Patent DE-10251927-A1 (DE)
Title: New 1,7,8-trisubstituted xanthine derivatives, are dipeptidylpeptidase-IV inhibitors useful e.g. for treating diabetes mellitus type I or II, arthritis or obesity
Inventor: HIMMELSBACH FRANK
IPC: C07D519/00
Filed: 2002-11-08
Abstract: 1-(Benzoheterocyclyl-alkyl)-7-alkyl-8-(N-containing heterocyclyl, amino-cycloalkyl or aminoalkyl)-xanthine derivatives (I) are new.  Xanthine derivatives of formula (I) and their tautomers, enantiomers, diastereomers (or mixtures), prodrugs and salts are new.  R1  =  -T-Ra;  T  =  1-3C alkyl;  Ra  =  e.g. 5-oxo-4,5-dihydro-benzo-(f)(1,3,4)-oxadiazepinyl; 11H-dibenz-(b,e)-azepinyl or 5H-dibenzo-(a,d)-cycloheptenyl (both optionally having a CH in the heterocycle replaced by S, O, CO, SO, SO2 or NRx); or phenanthridinyl, 1,2,3,4-tetrahydro-phenanthridinyl, 5H-dibenzo-(d,f)(1,3)-diazepinyl, 5H-benzo-(e)-pyrrolo-(1,2-a)(1,4)-diazepinyl, thieno-(3,2-b)(1,4)-benzoxazepinyl or 3-oxo-2,3-dihydro-isoindol-1-ylene; where all Ra groups are substituted by R10 - R13 (and optionally also by T) and optionally have 1-3 CH in the benzo ring replaced by N;  Rx  =  H, alkyl, 2-4C alkenyl, 2-4C alkynyl, cycloalkyl, -T-cycloalkyl, Ar or -T-Ar; 2-4C alkyl substituted by OH, OT, cycloalkoxy, NH2, NHT or NT2; COT, COOT, -T-COOT, COAr, SO2T or SO2Ar;  R10  =  e.g. H, halo, alkyl, Ar-SO2NH-, Ar-T-SO2NH-, -NT-COT, -NT-COAr, -NT-CO-T-Ar, -NT-COOT, N(T)CONH2, N(T)CONHT, N(T)CONT2, NTSO2T, NTSO2Ar or NTSO2-T-Ar; 2-oxo-imidazolidino;  R11, R12  =  H, halo, T, CF3, OH, OT or CN;  or R11 + R12  =  OCH2O, OCF2O or 3-5C n-alkylene (bonded to adjacent C);  R13  =  H, F, Cl, Br, T, CF3 or OT;  R2  =  e.g. H, cycloalkyl, -T-cycloalkyl, tetrahydrofuran-3-yl, tetrahydropyran-(3 or 4)-yl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, Ar, Ar-alkyl, Ar-(2-3C) alkenyl, ArCO-(1-2C) alkyl, Het-T-, furanyl-COCH2-, thienyl-COCH2-, thiazolyl-COCH2-, pyridyl-COCH2-, alkylcarbonyl-(1-2C) alkyl, Ar-A-T- or Rb-substituted alkyl;  A  =  O, S, NH, NT, SO or SO2;  Rb  =  CN, COOH, COOT, CONH2, CONHT, CONT2, -CO-pyrrolidino, -CO-piperidino, -CO-morpholino, -CO-piperazino, CO-(N-(methyl or ethyl)-piperazino) or 2-4C alkyl substituted (but not in the 1-position) by Rc;  Rc  =  OH, OT, NH2, NHT, NT2, pyrrolidino, piperidino, -morpholino, piperazino or N-(methyl or ethyl)-piperazino;  R3  =  3-8C alkyl or -T-Rd;  R4  =  azetidino or pyrrolidino, substituted in the 3-position by R19 and os by 1 or 2 T; piperidino or homopiperidino, substituted in the 3- or 4-position by R19 and os by 1 or 2 T; 3-amino-piperidino, ring-substituted by CONH2, mono- or di-(1-2C alkyl)-carbamyl, pyrrolidino-CO-, 2-cyano-pyrrolidino-CO-, thiazolidino-CO-, 4-cyano-thiazolidino-CO-, piperidino-CO- or morpholino-CO-; 3-amino-(4 or 5)-(hydroxy or methoxy)-piperidino; 3-amino-(2 or 6)-oxo-piperidino; piperidino or homopiperidino, substituted in the 3-position by R19 and carrying an alkylene bridge of 2-5C if bonded to the same C, 1-4C if bonded to adjacent C's or C's separated by one atom or 1-3C if bonded to C's separated by 2 atoms; azetidino, pyrrolidino, piperidino or homopiperidino substituted by -T-R19; piperazino, homopiperazino, 3-imino-piperazino, 3-imino-homopiperazino or 5-imino-homopiperazino (all os on C by 1 or 2 T); 6-amino-homopiperazino (os by 1 or 2 T); Cyc, Cyc-(1-2C) alkyl, Cyc-NH-, Cyc-NT-, Cyc-(1-2C) alkyl-NH- or Cyc-(1-2C) alkyl-NT-; R19-(2-4C) alkyl-NH- or R19-(2-4C) alkyl-NT- (in which R19 is separated from the amino N by at least 2C); NHR20, N(T)R20, R19-(3-4C)-n-alkyl (os in the alkyl by 1 or 2 T), 3-amino-2-oxo-piperidin-5-yl or 3-amino-2-oxo-1-methyl-piperidin-5-yl; pyrrolidin-3-yl, piperidin-(3 or 4)-yl or homopiperidin-(3 or 4)-yl, all substituted in the 1-position by R19; or azetidin-(2 or 3)-yl(m)ethyl, pyrrolidin-3-yl, pyrrolidin-(2 or 3)-yl(m)ethyl, piperidin-(3 or 4)-yl or piperidin-(2, 3 or 4)-yl(m)ethyl (all os by 1 or 2 T);  Rd = 3-7C cycloalkyl or 3-7C cycloalkenyl (both os by 1 or 2 T); aryl; furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl (all os by one or 2 T or by halo, CF3 CN, or OT); 3-8C alkenyl, 3-6C alkenyl (os by F, Cl, Br or CF3), alkynyl, aryl or aryl-2-4C alkenyl; Cyc  =  3-7C cycloalkyl ring-substituted by R19 or -T-R19; provided that in Cyc-NH- or Cyc-NT- substituted