| 摘要 |
#CMT# #/CMT# Glucopyranosyl-substituted benzene derivatives (I) and their tautomers, sterioisomers andsalts are new. #CMT# : #/CMT# 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. #CMT#[Image]#/CMT# #CMT#[Image]#/CMT# #CMT#ACTIVITY : #/CMT# Antidiabetic; Vasotropic; Analgesic; Antianginal; Antilipemic; Antiarteriosclerotic; Anorectic; Cardiant; Antiinflammatory. #CMT#MECHANISM OF ACTION : #/CMT# 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. #CMT#USE : #/CMT# (I) is useful for treating diseases or conditions which can be influenced by inhibiting the sodium-dependent glucose cotransporter (SGL). (I) is also useful for treating metabolic disorders (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, edema or hyperuricaemia), a sodium dependent glucose co-transporter SGLT2. (I) is also useful for preventing the degeneration of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells (all claimed). #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation (claimed): Preparation of (I) comprises reacting (II) with a reducing agent in the presence of a Lewis or Bronsted acid, while any protective groups present are cleaved simultaneously or subsequently (if desired converting (I) thus obtained (where R 6> denotes a hydrogen atom), is by acylation into a corresponding acyl (I) and/or if necessary cleaving any protective group used in the reactions described above, if desired a resolving (I) thus obtained into its stereoisomers and/or if desired converting (I) thus obtained into the salts, particularly for pharmaceutical use into the physiologically acceptable salts); or hydrolyzing a glucopyranosyl-substituted benzene derivatives of formula (III). Preferred Components: The organometallic compound is lithium or magnesium. #CMT#[Image]#/CMT# #CMT#DEFINITIONS : #/CMT# Full Definitions: 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 : 2-6C alkyn-1-yl, 2-6C alken-1-yl, 3-7C cycloalkyl, 5-7C cycloalkenyl, (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, piperazin-1-ylcarbonyl, 4-(1-4C alkyl)piperazin-1-ylcarbonyl, arylamino-carbonyl, heteroarylaminocarbonyl, 1-4C alkoxycarbonyl, aryl-1-3C alkoxycarbonyl, heteroaryl-1-3C alkoxycarbonyl, NH 2, 1-4C alkylamino, di-(1-3C 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-(1-3C alkyl)piperazin-1-yl, 1-4C alkylcarbonylamino, (hetero) arylcarbonylamino, 3-7C cycloalkyloxy, 5-7C cycloalkenyloxy, (hetero)aryloxy, 1-4C alkylsulfinyl, 1-4C alkylsulfonyl, 3-7C cycloalkylsulfanyl, 3-7C cycloalkylsulfinyl, 3-7C cycloalkylsulfonyl, 5-7C cycloalkenylsulfanyl, 5-7C cycloalkenylsulfinyl, 5-7C cycloalkenylsulfonyl, (hetero)arylsulfanyl, (hetero)arylsulfinyl, (hetero)arylsulfonyl, CN or NO 2 (while the above-mentioned alkynyl and alkenyl groups mono- or polysubstituted by F or Cl and the above-mentioned alkynyl and alkenyl groups mono- or disubstituted by identical or different groups L1 and the above-mentioned cycloalkyl and cycloalkenyl rings of one another mono- or disubstituted by substituents of F or 1-3C alkyl and in the above-mentioned cycloalkyl and cycloalkenyl rings 1-2 methylene groups optionally replaced of one another by O, S, CO, SO, SO 2 or NR-N); B 1> : tri-(1-4C alkyl)silyl-1-6C alkyl, 2-6C alkyn-1-yl, 2-6C alken-1-yl, NH 2, 1-3C alkylamino, di-(1-3C 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-(1-3C alkyl)piperazin-1-yl, (hetero)arylcarbonylamino, NO 2, 3-10C cycloalkyloxy, 5-10C cycloalkenyloxy, 3-10C cycloalkylsulfanyl, 3-10C cycloalkylsulfinyl, 3-10C cycloalkylsulfonyl, 5-10C cycloalkenylsulfanyl, 5-10C cycloalkenylsulfinyl, 5-10C cycloalkenyl-sulfonyl, (hetero)arylsulfanyl or (hetero) arylsulfinyl (while the above-mentioned alkynyl and alkenyl groups optionally mono- or polysubstituted by F or Cl 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 mono- or disubstituted optionally of one another by substituents of F or 1-3C alkyl and in the above-mentioned cycloalkyl and cycloalkenyl rings one or two methylene groups may be replaced of one another by O, S, CO, SO, SO 2 or NR-N); 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 : |
