Patent DE-102004054603-A1 (DE)
Title: New D-xylopyranosyl-substituted phenyl compounds are sodium-dependent glucose cotransporter inhibitors useful to prevent or treat e.g. diabetes mellitus, complications of diabetes, metabolic acidosis or ketosis
Inventor: ECKHARDT MATTHIAS
IPC: C07H7/06
Filed: 2004-11-11
Abstract: D-Xylopyranosyl-substituted phenyl compounds (I) and tautomers and/or stereoisomers and salts are new. D-Xylopyranosyl-substituted phenyl compound of formula (I) and tautomers and/or stereoisomers and salts are new. either R1 : H, F, Cl, Br, 1-6C alkyl, 2-6C alkynyl, 2-6C alkenyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C-alkyl, 5-7C cycloalkenyl, 5-7C cycloalkenyl-1-3C alkyl, 1-4C alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, 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, 1-4C alkoxycarbonyl, amino, 1-4C alkylamino, di-(1-3C alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-(1-4C alkyl)piperazin-1-yl, 1-4C alkylcarbonylamino, 1-6C alkyloxy, 3-7C cycloalkyloxy, 5-7C cycloalkenyloxy, aryloxy, 1-4C alkylsulfanyl, 1-4C alkylsulfinyl, 1-4C alkylsulfonyl, 3-7C cycloalkylsulfanyl, 3-7C cycloalkylsulfinyl, 3-7C cycloalkylsulfonyl, 5-7C cycloalkenylsulfanyl, 5-7C cycloalkenylsulfinyl, 5-7C cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, OH, CN or NO 2 (where the alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl partly or completely fluorinated or mono- or disubstituted by identical or different substituents of Cl, OH, 1-3C alkoxy or 1-3C alkyl; in cycloalkyl and cycloalkenyl, 1-2 methylene is replaced by O, S, CO, SO or SO 2 and in N-heterocycloalkyl, a methylene is replaced by CO or SO 2); R2 : H, F, Cl, Br, OH, 1-4C alkyl (mono- or polysubstituted by F), 1-4C-alkoxy, CN or NO 2; R3 : R1, (hetero)aryl or heteroaryloxy; and R4, R5 : H, F, Cl, Br, I, CN, NO 2, 1-3C alkyl or 1-3C alkoxy (methyl or methoxy substituted by 1-3F); or CR1R2, CR3R4 : phenyl ring; or R1R2, R3R4 : 3-5C alkylene or 3-5C alkenylene bridge, which may be partly or totally fluorinated or mono- or disubstituted by Cl, OH, 1-3C alkoxy or 1-3C alkyl and where 1-2 methylene groups are replaced by O, S, CO, SO, SO 2 or N-Rb; Rb : H or 1-4C alkyl; L : F, Cl, Br, I, 1-3C alkyl, CF 2, CF 3, 1-3C alkoxy, OCF 2, OCF 3 or CN; R7a, R7b, R7c : H, (1-8C alkyl)carbonyl, (1-18C alkyl)oxycarbonyl, arylcarbonyl or aryl-(1-3C alkyl)-carbonyl; X : H, 1-6C alkyl, 2-6C alkynyl, 2-6C alkenyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkyl, 5-7C cycloalkenyl (1-3C alkyl), aryl(1-3C alkyl), heteroaryl(1-3C alkyl), 1-4C alkylcarbonyl, arylcarbonyl, aminocarbonyl, 1-4C alkylaminocarbonyl, di-(1-3C-alkyl)aminocarbonyl, (aryl-1-3C-alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, hydroxycarbonyl, 1-4C alkoxycarbonyl, 1-4C alkylcarbonylamino-1-3C alkyl, N-(1-4C alkylcarbonyl)-N-(1-3C-alkyl)-amino-1-3C-alkyl, arylcarbonylamino-1-3C alkyl, 1-4C alkylsulfonylamino-1-3C alkyl, arylsulfonylamino-1-3C alkyl, 1-6C alkoxy-1-3C alkyl, 3-7C cycloalkyloxy-1-3C alkyl, 5-7C-cycloalkenyloxy-1-3C alkyl, aryloxy-1-3C-alkyl, heteroaryloxy-1-3C-alkyl, 1-4C alkylsulfanyl-1-3C-alkyl, 1-4C alkylsulfinyl-1-3C alkyl, 1-4C alkylsulfinyl, 1-4C alkylsulfonyl, 1-4C alkylsulfonyl-1-3C alkyl, 1-4C arylsulfanyl-1-3C alkyl, arylsulfonyl-1-3C alkyl, aryl-1-3C alkyl-sulfonyl-1-3C alkyl, 1-4C alkylsulfonyloxy- 1-3C alkyl, arylsulfonyloxy-1-3C alkyl, aryl-1-3C-alkyl-sulfonyloxy-1-3C alkyl, 3-7C-cycloalkylsulfanyl-1-3C alkyl, 3-7C-cycloalkylsulfinyl, 3-7C-cycloalkylsulfonyl, 5-7C-cycloalkenylsulfanyl-1-3C alkyl, 5-7C-cycloalkenylsulfinyl, 5-7C-cycloalkenylsulfonyl, 1-4C alkylcarbonylsulfanyl-1-3C alkyl or CN (where the alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl partly or totally fluorinated or mono- or disubstituted by Cl, CN, OH, mercapto, 1-3C alkoxy or 1-3C alkyl; and in cycloalkyl or cycloalkenyl, 1-2 methylene groups are replaced by O, S, CO, SO or SO 2; and in N-heterocycloalkyl, methylene is replaced by CO or SO 2); and Z : O, methylene, dimethylmethylene, difluoromethylene or carbonyl. Provided that X representing hydroxymethyl group is excluded and where the aryl represents phenyl or naphthyl optionally mono- or disubstituted by L; the heteroaryl (optionally mono- or disubstituted by groups L) represents pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl or pyrrolyl, furanyl, thienyl, pyridyl or imidazolyl (where 1-2 methyne groups are replaced by N) or indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl (where 1-3 methyne groups are replaced by N); the N-heterocycloalkyl is saturated carbocyclic ring which comprises an imino group in the ring, which may comprise another optionally substituted imino group or an O or S atom in the ring. Independent claims are also included for: (1) a pharmaceutical composition containing (I) optionally together with one or more inert carriers and/or diluents; and (2) preparations of (I). [Image] ACTIVITY : Antidiabetic; Vasotropic; Antilipemic; Antiarteriosclerotic; Anorectic; Hypotensive; Cardiant; Antiinflammatory. MECHANISM OF ACTION : Sodium-dependent glucose cotransporter (SGLT) inhibitor. The ability of (I) to inhibit SGLT was assessed using CHO-K1 cell lines. The results showed that median effective concentration (EC 50) value of (I) was less than 1000 (preferably less than 50) nM.