Patent DE-10254092-A1 (DE)
Title: New pyrimidine-4,6-dicarboxamide derivatives, are selective collagenase inhibitors useful e.g. for treating degenerative joint diseases, connective tissue disorders or cancer
Inventor: KLINGLER OTMAR
IPC: C07D239/28
Filed: 2002-11-20
Abstract: Pyrimidine-4,6-dicarboxylic acid 4-benzylamide 6-(substituted alkyl)-amide compounds (I) are new.  Pyrimidine derivatives of formula (I) (including all stereoisomeric forms and their mixtures in any ratio) and their salts are new.  R1  =  H or alkyl;  R2  =  alkyl, substituted by 1-3 groups R2a;  R2a  =  aryloxyalkyl; -R-N(R8)-COO-alkyl; -CONR9R10; aryl substituted by 1-3 groups R2b; -CO-NR8-R-Ar''; -CO-NR8-R-Het'; -NH-Ar''; or -NH-Het'';  R  =  direct bond or alkylene;  R8  =  H, alkyl (optionally substituted (os) by 1-3 of NH2, CN, OH, COOH, alkoxycarbonyl, CONHOH, NO2 or halo) or OH;  R9, R10  =  H or alkyl; or NR9R10  =  5-7 membered saturated ring, optionally containing 1 or 2 additional O, S, NH or N(alkyl) heteroatom(s);  R2b  =  -R-COOR8, -R-CONR9R10, -R-CONHCN, -R-CO-R-Het, -R-CO-R-OH, -O-R-CONR9R10, -S(O)y-alkylene-COOR8, -S(O)z-alkylene-CONR9R10, -R-CO-NR8-R-NR9R10, -R-CO-NR8-R-Het, -R-CO-NR8-R-Ar, -R-NR9R10, -(CH2)y-NR8-CO-Alk, -R'-NR8-CO-R-Ar, -R'-NR8-CO-R-Het, -R'-NR8-CO-O-Alk', -R'-NR8-CO-O-R-Ar, -R'-NR8-CO-O-R-Het, -R'-NR8-CO-R-NR11R12, -R'-NR8-SO2-R-Ar, -R'-NR8-SO2-R-Het, -R'-NR8-SO2-NR8-Alk, -R'-NR8-SO2-NR8-R-Ar, -R'-NR8-SO2-NR8-R-Het, -R'-NR8-CO-NR8-SO2-R13, -R'-SO2-NR8-R-Ar, -R'-SO2-NR8-R-Het, -R'-SO2-NR8-R-Alk, -R'-SO2-R-Ar, -R'-SO2-R-Het, -O-R-Het, -R'-Het or phenyl (os by 1-3 of halo, alkyl, alkoxy or SO2R16);  Het  =  saturated or unsaturated, mono- or bicyclic, 3-10 membered heterocyclic ring system, containing 1-3 of N, O and/or S as heteroatom(s)and os by 1-3 groups Q;  Q  =  halo, CN, NO2, OH, NH2, alkoxycarbonyl, COOH, alkyl (os by 1-3 halo), alkoxy (os by 1-3 of halo or NR9R10), =O, Het, alkenyl (os by 1-3 of halo or NR9R10) or alkynyl (os by 1-3 of halo or NR9R10);  y  =  1 or 2;  z  =  0-2;  Ar  =  aryl (os by 1-3 groups Q);  Alk  =  alkyl (os by 1-3 groups Q);  R'  =  direct bond or 1-4C alkylene;  Alk'  =  alkyl, alkenyl or alkynyl (all os by 1-3 groups Q);  R11, R12  =  H, alkyl, -R-Ar, -R-Het, -CO-Alk, -CO-Cyc, -CO-R-Ar, -CO-R-Het, -SO2-Alk, -NH-SO2-Alk, -SO2-R-Ar, -SO2-R-Ar'-alkyl or -SO2-R-Het;  Cyc  =  3-6C cycloalkyl (os by 1-3 groups Q);  Ar'  =  arylene (os by 1-3 groups Q);  R13  =  alkyl, aryl or arylalkyl;  R16  =  alkyl or NH2;  Ar''  =  aryl (os by 1-3 of R2b or Q);  R3 - R7  =  H, halo, alkyl (os by 1-3 halo), alkoxy (os by 1-3 halo) or alkylthio; or R4 + R5 or R5 + R6  =  group completing a 5- or 6-membered saturated or aromatic ring, optionally containing 1 or 2 N, O and/or S heteroatom(s) and os by 1 or 2 halo; or alternatively  R2'  =  alkyl substituted by 1-3 groups R2c;  R2c  =  -COOR'8; -alkylene-OR'8; aryl substituted by 1-3 groups R2d; or Het'';  R'8  =  H or alkyl;  R2d  =  -(2-6C) alkylene-COOR'8, -O-alkylene-COOR'8, -NR14R15, -(CH2)k-NR9R10, -O-(2-6C) alkylene-NR9R10, -NR'8-CO-alkyl (os in the alkyl by 1-3 of halo, CN, NO2, OH, NH2, alkoxycarbonyl or COOH) or phenyl (os by 1-3 of halo, alkyl, alkoxy or SO2R16);  Het''  =  as for Het, but where the optional substituents are selected from halo, CN, NO2, OH, NH2, alkylcarbony, COOH, alkyl (os by 1-3 halo), alkoxy (os by 1-3 halo), pyridyl or phenyl (os by one or more of halo, alkoxy and alkyl);  R3, R7 and the other of R4 and R6  =  H (provided that an unsubstituted benzo-(1,3)-dioxole ring is excluded).  Unless specified otherwise alkyl or alkylene moieties have 1-6C, alkenyl or alkynyl moieties 2-6C and aryl or arylene moieties 6-14C.  An Independent claim is included for the preparation of (I).