Quinazolinone derivatives as PARP inhibitors
The present invention provides compounds of formula (I), their use as PARP inhibitors as well as pharmaceutical compositions comprising said compounds of formula (I) wherein R 1 , R 2 , R 3 , L, X, Y and Z have defined meanings.
1. A compound of formula (I),
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
the dotted lines represent optional bonds;
X is >N—;
is —N—C(O)— or —N═CR 4 —, wherein R 4 is hydroxy;
L is a direct bond or a bivalent radical selected from —C(O)—, —C(O)—NH—, —NH—, —C(O)—C 1-6 alkanediyl-, —C(O)—O—C 1-6 alkanediyl- or —C 1-6 alkanediyl-;
R 1 is hydrogen, halo, C 1-6 alkyloxy or C 1-6 alkyl;
R 2 is hydrogen, hydroxy, C 1-6 alkyloxy or aminocarbonyl;
R 3 is hydrogen, or C 1-6 alkyloxy;
Z is
wherein R 5 is selected from hydrogen, halo, amino, C 1-6 alkyl or C 1-6 alkyloxy.
2. A compound as claimed in claim 1 wherein
L is a direct bond or a bivalent radical selected from —C(O)—, —C(O)—NH—, or —C(O)—O—C 1-6 alkanediyl-; and R 2 is hydrogen, hydroxy, or C 1-6 alkyloxy.
3. A compound according to claim 1 wherein
L is a direct bond; R 1 is hydrogen, halo or C 1-6 alkyl;
R 2 is hydrogen; R 3 is hydrogen; and each
R 5 is independently selected from hydrogen or halo.
4. A compound
5. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1 .
6. A process of preparing a pharmaceutical composition as claimed in claim 5 wherein the pharmaceutically acceptable carriers and the compound as claimed in claim 1 are intimately mixed.
7. A combination of a compound with a chemotherapeutic agent wherein said compound is a compound of formula (I)
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
the dotted lines represent optional bonds;
X is >N—;
is —N—C(O)— or —N═CR 4 —, wherein R 4 is hydroxy;
L is a direct bond or a bivalent radical selected from —C(O)—, —C(O)—NH—, —NH—, —C(O)—C 1-6 alkanediyl-, —C(O)—O—C 1-6 alkanediyl- or —C 1-6 alkanediyl-;
R 1 is hydrogen, halo, C 1-6 alkyloxy or C 1-6 alkyl;
R 2 is hydrogen, hydroxy, C 1-6 alkyloxy or aminocarbonyl;
R 3 is hydrogen, or C 1-6 alkyloxy;
Z is amino, cyano or a radical selected from
wherein R 5 is selected from hydrogen, halo, amino, C 1-6 alkyl or C 1-6 alkyloxy.
8. A process for preparing a compound as claimed in claim 1 , said process comprising:
reacting an intermediate of formula (II) with an intermediate of formula (III), wherein
W is an appropriate leaving group, with the formation of a compound of formula (I) and both dotted lines can be a bond, in a reaction-inert solvent and with the addition of an appropriate base,
9. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 2 .
10. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 3 .
11. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 4 .