US 2006.0035.841A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0035841A1 Eckhardt et al. (43) Pub. Date: Feb. 16, 2006 (54) D-XYLOPYRANOSYL-PHENYL-SUBSTITUTED Publication Classification CYCLES, MEDICAMENTS CONTAINING SUCH COMPOUNDS, THEIR USE AND (51) Int. Cl. PROCESS FOR THEIR MANUFACTURE C07H 5/04 (2006.01) A61K 31/7052 (2006.01) (75) Inventors: Matthias Eckhardt, Biberach (DE); (52) U.S. Cl. ............................................. 514/23: 536/18.7 Frank Himmelsbach, Mittelbiberach (DE); Peter Eickelmann, (57) ABSTRACT Mittelbiberach (DE); Leo Thomas, Biberach (DE); Edward Leon A D-Xylopyranosyl-phenyl-Substituted cycle compound of Barsoumian, Toyonaka (JP) general formula I Correspondence Address: MICHAEL P. MORRIS BOEHRINGER INGELHEM CORPORATION 900 RIDGEBURY ROAD P. O. BOX 368 RIDGEFIELD, CT 06877-0368 (US) (73) Assignee: Boehringer Ingelheim International GmbH, Ingelheim (DE) (21) Appl. No.: 11/199,962 (22) Filed: Aug. 9, 2005 wherein the groups R to R, Z, X, Cy and R', R7 and R' (30) Foreign Application Priority Data are defined as in claim 1, have an inhibiting effect on the Sodium-dependent glucose cotransporter SGLT. The present Aug. 11, 2004 (DE)........................... DE 102004O39096 invention also relates to pharmaceutical compositions for the Sep. 23, 2004 (DE)........................... DE 102004O46583 treatment of metabolic disorders. US 2006/0035.841 A1 Feb. 16, 2006 D-XYLOPYRANOSYL-PHENYL-SUBSTITUTED 0007. The invention also relates to a process for prepar CYCLES, MEDICAMENTS CONTAINING SUCH ing the compounds according to the invention. COMPOUNDS, THEIR USE AND PROCESS FOR 0008 Further aims of the present invention will imme THEIR MANUFACTURE diately become apparent to the skilled man from the remarks RELATED APPLICATIONS above and hereinafter. 0001. The present application claims the benefit of DE 102004039096 filed Aug. 11, 2004 and OBJECTS OF THE INVENTION DE102004046583 filed Sep. 23, 2004. The contents of both applications are incorporated herein. 0009. In a first aspect the invention relates to D-xylopy ranosyl-phenyl-Substituted cycles of general formula I THE INVENTION 0002 The present invention relates to D-xylopyranosyl phenyl-Substituted cycles of general formula I wherein - denotes a Single or double bond, and wherein the groups R to R', Z, X, Cy and R', R" and R' 0010 X denotes hydrogen, C-alkyl, C-alkynyl, C are as hereinafter defined, including the tautomers, the alkenyl, Co-cycloalkyl, Co-cycloalkyl-C-3-alkyl, stereoisomers, the mixtures thereof and the Salts thereof. The Cs-o-cycloalkenyl, C-3-cycloalkenyl-C-3-alkyl, aryl, invention further relates to pharmaceutical compositions aryl-C-alkyl, heteroaryl, heteroaryl-C-alkyl, C containing a compound of formula I according to the inven alkylcarbonyl, arylcarbonyl, aminocarbonyl, aminocarbo tion as well as the use of a compound according to the nyl-C-alkyl, C-alkylaminocarbonyl, C-alkylami invention for preparing a pharmaceutical composition for nocarbonyl-C-alkyl, di-(C-alkyl)aminocarbonyl, the treatment of metabolic disorders. The invention also di-(C-alkyl)-aminocarbonyl-C-alkyl, pyrrolidin-1- relates to processes for preparing a pharmaceutical compo ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbo Sition and a compound according to the invention. nyl, hydroxycarbonyl, hydroxycarbonyl-C-alkyl, C 0.003 Compounds which have an inhibitory effect on the alkoxycarbonyl, C-alkoxycarbonyl-C-alkyl, C Sodium-dependent glucose cotransporter SGLT are proposed alkylcarbonylamino-C-alkyl, N-(C- in the literature for the treatment of diseases, particularly alkylcarbonyl)-N-(C-alkyl)-amino-C-alkyl, diabetes. arylcarbonyl-amino-C-alkyl, C-alkylsulphony lamino-C-alkyl, arylsulphonylamino-C-alkyl, Co 0004 Glucopyranosyl-substituted aromatic groups and alkoxy-C-alkyl, Co-cycloalkyloxy-C-3-alkyl, the preparation thereof and their possible activity as SGLT2 Cs-ocycloalkenyl-oxy-C-3-alkyl, aryloxy-C-3-alkyl, inhibitors are known from published International Patent heteroaryloxy-C-alkyl, C-alkylsulphanyl-C-alkyl, Applications WO 98/31697, WO 01/27128, WO 02/083066, C-alkylsulphinyl, C-alkylsulphonyl, C-alkylsul WO 03/099836, WO 2004/063209, WO 2004/080990, WO phinyl-C-alkyl, C-alkylsulphonyl-C-alkyl, aryl 2004/013118, WO 2004/052902, WO 2004/052903, WO Sulphanyl-C-alkyl, arylsulphonyl-C-alkyl, aryl-C- 05/12326 and US application US 2003/0114390. alkyl-Sulphonyl-C-alkyl, C-alkylsulphonyloxy-C- AIM OF THE INVENTION alkyl, arylsulphonyloxy-C-alkyl, aryl-C-alkyl 0005 The aim of the present invention is to indicate new Sulphonyloxy-C-alkyl, Co-cyclo-alkylsulphanyl-C- pyranosyl-Substituted phenyls, particularly those which 3-alkyl, Co-cycloalkylsulphinyl, Cs-10 have an effect on Sodium-dependent glucose cotransporter cycloalkylsulphinyl-C-alkyl, C3-1o SGLT, particularly SGLT2. A further aim of the present cycloalkylsulphonyl, Co-cycloalkylsulphonyl-C- invention is to indicate pyranosyl-Substituted phenyls which, alkyl, Cso-cycloalkenylsulphanyl-C-alkyl, by comparison with known Structurally similar compounds, cycloalkenylsulphinyl, Cso-cycloalkenyl-Sulphinyl-C- have a greater inhibitory effect on the Sodium-dependent 3-alkyl, Co-cycloalkenylsulphonyl, glucose cotransporter SGLT2 in vitro and/or in vivo and/or cycloalkenylsulphinyl-C-alkyl, bromomethyl, have improved pharmacological or pharmacokinetic prop iodomethyl or cyano, erties. while alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl 0006 Moreover the present invention also sets out to groups may be partly or totally fluorinated or mono- or prepare new pharmaceutical compositions which are Suit disubstituted by identical or different substituents selected able for the prevention and/or treatment of metabolic dis from chlorine, cyano, hydroxy, mercapto, C-alkoxy and orders, particularly diabetes. C-alkyl, and US 2006/0035.841 A1 Feb. 16, 2006 in cycloalkyl and cycloalkenyl groups one or two methylene rine, hydroxy, C-alkoxy and C-alkyl and wherein groups may be replaced independently of one another by one or two methylene groups may be replaced indepen O, S, CO, SO or SO, and dently of one another by O, S, CO, SO, SO or NRS, and in N-heterocycloalkyl groups a methylene group may be wherein in the case of a butadienylene bridge one or two replaced by CO or SO, and methyne groups may be replaced by an N atom, and 0.015 R denotes hydrogen, fluorine, chlorine, bromine, X representing hydroxymethyl is preferably excluded, C6-alkyl, C2-alkynyl, C2-alkenyl, Co-cycloalkyl, 0.011) Cy denotes a 5- or 6-membered Saturated or Co-cycloalkyl-C-alkyl, Cso-cycloalkenyl, Cso monounsaturated carbocyclic ring, which may comprise cycloalkenyl-C-alkyl, aryl, heteroaryl, aryl-C-alkyl, one, two or three heteratoms Selected independently of heteroaryl-C-alkyl, C-alkylcarbonyl, arylcarbonyl, one another from N, O and S, and heteroarylcarbonyl, aminocarbonyl, C-alkylaminocar bonyl, di-(C-alkyl)aminocarbonyl, pyrrolidin-1-ylcar is substituted by R", RandR through a single bond and by bonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, R through a single or double bond, and piperazin-1-ylcarbonyl, 4-(C-alkyl)piperazin-1-ylcar wherein one or two methylene groups may be replaced by bonyl, hydroxycarbonyl, C-alkoxycarbonyl, aryl-C- CO or a Sulphanyl group by SO or SO, and alkoxycarbonyl, C-alkylamino, di-(C-alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piper wherein additionally one or more H atoms bound to carbon azin-1-yl, 4-(C-alkyl)piperazin-1-yl, C-alkylcarbo may be replaced by fluorine, nylamino, arylcarbonylamino, heteroarylcarbonylamino, 0012 Z denotes -O-, -CH-, -CH=, -NRN-, C-alkylsulphonylamino, arylsulphonylamino, C.- CO-, -S-, -SO- or SO-, while H atoms of the alkoxy, Co-cycloalkyloxy, Cs-o-cycloalkenyloxy, ary methylene or methanylylidene bridge may be Substituted loxy, heteroaryloxy, C-alkylsulphanyl, C-alkylsul independently of one another by CH or F; phinyl, C-alkylsulphonyl, Co-cycloalkylsulphanyl, 0013) R' denotes hydrogen, fluorine, chlorine, bromine, Co-cycloalkylsulphinyl, Co-cycloalkylsulphonyl, iodine, C6-alkyl, C6-alkynyl, C2-alkenyl, Co-cy Cso-cycloalkenylsulphanyl, Cso-cycloalkenylsulphi cloalkyl, Co-cycloalkyl-C-3-alkyl, Cs-o-cycloalkenyl, nyl, Cso-cycloalkenylsulphonyl, arylsulphanyl, arylsul Co-cycloalkenyl-C-alkyl, C-alkylcarbonyl, aryl phinyl, arylsulphonyl, amino, hydroxy, cyano or nitro, carbonyl, heteroarylcarbonyl, aminocarbonyl, C-alky while alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl laminocarbonyl, di-(C-alkyl)aminocarbonyl, pyrroli groups may be partly or totally fluorinated or mono- or din-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4- disubstituted by identical or different substituents selected ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C- from chlorine, hydroxy, C-alkoxy and C-alkyl, and alkyl)piperazin-1-ylcarbonyl, C-alkoxycarbonyl, amino, C-alkylamino, di-(C-alkyl)amino, pyrroli in cycloalkyl and cycloalkenyl groups one or two methylene din-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, groups may be replaced independently of one another by 4-(C-alkyl)piperazin-1-yl, C-alkylcarbonylamino, O, S, CO, SO or SO, and C6-alkyloxy, Co-cycloalkyloxy, Cso-cycloalkeny in N-heterocycloalkyl groups a methylene group may be loxy, aryloxy, C-alkylsulphanyl, C-alkylsulphinyl, replaced by CO or SO, or C-alkylsulphonyl, Co-cycloalkylsulphanyl, Co cycloalkylsulphinyl, Co-cycloalkylsulphonyl, Co R denotes a group Y connected to Cy through a double cycloalkenylsulphanyl, Co-cycloalkenylsulphinyl, bond, Co-cycloalkenylsulphonyl,