Sulfoximine-substituted pyrimidines as CDK-and/or VEGF inhibitors, their production and use as pharmaceutical agents
View Patent ↗This invention relates to pyrimidine derivatives of general formula I in which Q, R 1 , R 2 , R 3 , R 4 , R 5 , X, and m have the meanings that are contained in the description, as inhibitors of cyclin-dependent kinases and VEGF-receptor tyrosine kinases, their production as well as their use as medications for treatment of various diseases.
1. A compound of formula (I)
in which
Q is phenyl,
R 1 is hydrogen or halogen,
R 2 is C 1 -C 10 -alkyl, C 2 -C 10 -alkinyl, or aryl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkinyl, or —COR 7 ,
X is oxygen, sulfur, or —NH—,
R 3 is halogen, or C 1 -C 6 -alkyl, or C 1 -C 6 -alkoxy that is optionally substituted in one or more places with halogen,
m stands for 0-4,
R 4 is hydrogen, NO 2 , —CO—R 6 , —SO 2 R 7 or C 1 -C 10 -alkyl,
R 5 is C 1 -C 10 -alkyl or C 3 -C 10 -cycloalkyl that is optionally substituted in one or more places, in the same way or differently, with hydroxy or C 3 -C 10 -cycloalkyl,
R 6 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or C 3 -C 6 -cycloalkyl, which is optionally substituted in one or more places, in the same way or differently, with C 1 -C 6 -alkyl, and
R 7 is C 1 -C 10 -alkyl that is optionally substituted in one or more places, in the same way or differently, with trimethyisilanyl.
2. A compound according to claim 1 , in which
Q is phenyl,
R 1 is hydrogen or halogen,
R 2 is C 1 -C 10 -alkyl, C 2 C 10 -alkinyl or aryl that is optionally substituted in one or more places, in the way or differently, with hydroxy, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkinyl or —COR 16 ,
X is oxygen, sulfur or —NH—,
R 3 is halogen or C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy that is optionally substituted in one or more places with halogen,
m stands for 0-2,
R 4 is hydrogen, NO 2 , —CO—R 6 , —SO 2 R 7 or C 1 -C 10 -alkyl,
R 5 is C 1 -C 10 -alkyl or C 3 -C 10 -cycloalkyl that is optionally substituted in one or more places, in the same way or differently, with hydroxy or C 3 -C 10 -cycloalkyl,
R 6 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or C 3 -C 6 -cycloalkyl, which is optionally substituted in one or more places, in the way or differently, with C 1 -C 6 -alkyl,
R 7 is C 1 -C 10 -alkyl that is optionally substituted in one or more places, in the way or differently, with trimethylsilanyl.
3. A compound according to claim 1 , in which
Q is phenyl,
R 1 is hydrogen or halogen,
R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, isohexyl, propargyl or phenyl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, halogen, methyl, methoxy, ethinyl, —COH or —COCH 3 ,
X is oxygen, sulfur or —NH—,
R 3 is halogen, methyl, methoxy or —CF 3 ,
m stands for 0-1,
R 4 is hydrogen, methyl, NO 2 , —COOC 2 H 5 or —SO 2 —C 2 H 4 —Si(CH 3 ) 3 ,
R 5 is methyl, ethyl, cyclopropyl, cyclopentyl, —(CH 2 )-cyclopropyl or hydroxyethyl.
4. In a method of preparing a compound of claim 1 , the improvement comprising preparing said compound via an intermediate compound of formula (IIa) or (IIb)
in which
Q is phenyl,
Z is —NH 2 or NO 2 ,
m stands for 0-4,
R 3 is halogen, or C 1 -C 6 -alkyl, or C 1 -C 6 -alkoxy that is optionally substituted in one or more places with halogen,
R 4 is hydrogen, NO 2 , —CO—R 6 , —SO 2 R 6 , —SO 2 R 7 or C 1 -C 10 -alkyl,
R 5 is C 1 -C 10 -alkyl or C 3 -C 10 -cycloalkyl that is optionally substituted in one or more places, in the same way or differently, with hydroxyl or C 3 -C 10 -cycloalkyl,
R 6 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or C 3 -C 6 -cycloalkyl, which is optionally substituted in one or more places, in the same way or differently, with C 1 -C 6 -alkyl, and
R 7 is C 1 -C 10 -alkyl that is optionally substituted in one or more places, in the same way or differently, with trimethylsilanyl.
5. A method according to claim 4 , wherein
m stands for 0-2,
R 3 is halogen, or C 1 -C 10 -alkyl or C 1 -C 10 -alkoxy that is optionally substituted in one or more places with halogen,
R 4 is hydrogen, NO 2 , —SO 2 —R 7 , —CO—R 6 or C 1 -C 10 -alkyl,
R 5 is C 1 -C 10 -alkyl or C 3 -C 6 -cycloalkyl that is optionally substituted in one or more places with halogen or hydroxyl,
R 6 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or C 3 -C 6 -cycloalkyl, which is optionally substituted in one or more places, in the same way or differently, with C 1 -C 6 -alkyl, and
R 7 is C 1 -C 10 -alkyl that is optionally substituted in one or more places, in the same way or differently, with trimethylsilanyl.
6. In a method of preparing a compound of claim 1 , the improvement comprising preparing said compound via an intermediate compound of formula (IV),
in which
Hal is halogen,
W is halogen, hydroxy or X—R 2 ,
R 1 is hydrogen or halogen, R 2 is C 1 -C 10 -alkyl, C 2 -C 10 -alkinyl, or aryl that is optionally substituted in one or more places, in the same way or differently, with hydroxy, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkinyl, or —COR 7 ,
R 7 is C 1 -C 10 -alkyl that is optionally substituted in one or more places, in the same way or differently, with trimethylsilanyl, and
X is oxygen, sulfur, or —NH—.
7. A method according to claim 6 , in which
X is oxygen, sulfur or —NH—,
R 1 is halogen,
R 2 is C 1 -C 10 -alkyl or C 2 -C 10 -alkinyl that is optionally substituted with hydroxy, C 1 -C 6 -alkoxy or —CO—R 7 , and
R 7 is C 1 -C 10 -alkyl that is optionally substituted in one or more places, in the same way or differently, with trimethylsilanyl.
8. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition according to claim 8 , which is suitable for enteral, parenteral or oral administration.
10. A method for inhibiting the growth of MCF7 cells, NCI-H460 cells, HCT 116 cells, DU 145 cells, or MaTu-MDR cells comprising administering to a patient in need thereof a pharmaceutical composition comprising pharmaceutically acceptable carrier and a compound according to claim 2 .
11. A method for inhibiting the growth of MCF7 cells, NCI-H460 cells, HCT 116 cells, DU 145 cells, or MaTu-MDR cells comprising administering to a patient in need thereof a pharmaceutical composition comprising pharmaceutically acceptable carrier and a compound according to claim 3 .
12. A method for inhibiting the growth of MCF7 cells, NCI-H460 cells, HCT 116 cells, DU 145 cells, or MaTu-MDR cells comprising administering to a patient in need thereof a pharmaceutical composition according to claim 8 .
13. A compound according to claim 1 , wherein said compound is in the form of a diastereomer or enantiomer.