Abstract:
The present invention relates to a method for treating, preventing or slowing, delaying or reversing progression of one or more neurodegenerative disorders in a patient in need thereof characterized by administering a glucopyranosyl-substituted benzene derivative, a tautomer, stereoisomer, mixture or salt thereof, as defined in claim  1  to the patient in need thereof.

Description:
BACKGROUND OF THE INVENTION 
       [0001]    The present invention relates to methods for preventing and treating neurodegenerative disorders in patients in need thereof by administering a pharmaceutical composition comprising a compound of general formula I 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein the groups R 1  to R 6  and R 7a , R 7b , R 7c  are defined hereinafter, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof. In addition the present invention relates to the use of a compound of general formula I according to this invention for preparing a pharmaceutical composition for preventing and treating neurodegenerative disorders. 
       BACKGROUND OF THE INVENTION 
       [0002]    Glucopyranosyl-substituted benzene derivatives inhibit the sodium-dependent glucose cotransporters (SGLT), in particular SGLT2. Reuptake of filtered glucose across epithelial cells of the kidney proceeds via sodium-dependent glucose cotransporters (SGLTs) located in the brush-border membranes in the proximal tubuli along the sodium gradient (1) . There are at least 3 SGLT isoforms that differ in their expression pattern as well as in their physico-chemical properties (2) . SGLT2 is exclusively expressed in the kidney (3) . Under normoglycemia, glucose is completely reabsorbed by SGLTs in the kidney, whereas the reuptake capacity of the kidney is saturated at glucose concentrations higher than 10 mM, resulting in glucosuria (“diabetes mellitus”). This threshold concentration can be decreased by SGLT2-inhibition. Renal filtration and reuptake of glucose contributes, among other mechanisms, to the steady state plasma glucose concentration and can therefore serve as an antidiabetic target. Therefore the glucopyranosyl-substituted benzene derivatives are proposed as inducers of urinary sugar excretion and as medicaments in the treatment of diabetes.
   (1) Wright, E. M. (2001) Am. J. Renal Physiol. 280, F10-F18;   (2) Wright, E. M. et al. (2004) Pflugers Arch. 447(5):510-8;   (3) You, G. et al. (1995) J. Biol. Chem. 270 (49) 29365-29371;   
 
         [0006]    Alzheimer&#39;s disease (AD) is a progressive neurodegenerative disorder characterized by multiple cognitive deficits including worsening of memory, judgement, and comprehension and deterioration in global functioning. As the disease progresses, motor, sensory, and linguistic abilities are also affected until there is global impairment of multiple cognitive functions. These cognitive losses occur gradually, but typically lead to severe impairment and eventual death in the range of four to twelve years. Current treatments are not efficacious in every patient. 
         [0007]    Therefore there is an unmet medical need for drugs with a good efficacy with regard to the treatment, prevention or slowing, delaying or reversing progression of neurodegenerative disorders, such as dementia, in particular dementia of Alzheimer type, while at the same time showing an improved safety profile. 
       AIM OF THE INVENTION 
       [0008]    An aim of the present invention is to find a new method for treating of neurodegenerative disorders, in particular of a dementia. 
         [0009]    Another aim of the present invention is to find a new method for preventing or slowing, delaying or reversing progression of neurodegenerative disorders, in particular of a dementia. 
         [0010]    A further aim of the present invention is to find a new therapeutic use of a glucopyranosyl-substituted benzene derivative. 
         [0011]    A further aim of the present invention is to provide new pharmaceutical compositions which are suitable for the treatment of neurodegenerative disorders, in particular dementia. 
         [0012]    Other aims of the present invention will become apparent to the skilled man directly from the foregoing and following remarks. 
       OBJECT OF THE INVENTION 
       [0013]    In a first aspect the present invention relates to a method for treating of one or more neurodegenerative disorders in a patient in need thereof wherein said method comprises administering a glucopyranosyl-substituted benzene derivative of general formula (I) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein
   R 1  denotes hydrogen, fluorine, chlorine, bromine, iodine, cyano or nitro, or C 1-4 -alkyl, a methyl group substituted by 1 to 3 fluorine atoms, an ethyl group substituted by 1 to 5 fluorine atoms, a C 1-4 -alkyl group substituted by a hydroxy or C 1-3 -alkoxy group, or
       C 2-6 -alken-1-yl, C 2-4 -alkenyl-C 1-4 -alkyl, C 2-6 -alkyn-1-yl, C 2-4 -alkynyl-C 1-4 -alkyl, or C 2-4 -alkenyl-C 1-4 -alkoxy, C 2-4 -alkynyl-C 1-4 -alkoxy, or   C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-4 -alkyl, C 5-7 -cycloalkenyl, C 5-7 -cycloalkenyl-C 1-4 -alkyl, or   hydroxy, C 1-4 -alkoxy, a methoxy group substituted by 1 to 3 fluorine atoms, an ethoxy group substituted by 1 to 5 fluorine atoms, a C 2-4 -alkoxy group substituted by a hydroxy or C 1-3 -alkoxy group, or   C 3-7 -cycloalkyloxy, C 5-7 -cycloalkenyloxy, C 3-6 -cycloalkyl-C 1-3 -alkoxy or   C 1-4 -alkylcarbonyl, aminocarbonyl, C 1-4 -alkylaminocarbonyl, di-(C 1-3 -alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C 1-4 -alkyl)piperazin-1-ylcarbonyl, C 1-4 -alkoxycarbonyl, or   amino, C 1-4 -alkylamino, di-(C 1-3 -alkyl)amino, pyrrolidin-1-yl, pyrrolidin-2-on-1-yl, piperidin-1-yl, piperidin-2-on-1-yl, morpholin-4-yl, morpholin-3-on-4-yl, piperazin-1-yl, 4-(C 1-3 -alkyl)piperazin-1-yl, C 1-4 -alkylcarbonylamino, or   C 1-4 -alkylsulphinyl, C 1-4 -alkylsulphonyl, C 3-7 -cycloalkylsulphanyl, C 3-7 -cycloalkylsulphinyl, C 3-7 -cycloalkylsulphonyl, C 6-7 -cycloalkenylsulphanyl, C 6-7 -cycloalkenylsulphinyl, C 6-7 -cycloalkenylsulphonyl, or   aryl, heteroaryl, aryloxy, heteroaryloxy, arylcarbonyl, heteroarylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-C 1-3 -alkoxycarbonyl, heteroaryl-C 1-3 -alkoxycarbonyl, arylcarbonylamino, heteroarylcarbonylamino, arylsulphanyl, arylsulphinyl, arylsulphonyl, heteroarylsulphanyl, heteroarylsulphinyl, heteroarylsulphonyl,   while in the above-mentioned cycloalkyl and cycloalkenyl rings one or two methylene groups may be replaced independently of one another by O, S, CO, SO, SC 2  or NR N , and   while the above-mentioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine, and   the above-mentioned alkynyl and alkenyl groups may be mono- or disubstituted by identical or different groups L1, and   the above-mentioned cycloalkyl- and cycloalkenyl-rings independently of one another may be mono- or disubstituted by substituents selected from fluorine and C 1-3 -alkyl, and   
       R 2  denotes fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 1-4 -alkoxy, C 3-7 -cycloalkyloxy, C 6-7 -cycloalkenyloxy, C 1-4 -alkylsulfanyl, while the alkyl or alkoxy group may be mono- or polysubstituted by fluorine; and   R 3  denotes hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C 1-6 -alkyl, a methyl or methoxy group substituted by 1 to 3 fluorine atoms, a C 2-4 -alkyl or C 2-4 -alkoxy group substituted by 1 to 5 fluorine atoms, a C 1-4 -alkyl group substituted by a cyano group, a C 1-4 -alkyl group substituted by a hydroxy or C 1-3 -alkyloxy group, tri-(C 1-4 -alkyl)silyl-C 1-6 -alkyl,
       C 2-6 -alken-1-yl, C 2-4 -alkenyl-C 1-4 -alkyl,   C 2-6 -alkyn-1-yl, C 2-4 -alkynyl-C 1-4 -alkyl,   C 2-4 -alkenyl-C 1-4 -alkoxy, C 2-4 -alkynyl-C 1-4 -alkoxy,   C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-4 -alkyl, C 5-7 -cycloalkenyl, C 5-7 -cycloalkenyl-C 1-4 -alkyl, C 3-6 -cycloalkylidenmethyl,   hydroxy, C 1-6 -alkoxy, C 3-6 -cycloalkyl-C 1-3 -alkoxy, C 3-10 -cycloalkyloxy, C 5-10 -cycloalkenyloxy, or   C 3-7 -cycloalkylethinyl, tetrahydrofuranylethinyl, tetrahydropyranylethinyl, C 3-7 -cycloalkyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy or cycloalkanonyl, all of which may be substituted with one to four substituents L2, or   carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, (C 1-3 -alkylamino)carbonyl, di-(C 1-3 -alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-yl-carbonyl, 4-(C 1-3 -alkyl)-piperazin-1-ylcarbonyl, or   amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)amino, pyrrolidin-1-yl, pyrrolidin-2-on-1-yl, piperidin-1-yl, piperidin-2-on-1-yl, morpholin-4-yl, morpholin-3-on-4-yl, piperazin-1-yl, 4-(C 1-3 -alkyl)piperazin-1-yl, (C 1-4 -alkyl)carbonylamino, C 1-4 -alkylsulphonylamino, or   C 1-4 -alkylsulphanyl, C 1-4 -alkylsulphinyl, C 1-4 -alkylsulphonyl, C 3-10 -cycloalkylsulphanyl, C 3-10 -cycloalkylsulphinyl, C 3-10 -cycloalkylsulphonyl, C 5-10 -cycloalkenylsulphanyl, C 5-10 -cycloalkenylsulphinyl, C 5-10 -cycloalkenylsulphonyl, or   aryl, aryl-C 1-3 -alkyl, arylcarbonylamino, heteroarylcarbonylamino, heteroaryl, heteroaryl-C 1-3 -alkyl, aryloxy, aryl-C 1-3 -alkyl-oxy, arylsulphanyl, arylsulphinyl, heteroarylsulphanyl or heteroarylsulphinyl, arylsulphonylamino, aryl-C 1-3 -alkylsulphonylamino or arylsulphonyl, or   a arylethinyl-group or a 5- or 6-membered monocyclic heteroarylethinyl-group or a 5- or 6-membered monocyclic heteroaryloxy-group;   wherein a heteroaryl-group has 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; and   wherein a heteroaryl-group may possess 1 or 2 carbonyl groups as part of the monocyclic aromatic ring-system; and   wherein an N-atom of a heteroaryl ring-system may be oxidized to form the corresponding N-oxide; and   wherein one or more methine groups in a aryl- and heteroaryl-group may be substituted independently of one another with a substituent L1; and   wherein one or more imino-groups in a heteroaryl-group may be substituted independently of one another with a substituent R N ;   while the above-mentioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine, and   the above-mentioned alkynyl and alkenyl groups may be mono- or disubstituted by identical or different groups L1; and   while the above-mentioned cycloalkyl and cycloalkenyl rings may be mono- or disubstituted independently of one another by substituents selected from fluorine and C 1-3 -alkyl, and   in the above-mentioned cycloalkyl and cycloalkenyl rings one or two methylene groups may be replaced independently of one another by O, S, CO, SO, SC 2  or NR N ,   
       R 4 , R 5  independently of each other denote hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C 1-3 -alkyl, C 1-3 -alkoxy, methyl or methoxy substituted by 1 to 3 fluorine atoms, amino, C 1-3 -alkyl-amino or di(C 1-3 -alkyl)-amino; and   R N  denotes H, C 1-4 -alkyl, C 1-4 -alkylcarbonyl or C 1-4 -alkylsulphonyl,   L1 independently of one another are selected from among hydroxy, cyano, nitro, C 3-7 -cycloalkyl, C 1-4 -alkylcarbonyl, aminocarbonyl, C 1-4 -alkylaminocarbonyl, di-(C 1-3 -alkyl)aminocarbonyl, C 1-4 -alkoxycarbonyl and C 1-4 -alkyloxy; and   L2 independently of one another are selected from among fluorine, chlorine, bromine, iodine, C 1-3 -alkyl, difluoromethyl, trifluoromethyl, C 1-3 -alkoxy, difluoromethoxy, trifluoromethoxy and cyano; and   R 6 , R 7a ,   R 7b , R 7c  independently of one another have a meaning selected from among hydrogen, (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, arylcarbonyl and aryl-(C 1-3 -alkyl)-carbonyl,
 
while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups which may be mono- or disubstituted independently of one another by identical or different groups L2; and
 
by the heteroaryl groups mentioned in the definition of the above groups are meant a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl or tetrazolyl group,
 
or is meant a pyrrolyl, furanyl, thienyl or pyridyl group, wherein one or two methyne groups are replaced by nitrogen atoms,
 
or is meant an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group, wherein one to three methyne groups are replaced by nitrogen atoms,
 
while the above-mentioned heteroaryl groups independently of one another may be mono- or disubstituted by identical or different groups L2;
 
while, unless otherwise stated, the above-mentioned alkyl groups may be straight-chain or branched,
 
a tautomer thereof, a stereoisomer thereof, a mixture of compounds of the general formula (I) or a salt thereof,
 
to the patient in need thereof.
   
 
         [0055]    In a further aspect the present invention relates to a method for preventing or slowing, delaying or reversing progression of one or more neurodegenerative disorders in a patient in need thereof wherein said method comprises administering a glucopyranosyl-substituted benzene derivative of general formula (I), a tautomer, stereoisomer, mixture or salt thereof, as defined hereinbefore and hereinafter to the patient in need thereof. 
         [0056]    Another aspect of the present invention relates to the use of a glucopyranosyl-substituted benzene derivative of general formula (I), a tautomer, stereoisomer, mixture or salt thereof, as defined hereinbefore and hereinafter for the manufacture of a medicament for the treatment of one or more neurodegenerative disorders. 
         [0057]    Another aspect of the present invention relates to the use of a glucopyranosyl-substituted benzene derivative of general formula (I), a tautomer, stereoisomer, mixture or salt thereof, as hereinbefore and hereinafter for the manufacture of a medicament for preventing or slowing, delaying or reversing progression of one or more neurodegenerative disorders. 
         [0058]    Another aspect of the present invention relates to a pharmaceutical composition for the treatment of one or more neurodegenerative disorders comprising a glucopyranosyl-substituted benzene derivative of general formula (I), a tautomer, stereoisomer, mixture or salt thereof, as defined hereinbefore and hereinafter. 
         [0059]    Another aspect of the present invention relates to a pharmaceutical composition for preventing or slowing, delaying or reversing progression of one or more neurodegenerative disorders comprising a glucopyranosyl-substituted benzene derivative of general formula (I), a tautomer, stereoisomer, mixture or salt thereof, as defined hereinbefore and hereinafter. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0060]    Unless otherwise stated the groups, residues and substituents, particularly R 1  to R 6  and R 7a , R 7b , R 7c , are defined as above and hereinafter. 
         [0061]    If residues, substituents or groups occur several times in a compound, they may have the same or different meanings. 
         [0062]    The group R 1  preferably denotes hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro or cyano, hydroxy, C 1-4 -alkyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, C 1-4 -alkyl substituted by a hydroxy or C 1-3 -alkoxy group, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-4 -alkoxy, methoxy substituted by 1 to 3 fluorine atoms, ethoxy substituted by 1 to 5 fluorine atoms, C 2-4 -alkoxy substituted by a hydroxy or C 1-3 -alkoxy group, C 2-4 -alkenyl-C 1-4 -alkoxy, C 2-4 -alkynyl-C 1-4 -alkoxy, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, C 3-7 -cycloalkyloxy, C 3-6 -cycloalkyl-C 1-3 -alkoxy or C 5-7 -cycloalkenyloxy, while in the C 5-6 -cycloalkyl groups a methylene group may be replaced by O. 
         [0063]    Even more preferably the group R 1  denotes hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl, hydroxy, methoxy, ethoxy, difluoromethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuran-3-yloxy or tetrahydropyran-4-yl-oxy. 
         [0064]    Most preferred meanings of the group R 1  are methyl, chlorine, cyano and cyclopropyl. 
         [0065]    The group R 2  preferably denotes hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, methyl substituted by 1 to 3 fluorine atoms, hydroxy, methoxy, ethoxy, trifluoromethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy. 
         [0066]    According to a first preferred embodiment the group R 1  denotes cyano and R 2  denotes hydrogen. 
         [0067]    According to a second preferred embodiment the group R 1  denotes cyano and R 2  is defined as hereinbefore, but R 2  does not denote hydrogen. 
         [0068]    The group R 3  preferably denotes hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert.-butyl, ethynyl, 1-propynyl, trimethylsilylethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, cyclopentyloxy, difluoromethoxy, trifluoromethoxy, pentafluorethoxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-on-3-yloxy, methylsulphanyl, ethylsulphanyl, isopropylsulphanyl, cyclopropylidenemethyl, phenyl, fluorophenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, trimethylsilylethyl, ethynyl, 1-propyn-1-yl, 1-butyn-1-yl, tert.-butylethynyl, 2-hydroxyprop-2-ylethynyl, 2-methoxyprop-2-ylethynyl, 3-hydroxy-1-propyn-1-yl, 3-methoxy-1-propyn-1-yl, ethenyl, 1-propenyl, 1-butenyl, tert.-butylethenyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuranyloxy, tetrahydrothiophenyloxy, 1,1-dioxotetrahydrothiophenyloxy, tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1-dioxotetrahydrothiopyranyloxy, tetrahydrofuranonyloxy, piperidinyloxy, piperidinonyloxy, pyrrolidin-3-yloxy, pyrrolidinon-3-yloxy, tetrahydrofuranyl-sulphanyl, cyclopropylsulphanyl, cyclobutylsulphanyl, cyclopentylsulphanyl and cyclohexylsulphanyl, while the —NH group in a piperidinyl, piperidinonyl, pyrrolidinyl or pyrrolidinonyl ring may be substituted by R N , particularly C 1-3 -alkyl or acetyl; or 
         [0069]    1-hydroxy-cyclopropylethinyl, 1-hydroxy-cyclobutylethinyl, 1-hydroxy-cyclopentylethinyl, 1-hydroxy-cyclohexylethinyl, tetrahydrofuran-2-ylethinyl, tetrahydrofuran-3-ylethinyl, tetrahydropyran-4-ylethinyl, 4-hydroxy-tetrahydropyran-4-ylethinyl, 1-methoxy-cyclopropylethinyl, 1-methoxy-cyclobutylethinyl, 1-methoxy-cyclopentylethinyl, 1-methoxy-cyclohexylethinyl, 4-methoxy-tetrahydropyran-4-ylethinyl, 1-hydroxymethyl-cyclopropylethinyl, 1-hydroxymethyl-cyclobutylethinyl, 1-hydroxymethyl-cyclopentylethinyl, 1-hydroxymethyl-cyclohexylethinyl, 4-hydroxymethyl-tetrahydropyran-4-ylethinyl, all of which may be substituted with an additional substituent L2; or 
         [0070]    2-hydroxy-cyclopropyloxy, 2-hydroxy-cyclobutyloxy, 3-hydroxy-cyclobutyloxy, 2-hydroxy-cyclopentyloxy, 3-hydroxy-cyclopentyloxy, 2-hydroxy-cyclohexyloxy, 3-hydroxy-cyclohexyloxy, 4-hydroxy-cyclohexyloxy, 2-methoxy-cyclopropyloxy, 2-methoxy-cyclobutyloxy, 3-methoxy-cyclobutyloxy, 2-methoxy-cyclopentyloxy, 3-methoxy-cyclopentyloxy, 2-methoxy-cyclohexyloxy, 3-methoxy-cyclohexyloxy, 4-methoxy-cyclohexyloxy, 1-hydroxymethyl-cyclopentyloxy, 1-hydroxymethyl-cyclohexyloxy, 1-methoxymethyl-cyclopentyloxy, 1-methoxymethyl-cyclohexyloxy, 4-hydroxy-tetrahydrofuran-3-yloxy, 4-methoxy-tetrahydrofuran-3-yloxy, 3-hydroxy-tetrahydropyran-4-yloxy and 4-hydroxy-tetrahydropyran-3-yloxy, all of which may be substituted with an additional substituent L2; or 
         [0071]    2-oxo-cyclopentyl and 2-oxo-cyclohexyl, which may be substituted with an additional substituent L2; or 
         [0072]    phenylethinyl, pyridylethinyl, pyridazinylethinyl, pyrazinylethinyl, pyrimidinylethinyl, thienylethinyl, thiazolylethinyl, oxazolylethinyl, isoxazolylethinyl, [1,2,4]oxadiazolylethinyl, [1H-[1,2,4]triazolyl]ethinyl, [2H-tetrazolyl]ethinyl, [1,2-dihydro-2-oxo-pyridinyl]ethinyl or [1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl]ethinyl, wherein one or more methine-groups in said phenyl or said heteroaryl-groups may be substituted independently of one another with a substituent L1; and 
         [0073]    pyridyloxy, pyridazinyloxy, pyrazinyloxy, pyrimidinyloxy, pyrazolyloxy, imidazolyloxy, triazinyloxy, thienyloxy, thiazolyloxy, oxazolyloxy, isoxazolyloxy, [1,2,4]oxadiazolyloxy, [1H-[1,2,4]triazolyl]oxy, or [2H-tetrazolyl]oxy, 
         [0000]    wherein one or more methine-groups in said heteroaryl-groups may be substituted independently of one another with a substituent L1; and
 
wherein one or more imino-groups in said heteroaryl-groups may be substituted independently of one another with a substituent R N .
 
         [0074]    Even more preferably the group R 3  denotes hydrogen, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylidenemethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, methyloxy, ethyloxy, isopropyloxy, di-fluoromethyloxy, trifluoromethyloxy, pentafluorethoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, (S)-tetrahydrofuran-3-yloxy, (R)-tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuran-2-on-3-yloxy, 1-acetyl-piperidin-4-yloxy, 2-methyloxy-ethyloxy, methylsulfanyl, ethylsulphanyl, isopropylsulphanyl, methylsulfinyl, methlysulfonyl, ethyl-sulfinyl, ethylsulfonyl, trimethylsilyl, trimethylsilylethyl, ethynyl, 2-hydroxyprop-2-ylethynyl, 2-methoxyprop-2-ylethynyl, 3-hydroxy-1-propyn-1-yl, 3-methoxy-1-propyn-1-yl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy or N-acetylpiperidin-4-yloxy. 
         [0075]    The groups R 4 , R 5  preferably denote independently of each other hydrogen, fluorine, hydroxy, methoxy, ethoxy or methyl, particularly hydrogen or methyl. 
         [0076]    According to a preferred embodiment R 4  and R 5  denote H. 
         [0077]    According to another preferred embodiment R 4  denotes H and R 5  denotes F. 
         [0078]    According to another preferred embodiment R 4  denotes F and R 5  denotes H. 
         [0079]    According to another preferred embodiment R 4  and R 5  denote F. 
         [0080]    The group L1 preferably denotes fluorine, hydroxy, hydroxy-C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, C 1-4 -alkyl, trifluoromethyl, C 1-4 -alkyl-carbonylamino, hydroxycarbonyl or C 1-4 -alkoxycarbonyl; particularly fluorine, hydroxy, hydroxymethyl, methoxy or methyl. 
         [0081]    The group L2 preferably denotes fluorine, hydroxy, hydroxy-C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, C 1-4 -alkyl, trifluoromethyl, C 1-4 -alkyl-carbonylamino, hydroxycarbonyl or C 1-4 -alkoxycarbonyl; particularly hydroxy, hydroxymethyl, methoxy or methyl. 
         [0082]    The group R N  preferably denotes C 1-3 -alkyl or acetyl, in particular methyl. 
         [0083]    The group R 6  preferably denotes according to the invention hydrogen, (C 1-8 -alkyl)oxycarbonyl, C 1-8 -alkylcarbonyl or benzoyl, particularly hydrogen or (C 1-6 -alkyl)oxycarbonyl or C 1-6 -alkylcarbonyl, particularly preferably hydrogen, methylcarbonyl, methoxycarbonyl or ethoxycarbonyl, most particularly preferably hydrogen. 
         [0084]    The substituents R 7a , R 7b , R 7c  preferably represent independently of one another hydrogen, (C 1-8 -alkyl)oxycarbonyl, (C 1-18 -alkyl)carbonyl or benzoyl, particularly hydrogen, (C 1-6 -alkyl)oxycarbonyl or (C 1-8 -alkyl)carbonyl, particularly preferably hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl or ethylcarbonyl. Most particularly preferably R 7a , R 7b  and R 7c  represent hydrogen. 
         [0085]    In the methods, uses and pharmaceutical compositions according to this invention compounds of the formula (Ia) and (Ib) are preferred 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1  to R 6  are defined as hereinbefore. 
         [0086]    In the methods, uses and pharmaceutical compositions according to this invention the following compounds (1) to (382) are particularly preferred: 
         [0087]    Preferred compounds according to this invention are selected from the following table: 
         [0000]    
       
         
               
               
             
               
               
             
           
               
                   
               
               
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                 14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
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                 21 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 22 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
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                 27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 28 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 29 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
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                 39 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
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                 58 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 59 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
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                 63 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 64 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
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                 77 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 78 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 79 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 80 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 81 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
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                 83 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 84 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 85 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 86 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 87 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 88 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 89 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 90 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 91 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 92 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 93 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 94 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 95 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 96 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 97 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 98 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 99 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 100 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 101 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 102 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 103 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 104 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 105 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 106 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 107 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 108 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 109 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 110 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 111 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 112 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 113 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 114 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 115 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 116 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 117 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 118 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 119 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 120 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 121 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 122 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 123 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 124 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 125 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 126 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 127 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 128 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 129 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 130 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 131 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 132 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 133 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 134 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 135 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 136 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 137 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 138 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 139 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 140 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 141 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 142 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 143 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 144 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 145 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 146 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 147 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 148 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 149 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 150 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 151 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 152 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 153 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 154 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 155 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 156 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 157 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 158 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 159 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 160 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 161 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 162 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 163 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 164 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 165 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 166 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 167 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 168 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 169 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 170 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 171 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 172 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 173 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 174 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 175 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 176 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 177 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 178 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 179 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 180 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 181 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 182 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 183 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 184 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 185 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 186 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 187 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 188 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 189 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 190 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 191 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 192 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 193 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 194 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 195 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 196 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 197 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 198 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 199 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 200 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 201 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 202 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 203 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 204 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 205 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 206 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 208 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 209 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 210 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 211 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 212 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 213 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 214 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 215 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 216 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 217 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 218 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 219 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 220 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 221 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 222 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 223 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 224 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 225 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 226 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 227 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 228 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 229 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 230 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 231 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 232 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 233 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 234 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 235 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 236 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 237 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 238 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 239 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 240 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 241` 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 242 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 243 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 244 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 245 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 246 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 247 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 248 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 249 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 250 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 251 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 252 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 253 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 254 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 255 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 256 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 257 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 258 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 259 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 260 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 261 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 262 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
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         [0088]    Some terms used above and hereinafter to describe the compounds according to the invention will now be defined more closely. 
         [0089]    The term halogen denotes an atom selected from the group consisting of F, Cl, Br and I. 
         [0090]    The term C 1-n -alkyl, wherein n may have a value of 2 to 18, denotes a saturated, branched or unbranched hydrocarbon group with 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. 
         [0091]    The term C 2-n -alkynyl, wherein n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C≡C triple bond. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl etc. Unless otherwise stated alkynyl groups are connected to the remainder of the molecule via the C atom in position 1. Therefore terms such as 1-propynyl, 2-propynyl, 1-butynyl, etc. are equivalent to the terms 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, etc. This also applies analogously to C 2-n -alkenyl groups. 
         [0092]    The term C 1-n -alkoxy denotes a C 1-n -alkyl-O group, wherein C 1-n -alkyl is as hereinbefore defined. 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. 
         [0093]    The term C 1-n -alkylcarbonyl denotes a C 1-n -alkyl-C(═O) group, wherein C 1-n -alkyl is as hereinbefore defined. 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. 
         [0094]    The term C 3-n -cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group with 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, decalinyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc. Preferably the term C 3-n -cycloalkyl denotes saturated monocyclic groups. 
         [0095]    The term C 5-n -cycloalkenyl denotes a C 5-n -cycloalkyl group which is as hereinbefore defined and additionally has at least one unsaturated C═C double bond. 
         [0096]    The term C 3-n -cycloalkylcarbonyl denotes a C 3-n -cycloalkyl-C(═O) group wherein C 3-n -cycloalkyl is as hereinbefore defined. 
         [0097]    The term tri-(C 1-4 -alkyl)silyl comprises silyl groups which have identical or two or three different alkyl groups. 
         [0098]    The term di-(C 1-3 -alkyl)amino comprises amino groups which have identical or two different C 1-3 -alkyl groups. 
         [0099]    The term aryl preferably denotes naphthyl or phenyl, more preferably phenyl. 
         [0100]    The term heteroaryl denotes a 5- or 6-membered monocyclic aromatic ring possessing one to four identical or different heteroatoms selected from the group comprising N, O and S. Heteroaryl denotes preferably a pyrrolyl, furanyl, thienyl, pyridyl or tetrazolyl group, or 
         [0000]    a pyrrolyl, furanyl, thienyl or pyridyl group wherein one or two methine groups are replaced in each case by a nitrogen atom. 
         [0101]    The nomenclature in structural formulas used above and hereinafter, in which a bond of a substituent of a cyclic group, as e.g. a phenyl ring, is shown towards the centre of the cyclic group, denotes, unless otherwise stated, that this substituent may be bound to any free position of the cyclic group bearing an H atom. 
         [0102]    The compounds according to the invention may be obtained using methods of synthesis known in principle. Preferably the compounds are obtained by methods as described for example in WO 05/092877, WO 06/064033, WO 2006/120208, WO 06/089872, WO 06/108842 and in the literature cited therein. 
         [0103]    As already mentioned, the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibitory effect on the sodium-dependent glucose cotransporter SGLT, preferably SGLT2. In addition the compounds according to the invention of general formula I and the physiologically acceptable salts thereof are potential therapeutic agents in the treatment and/or prevention of neurodegenerative disorders, in particular dementia. 
         [0104]    Dementia is characterized by the development of multiple cognitive deficits and memory impairment. Such cognitive deficits may include one or more of aphasia, apraxia, agnosia and disturbance in executive functioning (see for example “Diagnostic and statistical manual of mental disorders”, 4 th  edition, American Psychiatric Association, 2000). 
         [0105]    The compounds according to this invention are potentially valuable in the treatment of one or more neurodegenerative disorders and in preventing or slowing, delaying or reversing progression of one or more neurodegenerative disorders in a patient in need thereof. 
         [0106]    The patient whose illness or condition is to be treated or prevented according to the invention is a mammal, particularly a human being. Preferably the term patient comprises an individual diagnosed to have a neurodegenerative disorder, in particular a dementia, especially dementia of the Alzheimer type. The term patient also comprises an individual diagnosed to have an increased risk to develop a neurodegenerative disorder, in particular a dementia, especially dementia of the Alzheimer type. 
         [0107]    In the context of this invention the term neurodegenerative disorder denotes in particular dementia. The term dementia comprises dementia of the Alzheimer type, vascular dementia, dementia in Parkinson and dementia due to other general medical conditions. Dementia due to other medical conditions comprises dementia in chorea Huntington, dystonias, degenerative ataxias, AIDS-related dementia, Creutzfeld-Jakob&#39;s syndrome, bovine spongiform encephalopathy, prion-related infections, diseases involving mitochondrial dysfunction, Down&#39;s syndrome, hepatic encephalopathy, amyotrophic lateral sclerosis, multiple sclerosis, olivoponto-cerebellar atrophy, post-operative cognitive deficit, mild cognitive impairment, hypoxia, ischaemia resulting from cardiac arrest, stroke, glioma and other tumours, attention deficit hyperactivity disorder, autism, convulsions, epilepsy, Korsakoff syndrome, depression and schizophrenia. 
         [0108]    The course of dementia of the Alzheimer Type is characterized by gradual onset and continuing cognitive decline. 
         [0109]    The compounds according to this invention may improve cognitive abilities and memory, in particular in a patient as defined hereinbefore. Therefore by the administration of a compound to a patient according to this invention a cognitive decline or memory impairment may be attenuated, slowed, delayed or even reversed. 
         [0110]    The effect of the compounds according to this invention with respect to cognitive abilities, learning and memory can be tested by methods described in the literature and known to the one skilled in the art. Examples of such tests are described in the following: 
         [0111]    Cognitive abilities, in particular those related to learning and memorizing, may be tested in the Morris water maze. The Morris water maze is a device to investigate spatial learning and memory in rodents. It consists of a large circular pool filled with opaque water in which a small escape platform is submerged underneath the water surface. During a number of training trials, animals learn to find the platform and escape from the pool, using the different extra-maze cues contained in the experimental room. Details are described by D&#39;Hooge R. and De Deyn P. P. (2001) “Applications of the Morris water maze in the study of learning and memory.”, Brain Research Reviews 36, 60-90. 
         [0112]    Another method to test cognitive abilities is based on contextual fear conditioning. Classical fear conditioning is a reference task to investigate fear memory. It is assessed in operant chambers where the animals receive a mild electric shock. The association between the experimental chamber and the shock is tested 24 hours later by returning the animals in the chambers in which training occurred (context) and measuring their freezing behaviour, i.e. the tendency of the animals to remain in motionless, defensive posture. Details are described by Kim J. J. and Jung M. W. (2006) “Neural circuits and mechanisms involved in Pavlovian fear conditioning: A critical review.”, Neuroscience and Biobehavioral Reviews 30, 188-202. 
         [0113]    A further test of cognitive abilities is related to the recognition of novel objects. The test is based on differential exploration of familiar and new objects. In the first trial (T1), animals are exposed to two identical objects (samples) and in a second Trial (T2), two dissimilar objects, a familiar (the sample) and a new one. Increased exploration of the novel object is a measure of recognition memory. Such a test is described by Prickaerts J. et al. (2004) “Phosphodiesterase type 5 inhibition improves early memory consolidation of object information”, Neurochemistry International 45, 915-928. 
         [0114]    The aforementioned tests of cognitive abilities can also be performed with Alzheimer disease animal models, for example with a transgenic mouse model, such as the Tg2576 mice. 
         [0115]    The dosage required to achieve the corresponding activity for treatment or prevention usually depends on the compound which is to be administered, the patient, the nature and gravity of the illness or condition and the method and frequency of administration and is for the patient&#39;s doctor to decide. Expediently, the dosage may be from 0.1 to 100 mg, preferably 0.1 to 30 mg, by intravenous route, and 0.1 to 500 mg, preferably 0.5 to 100 mg, by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, 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 suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories. 
       EXAMPLES OF FORMULATIONS 
       [0116]    The following examples of formulations, which may be obtained analogously to methods known in the art, serve to illustrate the present invention more fully without restricting it to the contents of these examples. The term “active substance” denotes a glucopyranosyl-substituted benzene derivative according to this invention. 
       Example 1 
     Dry Ampoule Containing 75 mg of Active Substance per 10 ml 
     Composition: 
       [0117]      
         [0000]    
       
         
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Active substance 
                 75.0 
                 mg 
               
               
                   
                 Mannitol 
                 50.0 
                 mg 
               
               
                   
                 water for injections 
                 ad 10.0 
                 ml 
               
               
                   
                   
               
             
          
         
       
     
       Preparation: 
       [0118]    Active substance and mannitol are dissolved in water. After packaging the solution is freeze-dried. To produce the solution ready for use, the product is dissolved in water for injections. 
       Example 2 
     Dry Ampoule Containing 35 mg of Active Substance per 2 ml 
     Composition: 
       [0119]      
         [0000]    
       
         
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Active substance 
                 35.0 
                 mg 
               
               
                   
                 Mannitol 
                 100.0 
                 mg 
               
               
                   
                 water for injections 
                 ad 2.0 
                 ml 
               
               
                   
                   
               
             
          
         
       
     
       Preparation: 
       [0120]    Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried. To produce the solution ready for use, the product is dissolved in water for injections. 
       Example 3 
     Tablet Containing 50 mg of Active Substance 
     Composition: 
       [0121]      
         [0000]    
       
         
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 (1) Active substance 
                 50.0 
                 mg 
               
               
                   
                 (2) Lactose 
                 98.0 
                 mg 
               
               
                   
                 (3) Maize starch 
                 50.0 
                 mg 
               
               
                   
                 (4) Polyvinylpyrrolidone 
                 15.0 
                 mg 
               
               
                   
                 (5) Magnesium stearate 
                 2.0 
                 mg 
               
               
                   
                   
                 215.0 
                 mg 
               
               
                   
                   
               
             
          
         
       
     
       Preparation: 
       [0122]    (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side. 
         [0123]    Diameter of the tablets: 9 mm. 
       Example 4 
     Tablet Containing 350 mg of Active Substance 
     Preparation: 
       [0124]      
         [0000]    
       
         
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 (1) Active substance 
                 350.0 
                 mg 
               
               
                   
                 (2) Lactose 
                 136.0 
                 mg 
               
               
                   
                 (3) Maize starch 
                 80.0 
                 mg 
               
               
                   
                 (4) Polyvinylpyrrolidone 
                 30.0 
                 mg 
               
               
                   
                 (5) Magnesium stearate 
                 4.0 
                 mg 
               
               
                   
                   
                 600.0 
                 mg 
               
               
                   
                   
               
             
          
         
       
     
         [0125]    (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side. 
         [0126]    Diameter of the tablets: 12 mm. 
       Example 5 
     Capsules Containing 50 mg of Active Substance 
     Composition: 
       [0127]      
         [0000]    
       
         
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 (1) Active substance 
                 50.0 
                 mg 
               
               
                   
                 (2) Dried maize starch 
                 58.0 
                 mg 
               
               
                   
                 (3) Powdered lactose 
                 50.0 
                 mg 
               
               
                   
                 (4) Magnesium stearate 
                 2.0 
                 mg 
               
               
                   
                   
                 160.0 
                 mg 
               
               
                   
                   
               
             
          
         
       
     
       Preparation: 
       [0128]    (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling machine. 
       Example 6 
     Capsules Containing 350 mg of Active Substance 
     Composition: 
       [0129]      
         [0000]    
       
         
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 (1) Active substance 
                 350.0 
                 mg 
               
               
                   
                 (2) Dried maize starch 
                 46.0 
                 mg 
               
               
                   
                 (3) Powdered lactose 
                 30.0 
                 mg 
               
               
                   
                 (4) Magnesium stearate 
                 4.0 
                 mg 
               
               
                   
                   
                 430.0 
                 mg 
               
               
                   
                   
               
             
          
         
       
     
       Preparation: 
       [0130]    (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 0 hard gelatin capsules in a capsule filling machine. 
       Example 7 
     Suppositories Containing 100 mg of Active Substance 
     Composition: 
       [0131]      
         [0000]    
       
         
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Active substance 
                 100.0 
                 mg 
               
               
                   
                 Polyethyleneglycol (M.W. 1500) 
                 600.0 
                 mg 
               
               
                   
                 Polyethyleneglycol (M.W. 6000) 
                 460.0 
                 mg 
               
               
                   
                 Polyethylenesorbitan monostearate 
                 840.0 
                 mg 
               
               
                   
                   
                 2,000.0 
                 mg