds:

example 1

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

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

To a solution of 0.05 g of 1-chloro-4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -2- (4-methoxybenzyl) - benzene in 3 ml of methanol is added 0.13 ml of 4M potassium hydroxide solution. The solution is stirred for 3 h at room temperature and then neutralized with 1 M hydrochloric acid. The solution is freed from methanol, treated with aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent removed. The residue is purified over silica gel (dichloromethane / methanol 1: 0 → 3: 1).
Yield: 0.01 g (28% of theory)
Mass spectrum (ESI ⁺ ): m / z = 420/422 (chlorine) [M + NH ₄ ] ⁺

Massenspektrum (ESI⁺): m/z = 403/405 (Chlor) [M+H]⁺ (2) 1-Chlor-4-β-D-glucopyranos-1-yl-2-(trans-4-methoxy-cyclohexyloxy)-benzol

Massenspektrum (ESI⁺): m/z = 420/422 (Chlor) [M+NH₄]⁺ (3) 1-Chlor-4-β-D-glucopyranos-1-yl-2-cyclohexylidenmethyl-benzol

Massenspektrum (ESI⁺): m/z = 386/388 (Chlor) [M+NH₄]⁺ (4) 1-β-D-glucopyranos-1-yl-3-(4-methoxy-cyclohexylmethyl)-benzol ausgehend von 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-3-(4-methoxy-cyclohexylmethyl)benzol [siehe Beispiel 2(1)]

Massenspektrum (ESI⁺): m/z = 367 [M+H]⁺ (5) 1-β-D-glucopyranos-1-yl-3-(4-hydroxy-cyclohexylidenmethyl)-benzol

Massenspektrum (ESI⁺): m/z = 368 [M+NH₄]⁺ Analogously to Example 1, the following compounds are obtained: (1) 1-Chloro-4-β-D-glucopyranos-1-yl-2- (cis-4-methoxycyclohexyloxy) benzene

Mass spectrum (ESI ⁺ ): m / z = 403/405 (chlorine) [M + H] ⁺ (2) 1-chloro-4-β-D-glucopyranos-1-yl-2- (trans-4-methoxy) cyclohexyloxy) -benzene

Mass spectrum (ESI ⁺ ): m / z = 420/422 (chlorine) [M + NH ₄ ] ⁺ (3) 1-chloro-4-β-D-glucopyranos-1-yl-2-cyclohexylidenemethylbenzene

Mass spectrum (ESI ⁺ ): m / z = 386/388 (chlorine) [M + NH ₄ ] ⁺ (4) 1-β-D-glucopyranos-1-yl-3- (4-methoxycyclohexylmethyl) benzene *** 1- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -3- (4-methoxycyclohexylmethyl) benzene [see Example 2 (1)]

Mass spectrum (ESI ⁺ ): m / z = 367 [M + H] ⁺ (5) 1-β-D-glucopyranos-1-yl-3- (4-hydroxycyclohexylidenemethyl) benzene

Mass spectrum (ESI ⁺ ): m / z = 368 [M + NH ₄ ] ⁺

Example 2

1-Chlor-4-β-D-glucopyranos-1-yl-2-cyclohexylmethyl-benzol

1-chloro-4-β-D-glucopyranos-1-yl-2-cyclohexylmethyl-benzene

To a solution of 0.10 g of 1-chloro-4-β-D-glucopyranos-1-yl-2-cyclohexylidenemethylbenzene in 5 mL of ethyl acetate is added 40 mg of 10% palladium on carbon. The solution is stirred for 1 h under a hydrogen atmosphere (1 atm) at room temperature. Thereafter, the catalyst is filtered off, the filtrate was concentrated and the residue chromatographed on silica gel (dichloromethane / methanol 4: 1).
Yield: 0.07 g (70% of theory)
Mass spectrum (ESI ⁺ ): m / z = 388/390 (chlorine) [M + NH ₄ ] ⁺

Massenspektrum (ESI⁺): m/z = 535 [M+H]⁺ (2) 1-β-D-glucopyranos-1-yl-3-(4-hydroxy-cyclohexylmethyl)-benzol

Massenspektrum (ESI⁺): m/z = 370 [M+NH₄]⁺ The following compounds are obtained analogously to Example 2: (1) 1- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -3- (4-methoxycyclohexylmethyl) benzene

Mass spectrum (ESI ⁺ ): m / z = 535 [M + H] ⁺ (2) 1-β-D-glucopyranos-1-yl-3- (4-hydroxycyclohexylmethyl) benzene

Mass spectrum (ESI ⁺ ): m / z = 370 [M + NH ₄ ] ⁺

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

following Examples of dosage forms are described in which the term "active ingredient" is one or more compounds of the invention, including their salts means. In the case of one of the combinations described with one or more further active substances, the term "active substance" 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, biplan with facet on both sides and one-sided part notch.

Example B

Tablets with 150 mg active substance

Composition: 1 tablet contains: active substance 150.0 mg Milk sugar powder. 89.0 mg corn starch 40.0 mg Colloidal silicic acid 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0

production:

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

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

Example C

Hard gelatin capsules with 150 mg active substance

Composition: 1 capsule contains: active substance 150.0 mg Corn starch drink. about 180.0 mg Milk sugar powder. about 87.0 mg

magnesium stearate 3.0 mg approximately 420.0 mg

production:

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

The final mixture is filled into size 1 hard gelatin capsules. Capsule filling: about 320 mg Capsule shell: Hard gelatin capsule size 1.

Example 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:

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

Example E

Ampoules with 10 mg active substance

Composition: active substance 10.0 mg 0.01 n hydrochloric acid sq Aqua bidest ad 2.0 ml

production:

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

Example F

Ampoules with 50 mg active substance

Composition: active substance 50.0 mg 0.01 n hydrochloric acid sq Aqua bidest ad 10.0 ml

production:

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

Claims (22)

D-Glucopyranosyl-phenyl substituted cycles of the general formula I.

Cy is a 5- or 6-membered saturated or monounsaturated carbocycle which may have one, two or three heteroatoms independently selected from N, O and S and which may be substituted with R ⁴ , R ⁵ and R ⁶ via a single bond and with R ³ is substituted by a single or a double bond, and in which one or two methylene groups may be replaced by CO or a sulfanyl group by SO or SO ₂ , and in which one or more carbon-bonded H atoms may be replaced by fluorine , Z represents -O-, -CH ₂ -, -CH =, -NR ^N -, -CO-, -S-, -SO- or -SO ₂ -, where H atoms of the methylene or methanylylidene bridge independently may be substituted by CH ₃ or F; R ^{1 is} hydrogen, fluorine, chlorine, bromine, iodine, C _1-6 -alkyl, C _2-6 -alkynyl, C _2-6 -alkenyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _{1- 3} -alkyl, C _5-7 -cycloalkenyl, C _5-7 -cycloalkenyl-C _1-3 -alkyl, 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, C _{1 4} alkoxycarbonyl, amino, C _1-4 alkylamino, di (C _1-3 alkyl) amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4 (C _1-4 alkyl) piperazin-1-yl, C _1-4 alkylcarbonylamino, C _1-6 alkyloxy, C _3-7 cycloalkyloxy, C _5-7 cycloalkenyloxy, aryloxy, C _1-4 Alkylsulfanyl, 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, arylsulf onyl, hydroxy, cyano and nitro, wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl radicals are partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxyl, C _1-3 alkoxy and C _1-3 alkyl may be substituted, and wherein in cycloalkyl and cycloalkenyl radicals one or two methylene groups may be independently substituted by O, S, CO, SO or SO ₂ , and wherein in N-heterocycloalkyl radicals a Methylene group may be substituted by CO or SO ₂ , and R ^{2 is} hydrogen, fluorine, chlorine, bromine, hydroxyl, C _1-4 -alkyl, C _1-4 -alkoxy, cyano or nitro, where alkyl radicals may be mono- or polysubstituted by fluorine, or in the event that R ¹ and R ² are bonded to two adjacent C atoms of the phenyl ring, R ¹ and R ^{2 may} be linked together such that R ¹ and R ² together form a C _3-5 alkylene, C _3-5 alkenylene or butadienylene bridge which may be partially or completely fluorinated or monosubstituted or disubstituted by identical or different substituents selected from chloro, hydroxy, C _1-3 alkoxy and C _1-3 alkyl and in which one or two Methylene groups may be independently substituted by O, S, CO, SO, SO ₂ or NR ^N , and in which in the case of a butadienylene bridge one or two methine groups may be replaced by an N atom, R ^{3 is} hydrogen, fluorine, chlorine , Bromo, C _1-6 -alkyl, C _2-6 -alkynyl, C _2-6 -alkenyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alky l, C _5-7 -cycloalkenyl, C _5-7 -cycloalkenyl-C _1-3 -alkyl, aryl, heteroaryl, arylC _1-3 -alkyl, heteroarylC _1-3 -alkyl, 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, hydroxycarbonyl, C _1-4 -alkoxycarbonyl, C _1-4 -alkylamino, di (C _1-3 -alkyl) -amino, pyrrolidin-1-yl, Piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4- (C _1-4 alkyl) piperazin-1-yl, C _1-4 alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C _1-4 Alkylsulfonylamino, arylsulfonylamino, C _1-6 alkoxy, C _3-7 cycloalkyloxy, C _5-7 cycloalkenyloxy, aryloxy, heteroaryloxy, C _1-4 alkylsulfanyl, 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, amino, hydroxy, cyano and nitro, wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl radicals are partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy , C _1-3 alkoxy and C _1-3 alkyl may be substituted, and wherein in cycloalkyl and cycloalkenyl radicals one or two methylene groups may be independently substituted by O, S, CO, SO or SO ₂ , and wherein in N-heterocycloalkyl radicals a methylene group may be substituted by CO or SO ₂ , or R ^{3 represents} a group Y linked via a double bond with Cy, R ^{4 is} hydrogen, fluorine, chlorine, cyano, nitro, amino, C _1-3 Alkylamino, di (C _1-3 alkyl) amino, C _1-3 alkylcarbonylamino, C _1-3 alkyl, C _1-3 alkoxy, hydroxycarbonyl, C _1-3 alkoxycarbonyl or by 1 to 3 Fluorine atoms substituted methyl or methoxy, or in the event that R ³ and R ⁴ on the same C-A can be joined together R ³ and R ^{4 in} such a way that R ³ and R ⁴ together form a C _2-6 alkylene or C _4-6 alkenylene bridge which is partially or completely fluorinated or may be substituted once or twice with identical or different substituents selected from chlorine, hydroxy, C _1-3 alkoxy and C _1-3 alkyl and in the one or two methylene groups independently of one another by O, S, CO, SO, SO ₂ or NR ^N may be substituted, or in the event that R ³ and R ^{4 are} attached to two adjacent atoms of the Cy cycle, R ³ and R ^{4 may} be linked together such that R ³ and R ⁴ together with the two adjacent atoms of the Cy cycle form a fused saturated or mono- or polyunsaturated 5- or 6-membered carbocycle in which one or two methylene groups independently of one another by O, S, CO, SO, SO ₂ or NR ^N and / or one or two methine groups can be replaced by N, and which is mono- or polyfluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxyl, C _1-3 -alkoxy and C _1-3 -alkyl or in the case of an aromatic fused cycle, once or twice with identical or different substituents Substituents L may be substituted, R ^{5 is} hydrogen, fluorine, chlorine, cyano, C _1-3 alkyl, C _1-3 alkoxy or by 1 to 3 fluorine atoms substituted methyl or methoxy, or R ⁴ and R ⁵ together are joined together that R ⁴ and R ⁵ together form a C _1-4 alkylene or C _2-4 alkenylene bridge which forms with 2, 3 or 4 atoms of the Cy cycle a fused or bridged cycle and the partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C _1-3 alkoxy and C _1-3 alkyl, and in which one or two methylene groups independently of one another by O, S, CO , SO, SO ₂ or NR ^{N can be} substituted kö and R ^{6 is} hydrogen, C _1-3 alkyl or fluorine, or R ⁴ , R ⁵ and R ⁶ are linked together such that R ⁴ , R ⁵ and R ⁶ together form a C _3-6 alkanetriyl bridge form together with the Cy cycle a bridged bicyclic or a tricyclic system, wherein the alkanetriyl bridge mono- or polyfluorinated one or two times with identical or different substituents selected from chlorine, hydroxy, C _1-3 alkoxy and C _1-3 alkyl may be substituted, and in which one or two methylene groups may be independently substituted by O, CO, SO ₂ or NR ^N , and Y is oxygen, or methylidene, fluoromethylidene, chloromethylidene, C _1-6 alkyl -methylidene, C _2-6 -alkenyl-methylidene, C _2-6 -alkynyl-me methylidene, C _3-7 -cycloalkylmethylidene, C _5-7 -cycloalkenyl-methylidene, C _3-7 -cycloalkylidene, C _5-7 -cycloalkenylidene, C _3-7 -cycloalkyl-C _1-3 -alkyl-methylidene, C _{5 -7-} cycloalkenyl-C _1-3 -alkyl-methylidene, arylmethylidene, heteroarylmethylidene, arylC _1-3 -alkyl-methylidene or heteroarylC _1-3 -alkyl-methylidene, where alkyl, alkenyl, alkynyl , Cycloalkyl, cycloalkenyl, cycloalkylidene and cycloalkenylidene radicals partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from the group consisting of chlorine, cyano, hydroxy, C _1-3 -alkoxy, C _1-3 -alkylsulfanyl and C _In addition, the above-mentioned unsubstituted methylidene group or the above-mentioned monosubstituted methylidene groups may additionally be easily substituted by fluorine, chlorine, C _1-3 -alkyl, trifluoromethyl, C _1-4 -alkoxy, cyano or nitro and wherein in cycloalkyl, cycloalkenyl, cycloalkylidene and cycloalkenylidene radicals one or two methylene groups may independently be substituted by O, S, CO, SO, SO ₂ or NR ^N , or Y represents a group according to the partial formula

in which D is carbonyl or sulphonyl, R ^{Y is} hydrogen, fluorine, chlorine, cyano, trifluoromethyl or C _1-3 -alkyl, B is a single bond, -O- or -NR ^N -, R ^{B is} hydrogen, C _1-6 - Alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _3-7 cycloalkyl C _1-3 alkyl, C _5-7 cycloalkenylC _1-3 alkyl, aryl, heteroaryl, arylC _1-3 alkyl or heteroarylC _1-3 alkyl, wherein alkyl, cycloalkyl and cycloalkenyl radicals partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, cyano, hydroxy, C _1-3 alkoxy and C _1-3 alkyl, or R ^B and B with each other to form a heterocyclic ring selected from pyrrolidine, morpholine, piperidine, piperazine and 4- (C _1-4 -alkyl) -piperazine, wherein the heterocyclic ring is bonded via the imino group to the group D, R ^N independently of one another are H or C _1-4 Alkyl, L independently of selected from the group consisting of fluorine, chlorine, bromine, iodine, C _1-3 -alkyl, difluoromethyl, trifluoromethyl, C _1-3 -alkoxy, difluoromethoxy, trifluoromethoxy and cyano, R ^7a , R ^7b , R ^7c , R ^7d independently of one another have a meaning 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, where among the definition of the abovementioned radicals aryl groups are to be understood as meaning phenyl or naphthyl groups which may be substituted independently of one another once or twice by identical or different radicals L; and the heteroaryl groups mentioned in the definition of the abovementioned radicals mean a pyrrolyl, furanyl, thienyl, imidazolyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group, or a pyrrolyl, Furanyl, thienyl, imidazolyl or pyridyl group in which one or two methine groups are replaced by nitrogen atoms, or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group in which one to three methine groups are to be understood are replaced by nitrogen atoms, wherein the above-mentioned heteroaryl groups may be independently of one another mono- or disubstituted by identical or different radicals L; wherein the N-heterocycloalkyl radical mentioned in the definition of the abovementioned radicals is to be understood as meaning a saturated carbocyclic ring which has an imino group in the ring which contains a further imino group or an O or S atom in the ring and, where not mentioned otherwise, the abovementioned alkyl groups may be straight-chain or branched, their tautomers, their stereoisomers, mixtures thereof and their salts, in particular their physiologically tolerable salts, the following compound (D1) not being included : (D1) 3 - [(3-.beta.-D-glucopyranosyl-4,5-dimethoxyphenyl) methyl] -4 - [(3,4-dimethoxyphenyl) methyl] -dihydro-2 (3H) -furanone. D-glucopyranosyl-phenyl-substituted cycles according to claim 1, characterized in that the cycle Cy cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, Tetrahy dropyran, 1,3-dioxane, 1,4-dioxane, tetrahydrothiophene, dithiolane or 1,3-dithian, in which a methylene group may be replaced by CO, and that as defined in claim 1 with R ³ , R ⁴ , R ⁵ and R ^{6 is} substituted, and in which additionally one or more carbon-bonded H atoms may be replaced by fluorine. D-glucopyranosyl-phenyl-substituted cycles according to claim 1 or 2, characterized by the formula I.1 or I.1 '

in which V1, V2 independently of one another denote C or N, U1, U2, U3, U4 independently of one another denote C, N, O, CO or SO ₂ , with the proviso that a maximum of 2 heteroatoms are selected in the ring formed by U and V. N and O are present, these heteroatoms are not directly connected to each other, and at most one group selected from CO and SO _{2 is} present, and remaining free chemical bonds to C and N atoms are saturated with hydrogen; and wherein R ¹ to R ⁶ , Z, R ^7a , R ^7b , R ^7c , R ^{7d have} the meanings according to claim 1. D-Glucopyranosyl-phenyl-substituted cycles according to claim 1 or 2, characterized by the formula I.2

in which V1, V2 independently of one another denote C or N, U1, U2, U3 independently of one another denote C, N, O, CO or SO ₂ , with the proviso that in the ring formed by U and V a maximum of 2 heteroatoms selected from N and O are present, these heteroatoms are not directly connected to each other, and at most one group selected from CO and SO _{2 is} present, and remaining free chemical bonds at C and N atoms are saturated with hydrogen; and wherein R ¹ to R ⁶ , Z, R ^7a , R ^7b , R ^7c , R ^{7d have} the meanings according to claim 1. D-Glucopyranosyl-phenyl-substituted cyclen according to one or more of claims 1 to 4, characterized in that R ^{1 is} hydrogen, fluorine, chlorine, bromine, iodine, C _1-6 alkyl, C _2-6 alkynyl, C _{2 -6-} alkenyl, C _3-7 -cycloalkyl, C _5-7 -cycloalkenyl, C _1-6 -alkyloxy, C _3-7 -cycloalkyloxy or cyano, wherein in cycloalkyl and cycloalkenyl groups one or two methylene units independently of one another by O or CO and alkyl, alkenyl and alkynyl radicals may be partially or completely fluorinated. D-glucopyranosyl-phenyl-substituted cyclen according to one or more of claims 1 to 5, characterized in that R ^{2 is} hydrogen, fluorine, chlorine, bromine, methyl, hydroxy, methoxy, ethoxy, trifluoromethoxy, cyano, nitro or by 1 to 3 Fluorine atoms substituted methyl means. D-glucopyranosyl-phenyl-substituted cyclen according to one or more of claims 1 to 6, characterized in that R ^{3 is} hydrogen, fluorine, chlorine, C _1-6 alkyl, C _2-6 alkynyl, C _2-6 alkenyl , C _3-7 cycloalkyl, C _3-7 cycloalkylmethyl, C _5-7 cycloalkenyl, C _3-7 cycloalkenylmethyl, aryl, heteroaryl, C _1-4 alkylcarbonyl, aminocarbonyl, C _1-4 alkylaminocarbonyl , Di (C _1-3 alkyl) aminocarbonyl, C _1-4 alkoxycarbonyl, di (C _1-3 alkyl) amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, C _1-4 alkylcarbonylamino, C _1-6 alkoxy, C _3-7 cycloalkyloxy, C _5-7 cycloalkenyloxy, aryloxy, heteroaryloxy, C _1-4 alkylsulfanyl, C _1-4 alkylsulfonyl, C _3-7 Cycloalkylsulfanyl, C _3-7 -cycloalkylsulfonyl, C _5-7 -cycloalkenylsulfanyl, C _5-7 -cycloalkenylsulfonyl, hydroxy or cyano, and in the event that R ^{3 is} attached to an N-atom, R ^{3 is} preferably hydrogen , Cyan, C _1-4 -alkyl, C _2-6 -alkynyl, C _2-6 -alkenyl, C _3-6 -cycloalkyl, C _3-6 -cycloalkyl-C _1-3 -alkyl, C _5-6 cycloalkenyl, C _5-6 cycloalkenylC _1-3 alkyl, aryl, heteroaryl, arylC _1-3 alkyl, heteroarylC _1-3 alkyl, C _1-4 alkylcarbonyl, Arylcarbonyl, heteroarylcarbonyl, C _1-4 -alkylsulfonyl, arylsulfonyl or heteroarylsulfonyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl radicals are partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy , C _1-3 alkoxy and C _1-3 alkyl may be substituted, and wherein in cycloalkyl and cycloalkenyl radicals one or two methylene groups may be independently substituted by O, S, CO, SO or SO ₂ , and wherein in N-heterocycloalkyl radicals a methylene group may be substituted by CO or SO ₂ , wherein the terms aryl and heteroaryl are defined according to claim 1 and aryl and heteroaryl groups independently of one another may be monosubstituted or disubstituted by identical or different radicals L. and L according to Anspruc h 1 is defined. D-glucopyranosyl-phenyl-substituted cyclen according to one or more of claims 1 to 6, characterized in that R ³ is bonded via a double bond to Cy and oxygen, C _1-6 alkyl-methylidene, C _2-6 alkynyl methyliden, C _2-6 -alkenyl-methylidene, C _3-7 -cycloalkyl-methylidene or C _3-7 -cycloalkylidene, where the abovementioned alkyl, alkenyl and alkynyl radicals are partially or completely fluorinated and independently of one another or may be substituted in duplicate with substituents selected from chlorine, hydroxy, C _1-3 alkoxy and C _1-3 alkyl, and wherein the above-mentioned unsubstituted methylidene group or the above-mentioned monosubstituted methylidene groups are additionally easily substituted with fluorine, C _1-3 Alkyl, trifluoromethyl or cyano, and wherein in a cycloalkylidene group a methylene group is represented by O, S or NR ^N or an ethylene group by -NR ^N -CO-, -CO-NR ^N -, -O-CO- or -CO-O- may be replaced od he Y a group according to the sub-formula T

in which R ^{Y is} hydrogen, fluorine, cyano, trifluoromethyl or C _1-3 -alkyl, D is carbonyl or sulfonyl, B is a single bond, -O- or -NR ^N -, R ^{B is} C _1-6 -alkyl -, C _3-7 -cycloalkyl, C _5-7 -cycloalkenyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, C _5-7 -cycloalkenyl-C _1-3 -alkyl-, aryl, Heteroaryl, arylC _1-3 -alkyl or heteroarylC _1-3 -alkyl-, wherein alkyl, cycloalkyl and cycloalkenyl radicals may be partially or completely fluorinated or mono- or disubstituted by identical or different substituents selected from cyano, hydroxy, C _1-3 alkoxy and C _1-3 alkyl, or R ^B and B are joined together to form a heterocyclic ring selected from pyrrolidine, morpholine, piperidine, piperazine and 4- (C _1-4 alkyl) piperazine, wherein the heterocyclic ring is bonded to the group D via the imino group and R ^{N is} as is defined in claim 1. D-Glucopyranosyl-phenyl-substituted cycles according to one or more of claims 1 to 8, characterized in that R ⁴ , R ⁵ and R ⁶ independently of one another are hydrogen, fluorine or methyl. D-Glucopyranosyl-phenyl-substituted cycles according to one or more of claims 1 to 8, characterized in that the radicals R ⁴ , R ⁵ and R ⁶ are joined together to form a C _4-5 alkanetriyl bridge and together with the Cyclus Cy is a tricyclic system selected from tricyclononane, tricyclodecane and tricycloundekane, more preferably adamantane, which is unsubstituted or mono- or polyfluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C _1-3 -alkoxy and C _1-3 alkyl may be substituted. D-glucopyranosyl-phenyl-substituted cyclen according to one or more of claims 1 to 10, characterized in that Z is -O-, -CH ₂ -, -CF ₂ -, -C (CH ₃ ) ₂ -, -CH =, -NR ^N - or -CO- means. D-glucopyranosyl-phenyl-substituted cyclen according to one or more of claims 1 to 11, characterized in that R ^7a , R ^7b , R ^7c , R ^7d independently hydrogen, (C _1-6 alkyl) oxycarbonyl, (C _1-8 alkyl) carbonyl or benzoyl, preferably hydrogen. Physiologically acceptable salts of the compounds according to one or more of claims 1 to 12 with inorganic or organic acids. Use of a compound after one or more the claims 1 to 12 or a physiologically acceptable salt according to claim 13, including the explicitly excluded in claim 1 compound (D1) or one of its physiologically compatible Salts, as medicines. A medicament containing a compound according to one or more of the claims 1 to 12 or a physiologically acceptable salt according to claim 13, including the explicitly excluded in claim 1 compound (D1) or one of its physiologically compatible Salts, optionally with 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, including the explicitly excluded in claim 1 compound (D1) or one of its physiologically compatible Salts 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 at least one compound after one or more of the claims 1 to 12 or a physiologically acceptable salt according to claim 13, including the explicitly excluded in claim 1 compound (D1) or one of its physiologically compatible Salts for the manufacture of a medicament for the treatment or Prophylaxis of metabolic diseases is suitable. Use according to claim 17, 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, including the explicitly excluded in claim 1 compound (D1) or one of its physiologically compatible Salts, for the manufacture of a medicament for inhibiting the sodium-dependent glucose cotransporter SGLT. Use of at least one compound according to at least one of claims 1 to 12 or one physiologically acceptable salt according to claim 13, including the compound (D1) or one of its physiologically tolerable salts explicitly excluded in claim 1, for the manufacture of a medicament for preventing the degeneration of pancreatic beta cells and / or for improving and / or restoring the functionality of pancreatic beta cells. 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, including the explicitly excluded in claim 1 compound (D1) or one of its physiologically compatible Salts, for the preparation of diuretics and / or antihypertensives. Process for the preparation of a medicament according to claim 15, 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, including the explicitly excluded in claim 1 compound (D1) or one of its physiologically compatible Salts, in one or more inert carriers and / or diluents is incorporated.