2,4-PYRIMIDINEDIAMINES USEFUL IN THE TREATMENT OF NEOPLASTIC DISEASES, INFLAMMATORY AND IMMUNE SYSTEM DISORDERS
Novel pyrimidine derivatives of formula I to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.
1 . A compound of formula I
wherein
each of R 0 , R 1 , and R 2 independently is hydrogen, —S(O) 0-2 NR 12 R 13 , —S(O) 0-2 R 13 , —NR 12 S(O) 0-2 R 13 or —C(O)NR 12 R 13 ;
R 3 is —S(O) 0-2 NR 12 R 13 or —NR 12 S(O) 0-2 R 13 ;
wherein R 12 is selected from hydrogen and C 1-6 alkyl; and R 13 is selected from hydrogen, C 1-6 alkyl and C 3-12 cycloalkyl;
R 4 is hydrogen;
each of R 5 and R 6 independently is hydrogen or halogen;
each of R 7 , R 8 , R 9 , and R 10 independently is ethoxy, ethyl, propyl, t-butyl, trifluoromethyl, nitrile, cyclobutyloxy, 2,2,2-trifluoroethoxy, isobutyloxy, t-butyloxy, isopropyloxy, methyl-amino-carbonyl, cyclopropyl-methoxy, dimethylamino-propyl-amino, methoxy-ethoxy, —XR 11 , —C(O)R 11 or —OXR 11 ; wherein X is a bond, methylene or ethylene; R 11 is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, azepanyl and 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl; wherein R 11 is optionally substituted by 1 to 3 radicals independently selected from methyl, isopropyl, acetyl, acetyl-methyl-amino, 3-dimethylamino-2,2-dimethyl-propylamino, ethyl-methyl-amino-ethoxy, diethyl-amino-ethoxy, amino-carbonyl, ethyl, 2-oxo-pyrrolidin-1-yl, pyrrolidinyl, pyrrolidinyl-methyl, piperidinyl optionally substituted with methyl or ethyl, morpholino, dimethylamino, dimethylamino-propyl-amino, methyl-amino and ethyl-amino;
wherein one of R 7 , R 8 and R 9 independently of each other can also be hydrogen; and
A is C; or
salts thereof;
with the proviso that said compound of Formula (I) is not
wherein Rx is
2 . The compound of claim 1 , wherein
each of R 0 or R 2 independently is hydrogen;
R 1 is hydrogen; and
R 3 is selected from dimethyl-sulfamoyl, isobutyl-sulfamoyl, methyl-sulfamoyl, ethyl-sulfamoyl, 1-ethyl-propyl-sulfamoyl, cyclopentyl-sulfamoyl, isopropyl-sulfamoyl, cyclopropyl-methyl-sulfamoyl or cyclobutyl-sulfamoyl.
3 . A pharmaceutical composition comprising a compound according to claim 1 , as active ingredient together with one or more pharmaceutically acceptable diluents or carriers.
4 . A combination comprising a therapeutically effective amount of a compound according to claim 1 and one or more further known drug substances, said further drug substance being useful in the treatment of neoplastic diseases or immune system disorders.
5 . A method for the treatment of breast tumor in a subject in need thereof which comprises administering an effective amount of a compound according to claim 1 .
6 . A compound of Formula I′
in which:
n′ is selected from 1 and 2;
R′ 1 is selected from pyridinyl, pyrazolyl and pyrimidinyl; each of which is substituted by 1 to 3 radicals independently selected from ethoxy, ethyl, propyl, methyl, t-butyl, trifluoromethyl, nitrile, cyclobutyloxy, 2,2,2-trifluoroethoxy, isobutyloxy, t-butyloxy, isopropyloxy, methyl-amino-carbonyl, cyclopropyl-methoxy, dimethylamino-propyl-amino, methoxy-ethoxy, —X′R′ 4 , —C(O)R′ 4 and —OX′R′ 4 ; wherein X′ is a bond, methylene or ethylene; R′ 4 is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, azepanyl and 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl; wherein R′ 4 is optionally substituted by 1 to 3 radicals independently selected from methyl, isopropyl, acetyl, acetyl-methyl-amino, 3-dimethylamino-2,2-dimethyl-propylamino, ethyl-methyl-amino-ethoxy, diethyl-amino-ethoxy, amino-carbonyl, ethyl, 2-oxo-pyrrolidin-1-yl, pyrrolidinyl, pyrrolidinyl-methyl, piperidinyl optionally substituted with methyl or ethyl, morpholino, dimethylamino, dimethylamino-propyl-amino, methyl-amino and ethyl-amino.
R′ 2 is selected from hydrogen and halo; and
R 3 is selected from dimethyl-sulfamoyl, isobutyl-sulfamoyl, methyl-sulfamoyl, ethyl-sulfamoyl, 1-ethyl-propyl-sulfamoyl, cyclopentyl-sulfamoyl, isopropyl-sulfamoyl, cyclopropyl-methyl-sulfamoyl or cyclobutyl-sulfamoyl.
7 . A pharmaceutical composition comprising a compound according to claim 6 , as active ingredient together with one or more pharmaceutically acceptable diluents or carriers.
8 . A combination comprising a therapeutically effective amount of a compound according to claim 6 and one or more further known drug substances, said further drug substance being useful in the treatment of neoplastic diseases or immune system disorders.
9 . A method for the treatment of breast tumor in a subject in need thereof which comprises administering an effective amount of a compound according to claim 6 .