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Details for Patent: 8,263,590

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Details for Patent: 8,263,590

Title:Pyrimidine derivatives
Abstract: Novel pyrimidine derivatives of formula I ##STR00001## to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.
Inventor(s): Garcia-Echeverria; Carlos (Saint-Cloud, FR), Kanazawa; Takanori (Tsukuba, JP), Kawahara; Eiji (Tsukuba, JP), Masuya; Keiichi (Bottmingen, CH), Matsuura; Naoko (Tsukuba, JP), Miyake; Takahiro (Hyogo, JP), Ohmori; Osamu (Shizuoka, JP), Umemura; Ichiro (Tsukuba, JP)
Assignee:
Filing Date:Apr 27, 2011
Application Number:13/095,760
Claims:1. A compound of formula I ##STR00545## wherein each of R.sup.0, R.sup.1, and R.sup.2, independently is hydrogen, C.sub.1-C.sub.8alkyl, C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8alkinyl, C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkylC.sub.1-C.sub.8alkyl, C.sub.5-C.sub.10arylC.sub.1-C.sub.8alkyl, hydroxyC.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxyC.sub.1-C.sub.8alkyl, aminoC.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, unsubstituted or substituted C.sub.5-C.sub.10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1, 2 or 3 hetero atoms selected from N, O and S, hydroxy, C.sub.1-C.sub.8alkoxy, hydroxyC.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8alkoxyC.sub.1-C.sub.8alkoxy, haloC.sub.1-C.sub.8alkoxy, unsubstituted or substituted C.sub.5-C.sub.10arylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted heterocyclyloxy, or unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, C.sub.1-C.sub.8alkylthio, C.sub.1-C.sub.8alkylsulfinyl, C.sub.1-C.sub.8alkylsulfonyl, C.sub.5-C.sub.10arylsulfonyl, halogen, carboxy, C.sub.1-C.sub.8alkoxycarbonyl, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl, cyano or nitro; R.sup.3 is unsubstituted or substituted sulfamoyl; Or the pair of adjacent substituents R.sup.2 and R.sup.3 forms --CH.sub.2--NH--CO-- or --CH.sub.2--NH--SO.sub.2-- or such pairs wherein NH is substituted by C.sub.1-C.sub.8-alkyl; R.sup.4 is hydrogen or C.sub.1-C.sub.8alkyl; R.sup.5 is halogen; R.sup.6 is hydrogen; each of R.sup.7, R.sup.8, R.sup.9, and R.sup.10 independently is C.sub.1-C.sub.8alkyl, C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8alkinyl, C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkylC.sub.1-C.sub.8alkyl, C.sub.5-C.sub.10arylC.sub.1-C.sub.8alkyl, hydroxyC.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxyC.sub.1-C.sub.8alkyl, aminoC.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, unsubstituted or substituted C.sub.5-C.sub.10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1, 2 or 3 hetero atoms selected from N, O and S, hydroxy, C.sub.1-C.sub.8alkoxy, hydroxyC.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8alkoxyC.sub.1-C.sub.8alkoxy, haloC.sub.1-C.sub.8alkoxy, unsubstituted or substituted C.sub.5-C.sub.10arylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted heterocyclyloxy, or unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, C.sub.1-C.sub.8alkylthio, C.sub.1-C.sub.8alkylsulfinyl, C.sub.1-C.sub.8alkylsulfonyl, C.sub.5-C.sub.10arylsulfonyl, halogen, carboxy, C.sub.1-C.sub.8alkoxycarbonyl, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl, cyano or nitro; wherein R.sup.7, R.sup.8 and R.sup.9 independently of each other can also be hydrogen; or R.sup.7 and R.sup.8, R.sup.8 and R.sup.9, and/or R.sup.9 and R.sup.10 form together with the carbon atoms to which they are attached, a 5 or 6 membered carbocyclic or heterocyclic ring comprising 0, 1, 2 or 3 heteroatoms selected from N, O and S that is unsubstituted or substituted by C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkoxy, halo-C.sub.1-C.sub.8-alkyl, hydroxyl, amino, substituted amino, halogen, carboxy, C.sub.1-C.sub.8alkoxycarbonyl, carbamoyl, cyano, or oxo; A is C; and salts thereof.

2. A compound of formula I according to claim 1, wherein each of R.sup.0 or R.sup.2 independently is hydrogen, C.sub.1-C.sub.8alkyl, hydroxyC.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, unsubstituted or substituted C.sub.5-C.sub.10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C.sub.1-C.sub.8alkoxy, haloC.sub.1-C.sub.8alkoxy, C.sub.5-C.sub.10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, C.sub.1-C.sub.8alkylsulfonyl, halogen, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl; R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl, hydroxyC.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, unsubstituted or substituted C.sub.5-C.sub.10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C.sub.1-C.sub.8alkoxy, haloC.sub.1-C.sub.8alkoxy, C.sub.5-C.sub.10 aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, C.sub.1-C.sub.8alkylsulfonyl, halogen, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl; R.sup.3 is unsubstituted or substituted sulfamoyl; or the pair of adjacent substituents R.sup.2 and R.sup.3 forms --CH.sub.2--NH--CO-- or CH.sub.2--NH--SO.sub.2-- or such pairs wherein NH is substituted by C.sub.1-C.sub.8-alkyl; R.sup.4 is hydrogen or C.sub.1-C.sub.8alkyl; R.sup.5 is halogen; R.sup.6 is hydrogen; each of R.sup.7 and R.sup.9 independently is hydrogen, C.sub.1-C.sub.8alkyl, hydroxyC.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, unsubstituted or substituted C.sub.5-C.sub.10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C.sub.1-C.sub.8alkoxy, haloC.sub.1-C.sub.8alkoxy, C.sub.5-C.sub.10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, C.sub.1-C.sub.8alkylsulfonyl, halogen, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl; R.sup.8 is hydrogen, C.sub.1-C.sub.8alkyl, hydroxyC.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, C.sub.5-C.sub.10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C.sub.1-C.sub.8alkoxy, haloC.sub.1-C.sub.8alkoxy, C.sub.5-C.sub.10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, C.sub.1-C.sub.8alkylsulfonyl, halogen, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl, cyano, or nitro; and R.sup.10 is C.sub.1-C.sub.8alkyl, hydroxyC.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxy, unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, halogen, carboxy, carbamoyl, or unsubstituted or substituted sulfamoyl; or each pair of adjacent substituents R.sup.7 and R.sup.8, or R.sup.8 and R.sup.9 or R.sup.9 and R.sup.10, is --NH--CH.dbd.CH--, --CH.dbd.CH--NH--, --NH--N.dbd.CH--, --CH.dbd.N--NH--, --CH.sub.2--CH.sub.2--CH.sub.2--, --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, --CH.sub.2--CH.sub.2--O--, --CH.dbd.CH--O--, --O--CH.sub.2--O--, or --O--CF.sub.2--O-- A is C.

3. A compound of formula I according to claim 1, wherein each of R.sup.0 or R.sup.2 independently is hydrogen, C.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C.sub.1-C.sub.8alkoxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, or halogen; R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C.sub.1-C.sub.8alkoxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, halogen; R.sup.3 is unsubstituted or substituted sulfamoyl; or the pair of adjacent substituents R.sup.2 and R.sup.3 forms --CH.sub.2--NH--CO-- or CH.sub.2--NH--SO.sub.2-- or such pairs wherein NH is substituted by C.sub.1-C.sub.8-alkyl; R.sup.4 is hydrogen; R.sup.5 is halogen; R.sup.6 is hydrogen; each of R.sup.7 and R.sup.9 independently is hydrogen, C.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, unsubstituted or substituted C.sub.5-C.sub.10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C.sub.1-C.sub.8alkoxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, halogen, unsubstituted or substituted carbamoyl, or unsubstituted or substituted sulfamoyl; R.sup.8 is hydrogen, C.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, C.sub.5-C.sub.10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C.sub.1-C.sub.8alkoxy, haloC.sub.1-C.sub.8alkoxy, C.sub.5-C.sub.10aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, halogen, unsubstituted or substituted sulfamoyl, or nitro; and R.sup.10 is C.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxy, unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, or halogen; or each pair of adjacent substituents R.sup.7 and R.sup.8, or R.sup.8 and R.sup.9 or R.sup.9 and R.sup.10, is --NH--CH.dbd.CH--, --CH.dbd.CH--NH--, --NH--N.dbd.CH--, --CH.dbd.N--NH--, --CH.sub.2--CH.sub.2--CH.sub.2--, --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, --O--CH.sub.2--O--, or --O--CF.sub.2--O--; A is C.

4. A compound of formula I according to claim 1, wherein each of R.sup.0 or R.sup.2 independently is hydrogen, piperazino, N-methylpiperazino or 1-methyl-4-piperidyloxy; R.sup.1 is hydrogen, piperazino, N-methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3-morpholinopropoxy or 2-morpholinoethoxy; R.sup.3 is sulfamoyl, methylsulfamoyl or propylsulfamoyl; or the pair of adjacent substituents R.sup.2 and R.sup.3 is --CH.sub.2--NH--CO-- or --CH.sub.2--NH--SO.sub.2--; R.sup.4 is hydrogen; R.sup.5 is chloro, or bromo; R.sup.6 is hydrogen; each of R.sup.7 and R.sup.9 independently is hydrogen, C.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, unsubstituted or substituted C.sub.5-C.sub.10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C.sub.1-C.sub.8alkoxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, halogen, unsubstituted or substituted carbamoyl, or unsubstituted or substituted sulfamoyl; R.sup.8 is hydrogen, C.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, C.sub.5-C.sub.10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, C.sub.1-C.sub.8alkoxy, haloC.sub.1-C.sub.8alkoxy, C.sub.5-C.sub.10 aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, halogen, unsubstituted or substituted sulfamoyl, or nitro; and R.sup.10 is C.sub.1-C.sub.8alkyl, haloC.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxy, unsubstituted or substituted heterocyclylC.sub.1-C.sub.8alkoxy, unsubstituted or substituted amino, or halogen; or each pair of adjacent substituents R.sup.7 and R.sup.8, or R.sup.8 and R.sup.9 or R.sup.9 and R.sup.10, is --NH--CH.dbd.CH--, --CH.dbd.CH--NH--, --NH--N.dbd.CH--, --CH.dbd.N--NH--, --CH.sub.2--CH.sub.2--CH.sub.2--, --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, --O--CH.sub.2--O--, or --O--CF.sub.2--O--; A is C.

5. A compound of formula I according to claim 1, wherein each of R.sup.0 or R.sup.2 independently is hydrogen, piperazino, N-methylpiperazino or 1-methyl-4-piperidyloxy; R.sup.1 is hydrogen, piperazino, N-methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3-morpholinopropoxy or 2-morpholinoethoxy; R.sup.3 is sulfamoyl, methylsulfamoyl or propylsulfamoyl; or the pair of adjacent substituents R.sup.2 and R.sup.3 is --CH.sub.2--NH--CO-- or --CH.sub.2--NH--SO.sub.2--; R.sup.4 is hydrogen; R.sup.5 is hydrogen, chloro, bromo, trifluoromethyl or nitro; R.sup.6 is hydrogen; each of R.sup.7 and R.sup.9 independently is hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, o-, m- or p-methoxyphenyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 2-(1-imidazolyl)ethoxy, dimethylamino, fluoro, morpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl; R.sup.8 is hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoromethoxy, phenoxy, 1-methyl-4-piperidyloxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-(N-methylpiperazino)-propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro; and R.sup.10 is methyl, butyl, methoxy, ethoxy, 2-(1-imidazolyl)ethoxy, methylamino, dimethylamino or fluoro; or the pair of adjacent substituents R.sup.7 and R.sup.8 or R.sup.8 and R.sup.9 is --O--CH.sub.2--O-- or the pair of adjacent substituents R.sup.9 and R.sup.10 is --NH--CH.dbd.CH--, --CH.dbd.N--NH--, --CH.sub.2--CH.sub.2--CH.sub.2--, --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- or --O--CF.sub.2--O--; A is C.

6. A compound of formula I according to claim 1, wherein each of R.sup.0, R.sup.1 or R.sup.2 is hydrogen; R.sup.3 is sulfamoyl, methylsulfamoyl or propylsulfamoyl; R.sup.4 is hydrogen; R.sup.5 is chloro or bromo; R.sup.6 is hydrogen; each of R.sup.7 and R.sup.9 independently is hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, o-, m- or p-methoxyphenyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 2-(1-imidazolyl)ethoxy, dimethylamino, fluoro, morpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl; R.sup.8 is hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoromethoxy, phenoxy, 1-methyl-4-piperidyloxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-(N-methylpiperazino)-propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro; and R.sup.10 is methyl, butyl, methoxy, ethoxy, 2-(1-imidazolyl)ethoxy, methylamino, dimethylamino or fluoro; or the pair of adjacent substituents R.sup.7 and R.sup.8 or R.sup.8 and R.sup.9 is --O--CH.sub.2--O--, or the pair of adjacent substituents R.sup.9 and R.sup.10 is --NH--CH.dbd.CH--, --CH.dbd.N--NH--, --CH.sub.2--CH.sub.2--CH.sub.2--, --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- or --O--CF.sub.2--O--; A is C.

7. The compound of formula I according to claim 1, wherein each of R.sup.0, R.sup.1 or R.sup.2 is hydrogen, R.sup.3 is methylsulfamoyl, R.sup.4 is hydrogen, R.sup.5 is bromo, R.sup.6 is hydrogen, each of R.sup.7 and R.sup.8 is methoxy, R.sup.9 is hydrogen, and R.sup.10 is methyl, and A is C.

8. The compound of formula I according to claim 1, wherein each of R.sup.0, R.sup.1 or R.sup.2 is hydrogen, R.sup.3 is methylsulfamoyl, R.sup.4 is hydrogen, R.sup.5 is bromo, R.sup.6 is hydrogen, each of R.sup.7 and R.sup.8 is hydrogen, and the pair of adjacent substituents R.sup.9 and R.sup.10 is --CH.sub.2--CH.sub.2--CH.sub.2--, and A is C.

9. The compound 2-{5-Chloro-2-[4-(3-methylamino-pyrrolidin-1-yl)-phenylamino]-pyrimidin-4- -ylamino}-N-isopropyl-benzenesulfonamide.

10. A process for the production of a compound of formula I according to claim 1, comprising reacting a compound of formula II ##STR00546## wherein R.sup.0, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are as defined in claim 1, and Y is a leaving group, with a compound of formula III ##STR00547## wherein A, R.sup.7, R.sup.8, R.sup.9 and R.sup.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.

11. A pharmaceutical composition comprising a compound according to claim 1, as active ingredient together with one or more pharmaceutically acceptable diluents or carriers.

12. 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.

13. 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.
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