2,4-di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders
Novel pyrimidine derivatives of formula I to process for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.
1. A compound of formula I
each of R 0 or R 2 independently is hydrogen, C 1 -C 8 alkyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C 1 -C 8 alkoxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC 1 -C 8 alkoxy, unsubstituted or substituted amino, or halogen;
R 1 is hydrogen, C 1 -C 8 alkyl, haloC 1 -C 8 alkyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C 1 -C 8 alkoxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted HeterocyclylC 1 -C 8 alkoxy, unsubstituted or substituted amino, halogen;
R 3 is C 1 -C 8 alkylsulfinyl, C 1 -C 8 alkylsulfonyl, C 5 -C 10 arylsulfonyl, or unsubstituted or substituted carbamoyl;
R 4 is hydrogen;
R 5 is chloro or bromo;
R 6 is hydrogen;
each of R 7 and R 9 independently is hydrogen, C 1 -C 8 alkyl, haloC 1 -C 8 alkyl, unsubstituted or substituted C 5 -C 10 aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C 1 -C 8 alkoxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC 1 -C 8 alkoxy, unsubstituted or substituted amino, halogen, unsubstituted or substituted carbamoyl, or unsubstituted or substituted sulfamoyl;
R 8 is C 5 -C 10 aryl; unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S; C 5 -C 10 aryloxy; unsubstituted or substituted heterocyclyloxy; or unsubstituted or substituted heterocyclylC 1 -C 8 alkoxy; and
R 10 is C 1 -C 8 alkyl, haloC 1 -C 8 alkyl, C 1 -C 8 alkoxy, unsubstituted or substituted heterocyclylC 1 -C 8 alkoxy, unsubstituted or substituted amino, or halogen; and
A is C;
or salts thereof.
2. The compound of claim 1 , wherein each of R 0 , R 1 or R 2 is hydrogen.
3. The compound of claim 1 , wherein R 3 is C 1 -C 8 alkylsulfonyl, C 5 -C 10 arylsulfonyl or unsubstituted or substituted carbamoyl.
4. The compound of claim 1 , wherein R 3 is C 1 -C 8 alkylsulfonyl.
5. The compound of claim 1 , wherein R 3 is C 5 -C 10 arylsulfonyl.
6. The compound of claim 1 , wherein R 3 is unsubstituted or substituted carbamoyl.
7. The compound of claim 1 , wherein R 8 is piperidino, piperazino, N-methylpiperazino, morpholino, phenoxy, 1-methyl-4-piperidyloxy, 3-morpholinopropoxy, 2-morpholinoethoxy or 3-(N-methylpiperazino)-propoxy.
8. The compound of claim 1 , wherein R 8 is unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S.
9. The compound of claim 1 , wherein R 0 , R 1 or R 2 is hydrogen; R 3 is C 1 -C 8 alkylsulfonyl; and R 8 is unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S.
10. The compound of claim 9 , wherein R 8 is piperidino, piperazino, N-methylpiperazino or morpholino.
11. The compound of claim 1 , wherein said compound is selected from the group of compounds with the following names or formulae: 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl -phenylamino)-pyrimidin-4-ylamino]-N-methyl -benzamide;
a compound of the formula
wherein Rx has one of the meanings given in the following table:
Compound No.
Rx
7-1
7-2
7-3
7-4
7-5
7-7
7-8
7-9
7-10
7-11
7-12
7-13
7-14
7-17
7-18
7-20
7-21
7-25
7-26
a compound of the formula
wherein Rx has one of the meanings given in the following table:
Compound
Rx
8-2
a compound of the formula
wherein Rx has one of the meanings given in the following table:
Compound
Rx
9-1
9-2
9-3
9-4
9-5
9-6
a compound of the formula
wherein Rx has one of the meanings given in the following table:
Compound
Rx
10-1
10-2
10-3
a compound of the formula
wherein Rx has one of the meanings given in the following table:
Compound
Rx
11-1
11-2
11-4
a compound of the formula
wherein Ry has one of the meanings given in the following table:
Compound
R
14-1
14-2
14-3
14-5
14-6
a compound of the formula
wherein Rx has one of the meanings given in the following table:
Compound
Rx
15-1
15-2
15-3
a compound of the formula
wherein Rx has one of the meanings given in the following table:
Compound
Rx
18-1
a compound of the formula
wherein Rx has one of the meanings given in the following table:
Compound
Rx
26-1
26-2
26-3
26-4
26-5
26-6
26-7
26-8
26-9
26-10
26-11
26-12
26-13
26-14
26-18
26-21
26-22
26-23
26-24
26-25
26-26
26-27
26-28
26-29
a compound of the formula
wherein Rx has one of the meanings given in the following table:
Compound
Rx
27-1
27-2
27-3
27-4
27-5
27-6
27-8
27-9
a compound of the formula
wherein Rx has one of the meanings given in the following table:
Compound
Rx
28-1
28-2
28-3
28-4
28-5
28-6
28-8
28-9
28-10
28-11
28-12
28-13
28-14
28-15
28-16
28-17
28-18
28-19
28-20
28-21
28-22
28-23
28-24
28-25
28-27
28-28
a compound of the formula
wherein Rx has one of the meanings given in the following table:
Compound
Rx
29-1
29-2
29-3
a compound of the formula
wherein Rx has one of the meanings given in the following table:
Compound
Rx
31-2
a compound of the formula
wherein Rx has one of the meanings given in the following table:
Compound
Rx
32-1
32-2
a compound of the formula
wherein Ry has one of the meanings given in the following table:
Compound
Ry
34-1
34-3
34-4
34-6
a compound of the formula
wherein Rx has one of the meanings given in the following table:
Compound
Rx
35-1
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , wherein said compound is 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl -phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide, or N 2 -(4-[1,4′]Bipiperidinyl-1′-yl-2-methoxy-phenyl)-5-chloro-N 4 -[2-(propane-1-sulfonyl)-phenyl]-pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof.
13. A process for the production of a compound of formula I according to claim 1 , comprising reacting a compound of formula II
wherein R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined in claim 1 , and Y is a leaving group, with a compound of formula III
wherein A, R 7 , R 8 , R 9 and R 10 are as defined in claim 1 ;
and, if desired, converting a compound of formula I, wherein the substituents have the meaning as defined in claim 1 , into another compound of formula I as defined in claim 1 ;
and recovering the resulting compound of formula I in free from or as a salt, and, when required, converting the compound of formula I obtained in free form into the desired salt, or an obtained salt into the free form.
14. A pharmaceutical composition comprising a compound according to claim 1 , as active ingredient together with one or more pharmaceutically acceptable diluents or carriers.
15. A combination comprising a therapeutically effective amount of a compound according to claim 1 and one or more known drug substances, said further drug substance being useful in the treatment of neoplastic diseases or immune system disorders.
16. A method for the treatment of breast tumors in a subject in need thereof which comprises administering an effective amount of a compound according to claim 1 or a pharmaceutical composition comprising same.
17. The method of claim 16 , wherein said compound is 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl -phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide, or N 2 -(4-[1,4′]Bipiperidinyl-1′-yl-2-methoxy-phenyl)-5-chloro-N 4 -[2-(propane-1-sulfonyl)-phenyl]-pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof.