Equilibrative nucleoside transporter ENT1 inhibitors
The present invention is related to novel compounds of formula (I) having equilibrative nucleoside transporter ENT1 inhibiting properties, pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds and their use in the treatment of diseases linked to the inhibition of ENT1 receptors in animals, in particular humans.
1. Compound of formula (I)
including any stereochemically isomeric form thereof, wherein -A-B— represents
wherein n is an integer 0 or 1;
R 13 represents hydroxy or halo;
R 14 represents hydrogen or C 1-6 alkyl;
in the bivalent radicals (a-4), (a-5) and (a-6) any of the hydrogen atoms on the same or a different carbon atom may be replaced by halo;
R 1 and R 2 are each independently selected from hydrogen, halo or C 1-6 alkyl;
R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, C 3-6 cycloalkyl, NO 2 , Cycle 1 , Cycle 2 ,
or X—R 8 wherein X represents O or NR 9 ,
wherein R 9 is hydrogen, C 1-6 alkyl or C 1-6 alkyloxyC 1-6 alkyl, and
wherein R 8 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyl, polyhaloC 1-6 alkylcarbonyl, Cycle 2 , —(C═O)—(CH 2 ) m -Cycle 2 , —(C═O)—(CH 2 ) m —CH 2 —OH, —(C═O)—(CH 2 ) m —CH 2 —O—C 1-4 alkyl, or C 1-6 alkyl substituted with halo, hydroxy, cyano, C 3-6 cycloalkyl,
C 1-6 alkyloxy, aminocarbonyl, phenyl, Cycle 1 , or Cycle 2 , or NR 11 R 12 wherein R 11 and R 12 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, or C 1-6 alkyloxycarbonyl;
m is an integer 0, 1 or 2;
Cycle 1 is selected from
wherein R 10 is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, or C 1-6 alkyloxycarbonyl; and
Cycle 2 is selected from
wherein R 10 is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl or C 1-6 alkyloxycarbonyl substituted with halo or hydroxy;
or a pharmaceutically acceptable acid addition salt thereof, or an N-oxide form thereof.
2. A compound as claimed in claim 1 wherein R 1 and R 2 are both halo.
3. A compound as claimed in claim 1 wherein R 1 and R 2 are both C 1-4 alkyl.
4. A compound as claimed in claim 1 wherein radical -A-B— represents (a-1).
5. A compound as claimed in claim 1 wherein radical -A-B— represents (a-2).
6. A compound as claimed in claim 1 wherein R 3 is hydrogen and R 5 is X—R 8 .
7. A compound as claimed in claim 1 wherein the compound is N-(2-{7-[(1-acetylpiperidin-4-yl)oxy]-6-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl}ethyl)-2,6-dichlorobenzamide or a pharmaceutically acceptable acid addition salt thereof.
8. A compound as claimed in claim 1 wherein the compound is N-[2-(7-amino-8-chloro-4-oxo-3,4-dihydro-1′H-spiro[1,3-benzoxazine-2,4′-piperidin]-1′-yl)ethyl]-2,6-dichlorobenzamide or a pharmaceutically acceptable acid addition salt thereof.
9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to claim 1 .
10. A process for preparing a compound of formula (I) wherein
a) a compound of formula (III) is N-alkylated with a compound of formula (II) in a reaction-inert solvent,
or; b) a compound of formula (IV) is reacted with a compound of formula (V) in a reaction-inert solvent,
or c) compounds of formula (I) are converted into each other following art-known transformation reactions.
11. A method of treating acute and chronic pain in a mammalian subject, which method comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
12. A process according to claim 10 wherein the reaction occurs in the presence of a suitable base.