Tetrasubstituted glucopyranosylated benzene derivatives, medicaments containing such compounds, their use and process for their manufacture

1. Glucopyranosylated benzene derivatives of general formula I

wherein

R 1 denotes chlorine or methyl,

R 2 denotes C 3-7 -cycloalkyl or C 3-7 -cycloalkyloxy,

while the above-mentioned cycloalkyl-rings may be mono- or polysubstituted by fluorine and/or mono- or disubstituted by identical or different substituents L2, and/or

in the above-mentioned cycloalkyl rings one methylene group may be replaced by O, and

R 3 hydrogen, fluorine, chlorine, bromine, iodine, C 1-6 -alkyl, C 2-6 -alkynyl, C 2-6 -alkenyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 5-7 -cycloalkenyl, C 5-7 -cycloalkenyl-C 1-3 -alkyl, aryl, heteroaryl, C 1-4 -alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, C 1-4 -alkylaminocarbonyl, di-(C 1-3 -alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C 1-4 -alkyl)piperazin-1-ylcarbonyl, hydroxycarbonyl, C 1-4 -alkoxycarbonyl, C 1-4 -alkylamino, di-(C 1-3 -alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-(C 1-4 -alkyl)piperazin-1-yl, C 1-4 -alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C 1-4 -alkylsulfonylamino, arylsulfonylamino, C 1-6 -alkoxy, C 3-7 cycloalkyloxy, C 5-7 -cycloalkenyloxy, aryloxy, heteroaryloxy, C 1-4 -alkylsulfanyl, C 1-4 -alkylsulfinyl, C 1-4 -alkylsulfonyl, C 3-7 -cycloalkylsulfanyl, C 3-7 -cycloalkylsulfinyl, C 3-7 -cycloalkylsulfonyl, C 5-7 -cycloalkenylsulfanyl, C 5-7 -cycloalkenylsulfinyl, C 5-7 -cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, heteroarylsulfanyl, heteroarylsulfinyl, heteroarylsulfonyl, amino, hydroxy, cyano and nitro,

while the above-mentioned alkyl-, alkenyl-, alkynyl-, cycloalkyl- and cycloalkenyl-residues may be mono- or polysubstituted by fluorine and/or mono- or disubstituted by identical or different substituents L2, and

while in the above-mentioned C 5-6 -cycloalkyl and C 5-6 -cycloalkenyl rings one or two methylene groups may be replaced independently of one another by O, S, CO, SO or SO 2 , and

while in the above-mentioned N-heterocycloalkyl rings one methylene group may be replaced by CO or SO 2 , and

R 4 , R 5 independently of one another denote hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C 1-3 -alkyl, C 1-3 -alkoxy, or a methyl- or methoxy-group substituted by 1 to 3 fluorine atoms,

L1 independently of one another are selected from among fluorine, chlorine, bromine, iodine, hydroxy, cyano, C 1-3 -alkyl, difluoromethyl, trifluoromethyl, C 1-3 -alkoxy, difluoromethoxy, trifluoromethoxy, amino, C 1-3 -alkyl-amino and di(C 1-3 -alkyl)-amino; and

L2 independently of one another are selected from among fluorine, chlorine, hydroxy, hydroxyl-C 1-4 -alkyl, C 1-4 -alkoxy, trifluoromethoxy, C 1-4 -alkoxy-C 1-4 -alkyl, cyano, hydroxycarbonyl, (C 1-4 -alkyl)oxycarbonyl, aminocarbonyl, C 1-4 -alkyl, trifluoromethyl, amino, C 1-4 -alkyl-carbonylamino, C 1-3 -alkyl-amino and di(C 1-3 -alkyl)-amino; 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 the aryl-groups may be mono- or disubstituted independently of one another by identical or different groups L1;

while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups which may be substituted as defined; and

while, unless otherwise stated, the above-mentioned alkyl groups may be straight-chain or branched,

including tautomers, stereoisomers thereof or mixtures thereof, and physiologically acceptable salts thereof.

2. Glucopyranosylated benzene derivatives according to claim 1 characterized in that R 2 denotes C 3-7 -cycloalkyl or C 3-7 -cycloalkyloxy, while in the cycloalkyl rings a methylene group may be replaced by O, and wherein the cycloalkyl rings may be mono- or poly-fluorinated and/or mono- or disubstituted with identical or different substituents L2, wherein L2 is defined as in claim 1 .

3. Glucopyranosylated benzene derivatives according to claim 1 characterized in that R 3 denotes chlorine, bromine, iodine, C 1-4 -alkyl, C 3-7 -cycloalkyl, hydroxyl, C 1-4 -alkyloxy, C 3-7 -cycloalkyloxy, C 1-4 -alkylsulfanyl, C 3-7 -cycloalkylsulfanyl, while in a C 5-6 -cycloalkyl ring a methylene group may be replaced by O, and wherein any alkyl group and cycloalkyl ring may be mono- or polyfluorinated and/or mono- or disubstituted with identical or different substituents L2, wherein L2 is defined as in claim 1 .

4. Glucopyranosylated benzene derivatives according to claim 1 characterized in that R 6 denotes hydrogen, (C 1-8 -alkyl)oxycarbonyl, C 1-8 -alkylcarbonyl or benzoyl and R 7a , R 7b , R 7c represent independently of one another hydrogen, (C 1-8 -alkyl)oxycarbonyl, (C 1-8 -alkyl)carbonyl or benzoyl.

5. Glucopyranosylated benzene derivatives according to claim 4 characterized in that R 6 , R 7a , R 7b , R 7c represent hydrogen.

6. Physiologically acceptable salts of the compounds according to claim 1 with inorganic or organic acids.

7. A pharmaceutical composition, comprising a compound according to claim 1 or a physiologically acceptable salt thereof with inorganic or organic acids, optionally together with one or more inert carriers and/or diluents.

8. A method for the treatment of diseases or conditions which can be influenced by inhibiting the sodium-dependent glucose cotransporter SGLT comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a physiologically acceptable salt thereof with inorganic or organic acids wherein the disease or condition is selected from the group consisting of type 1 and type 2 diabetes mellitus, complications of diabetes, metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hyperuricaemia.

9. A method for the treatment of one or more metabolic disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a physiologically acceptable salt thereof with inorganic or organic acids wherein the metabolic disorder is selected from the group consisting of type 1 and type 2 diabetes mellitus, complications of diabetes, metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hyperuricaemia.

10. A method for inhibiting the sodium-dependent glucose cotransporter SGLT2 comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a physiologically acceptable salt thereof with inorganic or organic acids.

11. A method for treating the degeneration of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a physiologically acceptable salt thereof with inorganic or organic acids.

12. A method for treating diseases or conditions attributed to an abnormal accumulation of liver fat in a patient in need thereof comprising administering to a patient a therapeutically effective amount of a compound according to claim 1 or a physiologically acceptable salt thereof with inorganic or organic acids.

13. A process for preparing a compound according to claim 1 characterised in that

a) a compound of general formula II

wherein

R′ denotes H, C 1-4 -alkyl, (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, arylcarbonyl and aryl-(C 1-3 -alkyl)-carbonyl, wherein the alkyl or aryl groups may be mono- or polysubstituted by halogen;

R 8a , R 8b ,

R 8c , R 8d independently of one another have one of the meanings given hereinbefore and hereinafter for the groups R 6 , R 7a , R 7b , R 7c , or denote a benzyl or allyl group or a R a R b R c Si group or a ketal or acetal group, particularly an alkylidene or arylalkylidene ketal or acetal group, while in each case two adjacent groups R 8a , R 8b , R 8c , R 8d may form a cyclic silyl ketal, ketal or acetal group or a 1,2-di(C 1-3 -alkoxy) -1,2-di(C 1-3 -alkyl)-ethylene bridge, while the above-mentioned ethylene bridge forms, together with two oxygen atoms and the two associated carbon atoms of the pyranose ring, a substituted dioxane ring, particularly a 2,3-dimethyl 2,3-di(C 1-3 -alkoxy)-1,4-dioxane ring, and while alkyl, aryl and/or benzyl groups may be mono- or polysubstituted by halogen or C 1-3 -alkoxy, and while benzyl groups may also be substituted by a di-(C 1-3 -alkyl)amino group; and

R a , R b , R c independently of one another denote C 1-4 -alkyl, aryl or aryl-C 1-3 -alkyl, wherein the aryl or alkyl groups may be mono- or polysubstituted by halogen;

while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups, preferably phenyl groups;

and wherein the groups R 1 to R 6 , R 7a , R 7b , R 7c are defined as in claim 1 ;

is reacted with a reducing agent in the presence of a Lewis or Brønsted acid, while any protective groups present are cleaved simultaneously or subsequently; or

b) a compound of general formula III

wherein R 8a , R 8b , R 8c , R 8d and R 1 to R 5 are defined as in claim 1 , but at least one of the groups R 8a , R 8b , R 8c , R 8d does not denote hydrogen, is hydrolysed to yield a compound of the formula I defined as in claim 1 wherein R 6 , R 7a , R 7b and R 7c denote hydrogen, and

if desired a compound of formula I thus obtained wherein R 6 denotes a hydrogen atom, is converted by acylation into a corresponding acyl compound of general formula I, and/or

if necessary any protective group used in the reactions described above is cleaved and/or

if desired a compound of formula I thus obtained is resolved into its stereoisomers and/or

if desired a compound of formula I thus obtained is converted into the salts thereof.

14. A process for preparing compounds of general formula II

wherein

R′ denotes H, C 1-4 -alkyl, (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, arylcarbonyl and aryl-(C 1-3 -alkyl)-carbonyl, wherein the alkyl or aryl groups may be mono- or polysubstituted by halogen;

R 8a ,R 8b ,

R 8c , R 8d independently of one another has one of the meanings given for the groups R 6 , R 7a , R 7b , R 7c , or denote a benzyl or allyl group or a R a R b R c Si group or a ketal or acetal group, while in each case two adjacent groups R 8a , R 8b , R 8c , R 8d may form a cyclic silyl ketal, ketal or acetal group or may form, with two oxygen atoms of the pyranose ring, a substituted 2,3-oxydioxane ring, particularly a 2,3-dimethyl-2,3-di(C 1-3 -alkoxy)-1,4-dioxane ring, and while alkyl, aryl and/or benzyl groups may be mono- or polysubstituted by halogen or C 1-3 -alkoxy, and while benzyl groups may also be substituted by a di-(C 1-3 -alkyl)amino group; and

R a , R b , R c independently of one another denote C 1-4 -alkyl, aryl or aryl-C 1-3 -alkyl, while the alkyl or aryl groups may be mono- or polysubstituted by halogen;

while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups, preferably phenyl groups;

and R 1 to R 6 , R 7a ,R 7b , R 7c are defined as in claim 1 ,

wherein an organometallic compound (V) which may be obtained by halogen-metal exchange or by inserting a metal in the carbon-halogen bond of a halogen-benzylbenzene compound of general formula IV

wherein Hal denotes Cl, Br and I and R 1 to R 5 are defined as in claim 1 , and optionally subsequent transmetallation, is added to a gluconolactone of general formula VI

wherein R 8a , R 8b , R 8c , R 8d are defined as in claim 1 , and

then the resulting adduct is reacted with water or an alcohol R′—OH, while R′ denotes optionally substituted C 1-4 -alkyl, in the presence of an acid and optionally the product obtained in the reaction with water wherein R′ denotes H is converted, in a subsequent reaction, with an acylating agent into the product of formula II wherein R′ denotes (C 1-18 -alkyl) carbonyl, (C 1-18 -alkyl)oxycarbonyl, arylcarbonyl or aryl-(C 1-3 -alkyl)-carbonyl, which may be substituted as specified.

15. A compound of general formula IV

wherein Hal denotes chlorine, bromine or iodine and the groups R 1 to R 5 are defined as in claim 1 .

16. A compound of general formula II

wherein R′, R 8a , R 8b , R 8c , R 8d and R 1 to R 5 are defined as in claim 14 .