Antibacterial piperidinyl substituted 3,4-dihydro-1H-[1,8]naphthyridinones
The present invention is related to novel compounds of formula (I) that inhibit the activity of the Fab1 enzyme which are therefore useful in the treatment of bacterial infections. It further relates to pharmaceutical compositions comprising these compounds, and chemical processes for preparing these compounds.
1. A compound of formula (I)
wherein
X is C and the bond is a double bond; or
X is N and the bond is a single bond;
and wherein
Z 1 is CH;
R 1 is hydrogen, C 1-4 alkyl or halo;
R 2 is hydrogen, C 1-4 alkyl or halo;
R 3 is hydrogen, C 1-6 alkyl, hydroxy or halo;
R 4 is hydrogen, C 1-6 alkyl, halo, aryl, aryloxy, arylcarbonyl, heteroaryl, C 1-6 alkyl substituted with aryl or aryloxy, or C 1-6 alkyl substituted with heteroaryl;
and when the substituents R 3 and R 4 are located on adjacent positions said R 3 and R 4 may be taken together to form a radical of formula ═CH—CH═CH—CH═ with the proviso that X is carbon and the bond is a single bond;
aryl is phenyl; phenyl substituted with one, two or three substituents each individually selected from halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, polyhaloC 1-4 alkyloxy, cyano, nitro, and amino;
heteroaryl is furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, triazolyl, tetrazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzo[1,3]dioxolyl, benzofuranyl, benzothiazolyl, indolyl, 2,3-dihydro-1H-indolyl, tetrahydrothiophenyl, or quinolinyl;
wherein each heteroaryl may be substituted with one or two substituents each independently selected from halo, cyano, C 1-4 alkyl, C 1-4 alkyloxy, C 1-4 alkylcarbonyl, or phenyl;
or a pharmaceutically acceptable acid addition salt thereof.
2. A compound as claimed in claim 1 wherein:
Z 1 is CH;
R 1 is hydrogen or C 1-4 alkyl; and
R 2 is hydrogen or C 1-4 alkyl.
3. A compound as claimed in claim 1 where the X-containing ring is:
4. A compound as claimed in claim 1 wherein R 1 is hydrogen and R 2 is hydrogen.
5. A compound as claimed in claim 1 wherein R 3 is hydrogen.
6. A compound as claimed in claim 1 wherein R 4 is aryl.
7. A compound as claimed in claim 1 wherein R 4 is heteroaryl.
8. A compound as claimed in claim 1 wherein R 4 is C 1-6 alkyl substituted with aryl.
9. A compound as claimed in claim 1 wherein X is nitrogen and the bond represents a single bond.
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in claim 1 .
11. A process for preparing a pharmaceutical composition as claimed in claim 10 wherein a therapeutically active amount of a compound as claimed in claim 1 is intimately mixed with a pharmaceutically acceptable carrier.
12. A method of treatment of a subject suffering from a bacterial infection, comprising administering to the subject a effective amount of a compound of formula (I) as claimed in claim 1 .
13. A method of treatment as claimed in claim 12 wherein the bacterial infection is caused by a bacterium that expresses a FabI enzyme.
14. A process for preparing a compound of formula (I), as claimed in claim 1 , comprising (i) reacting an intermediate of formula (II) with an intermediate of formula (III),
or
(ii) reacting an intermediate of formula (V) with an intermediate of formula (VI),
wherein Xa 1 is a suitable leaving group and the other substituents are as defined in claim 1 .