Patent FR-2831537-A1 (FR)
Title: Composition useful for treating inflammatory disease, cancer, chronic obstructive pulmonary disease, asthma, allergic rhinitis, or atopic dermatitis comprises benzimidazoles derivatives
Inventor: BABIN FABIENNE
IPC: C07D487/04
Filed: 2001-10-26
Abstract: A composition comprises benzimidazoles (I) and their analogs.  A composition comprises benzimidazoles of formula (I), their analogs, N-oxide, prodrug, acid bioisostere, salt or solvate.  X = C-R2;  W, Y and Z = CH or CR3;  A5 = H or alkyl;  R1 = (hetero)aryl (optionally substituted by at least one carboxy, cyano, halo, haloalkyl, OH, nitro, R4, -C(=O)R4, -C(=O)NY1Y2, -C(=O)OR4, -N(R6)C(=O)R4, -N(R6)C(=O)NY1Y2, -N(R6)C(=O)OR4, -N(R6)SO2R4, -N(R6)SO2NY1Y2, -NY1Y2, -OR4, -OCF2H, -OCF3, -OC(=O)R4, -OC(=O)NY1Y2, -OS(O)nR4, -S(O)nR4, -S(O)nNY1Y2 or -S(O)nOR4; R2 and R3 = T1;  T1 = H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4, -C(=O)R4, -C(=O)NY1Y2, -C(=O)OR4, -NY1Y2, -N(R6)C(=O)R4, -N(R6)C(=O)NY1Y2, -N(R6)C(=O)OR4, -N(R6)SO2R4, -N(R6)SO2NY1Y2, -OR4, -OCF2H, -OCF3, -OC(=O)R4, -OC(=O)NY1Y2, -S(O)nR4, -S(O)nNY1Y2 or -S(O)nOR4;  R2+R3 = 5 - 6 membered carbon-based ring (containing at least one O, N or S and optionally substituted by alkyl);  R4 = alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl or (hetero)aryl (all optionally substituted by at least one (hetero)aryl, (cyclo)alkyl, heterocycloalkyl, halo, OH, hydroxyalkyl, -C(=O)NY3Y4, -C(=O)OR6, -N(R6)C(=O)NY1Y2, -NY1Y2, -OR5 or alkyl substituted by -NY3Y4);  R5 and R6  = alkyl, alkenyl, (hetero)aryl, (hetero)arylalkyl, (hetero)cycloalkyl or (hetero)cycloalkylalkyl;  n = 0 - 2;  Y1 and Y2 = alkyl (optionally substituted by at least one CN, (hetero)aryl, hydroxy, -C(=O)OR6, -C(=O)NY3Y4, -NY3Y4 or -OR5), H, alkenyl, (hetero)aryl, (hetero)cycloalkyl, heterocycloalkylalkyl;  NY1Y2 and NY3Y4 = cyclic amine; and Y3 and Y4 = H, alkenyl, (cyclo)alkyl, (hetero)aryl or (hetero)arylalkyl. The following combinations of W, X, Y and Z are also cliamed: (a) when W is CH; X is N; Y is CH or CH3; then Z is CH or CR3;  (b) when W is N; X is CH or CR2; Y is CH or CR3; then Z is CH or CR3;  (c) when W is N; X is CH or CR2; Y is N; then Z is CH or CR3;  (d) when W is N; X is CH or CR2; Y is CH or CR3; then Z is N; and  (e) when W is N; X is N; Y is CH or CR3; then Z is CH or CR3. Provided that when R2 is T1, then R3 is alkyl, haloalkyl, halo or OR6. The alkyl, alk, alkenyl, (hetero)cycloalkyl, (hetero)aryl or (hetero)arylalkyl are optionally substituted by at least one halo, OH, cyano, alkyl, alkoxy, acylamino (NH-COalk), -C(=O)OR6, -C(=O)R6, hydroxyalkyl, carboxyalkyl, S(O)n-alk, S(O)nNH2, S(O)nNH(alk), S(O)nN(alk)2, CF3, OCF3, NO2, arylalkoxy, (hetero)aryl, aryloxy, aryloxyalkyl, -C(=O)-NY3Y4 or NY3Y4 (where alkyl or (hetero)aryl are optionally substituted by at least one halo, alkyl, acylamino radical (NH-C(O)R5), or free, salified or esterified carboxyl radicals).  Independent claims are included for the following:  (1) preparation of (I); and  (2) use of (I) in the manufacture of medicinal product for inhibiting the activity of kinase protein (preferably tyrosine kinase protein, especially FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-IR, KDR, PDGFR, tie2 or VEGFR).