Patent EP-2295422-A2 (EP)
Inventor: HIMMELSBACH FRANK
IPC: C07H15/26
Filed: 2005-03-11
Abstract: Glucopyranosyl-substituted benzene derivatives (I) and their tautomers, sterioisomers andsalts are new. Glucopyranosyl-substituted benzene derivatives of formula (I) and their tautomers, stereoisomers and salts are new. R 1> : definitions of the group A; R 2> : H, F, Cl, Br, OH, 1-4C alkyl, 1-4C alkoxy, CN or NO 2 (while the alkyl or alkoxy group mono- or polysubstituted by F); R 3> : definitions of the group B 1>; R 4>, R 5> : H, F, Cl, Br, I, CN, NO 2, 1-3C alkyl, 1-3C alkoxy, methyl or methoxy (substituted by 1-3 F atoms); A : e.g. 2-6C alkyn-1-yl, 2-6C alken-1-yl or 3-7C cycloalkyl; B 1> : e.g. tri-(1-4C alkyl)silyl-1-6C alkyl, 2-6C alkyn-1-yl or 2-6C alken-1-yl; R-N : H, 1-4C alkyl, 1-4C alkylcarbonyl or 1-4C alkylsulfonyl; L1 : OH, CN, NO 2, 3-7C cycloalkyl, (hetero)aryl, 1-4C alkylcarbonyl, (hetero)arylcarbonyl, aminocarbonyl, 1-4C alkylaminocarbonyl, di-(1-3C alkyl)-aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, (hetero)arylaminocarbonyl, 1-4C alkoxycarbonyl, (hetero)aryl-1-3C alkoxycarbonyl, 1-4C alkyloxy, (hetero)aryloxy, 1-4C alkylsulfanyl, (hetero)arylsulfanyl, 1-4C alkylsulfinyl, (hetero)arylsulfinyl, 1-4C alkylsulfonyl or (hetero)arylsulfonyl; L2 : F, Cl, Br, I, 1-3C alkyl, difluoromethyl, trifluoromethyl, 1-3C alkoxy, difluoromethoxy, OCF 3 or CN; and R 6>, R-7a, R-7b, R-7c : H, (1-18C alkyl)carbonyl, (1-18C alkyl)oxycarbonyl, arylcarbonyl or aryl-(1-3C alkyl)-carbonyl (while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups which mono- or disubstituted of one another by identical or different groups L2 and by the heteroaryl groups mentioned in the definition of the above groups are meant a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl or tetrazolyl group or is meant a pyrrolyl, furanyl, thienyl or pyridyl group where 1-2 methyne groups are replaced by nitrogen atoms or meant an indolyl, benzofuranyl, benzothiophenyl or (iso)quinolinyl group, where 1-3 methyne groups are replaced by nitrogen atoms, while the above-mentioned heteroaryl groups of one another may be mono- or disubstituted by identical or different groups L2. Provisos are given. Full definitions are given in the "Definitions" section. Independent claims are also included for: (1) physiologically acceptable salts of (I) with inorganic or organic acids; (2) a glucopyranosyl-substituted benzene derivatives of formula (II); (3) composition containing (I) or a physiologically acceptable salt optionally together with one or more inert carriers and/or diluents; (4) process for preparing a composition comprising the step of incorporating one or more inert carriers and/or diluents into the composition by a non-chemical method. (5) a benzene derivatives of formula (IV); (6) the preparation of (I); (7) the preparation of (II) comprises an organometallic compound (V) which may be obtained by halogen-metal exchange or by the insertion of a metal in the carbon-halogen bond of (IV) and optionally subsequent transmetallation, is added to a gluconolactone of formula (VI) then reacting the adduct obtained with water or an alcohol of formula (R-a-OH), in the presence of an acid and optionally the product obtained in the reaction with water is converted in a subsequent reaction with an acylating agent to give (II); and (8) a pharmaceutical composition for use as a diuretic or hypertensive, the composition comprising (I). R-s : H, 1-4C alkyl, (1-8Calkyl)carbonyl, (1-18C-alkyl)oxycarbonyl, arylcarbonyl or aryl-(C1 3-alkyl)-carbonyl (where the alkyl or aryl groups may be mono- or polysubstituted by halo); either R-8a-R-8d : R 6>, R-7a-R-7c or denote a benzyl group or a R-aR-bR-cSi group or a ketal or acetal group; or R-8a-R-8d : may form a cyclic ketal or acetal group or a 1,2-di(1-3C-alkoxy)-1,2-di(13C-alkyl)-ethylene bridge, (while the above-mentioned ethylene bridge forms, together with two oxygen atoms and the two associated carbon atoms of the pyranose ring, a substituted dioxane ring and alkyl, aryl and/or benzyl groups may be mono- or polysubstituted by halogen or 13C-alkoxy and benzyl groups may also be substituted by a di-(1-3C-alkyl)amino group); R-a, R-b, R-c : 1-4C alkyl, aryl or aryl-1-3C-alkyl; and aryl : phenyl (preferred) or naphthyl groups. [Image] [Image] ACTIVITY : Antidiabetic; Vasotropic; Analgesic; Antianginal; Antilipemic; Antiarteriosclerotic; Anorectic; Cardiant; Antiinflammatory. MECHANISM OF ACTION : Sodium-dependent glucose cotransporter inhibitor. The ability of (I) to inhibit sodium-dependent glucose cotransporter was tested in biological assays. The results showed that (I) exhibits a median effective concentration value of less than 50 nM.