Pyrrolidin-2-ones
The present invention provides compounds of formula (I) or (Ia) which are ligands binding to the HDM2 protein, inducing apoptosis and inhibiting proliferation, and having therapeutic utility in cancer therapy and prevention. Compounds of formula (I) or (Ia) can be used as therapeutics for treating stroke, myocardial infarction, ischemia, multi-organ failure, spinal cord injury, Alzheimer's Disease, injury from ischemic events and heart valvular degenerative disease. Moreover, compounds of formula (I) or (Ia) can be used to decrease the side effects from cytotoxic cancer agents, radiation and to treat viral infections.
1. A compound of formula (Ia)
wherein
R 1 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 2 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 3 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 4 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 5 is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, or heteroaralkyl radical;
R 6 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
or the radicals R 5 and R 6 together are part of an optionally substituted heterocycloalkyl, heteroalkylcycloalkyl, heteroaryl or heteroarylalkyl ring system, and/or R 2 and R 3 together are part of an optionally substituted cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, aralkyl or heteroaralkyl ring system;
or a pharmaceutically acceptable salt, ester, or a pharmaceutically acceptable formulation thereof;
with the exception of compounds:
2. A compound (Ia), according to wherein R 1 is an aryl, heteroaryl, aralkyl or heteroaralkyl radical.
3. A compound of formula (Ia), according to claim 1 wherein R 1 is a group of formula -A-Ar or A-Cy wherein A is a bond, C 1 -C 4 alkyl or C 1 -C 6 heteroalkyl or wherein A is a group of formula —CHR 1a — wherein R 1a is a C 1 -C 6 heteroalkyl
group, Cy is an optionally substituted C 3 -C 7 cycloalkyl group or an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms and Ar is an optionally substituted phenyl ring or an optionally substituted heteroaryl ring containing 5 or 6 ring atoms, especially preferably Ar is an optionally substituted phenyl or an optionally substituted pyridyl residue.
4. A compound of formula (Ia), according to claim 1 wherein R 2 is hydrogen.
5. A compound of formula (Ia), according to claim 1 wherein R 3 is an optionally substituted phenyl group, an optionally substituted benzyl group or an
optionally substituted heteroaryl residue having 1 or 2 rings and from 5 to 10 ring atoms including 1, 2, 3 or 4 heteroatoms selected from O, S and N.
6. A compound of formula (Ia), according to claim 1 wherein R 3 has the following structure
wherein E is N or CH, R 3a is H, C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl, R 3b is H, F, Cl, Br, CH 3 , OCH 3 or CF 3 and R 3c is H, F, Cl, Br, CH 3 , OCH 3 or CF 3 .
7. A compound of formula (Ia), according to claim 1 wherein R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, optionally substituted C 1 -C 4 alkyl-C 3 -C 7 cycloalkyl, an optionally substituted phenyl ring, an optionally substituted benzyl group or an optionally substituted heteroaryl ring having 5 or 6 ring atoms and including from 1 to 3 heteroatoms selected from O, S and N.
8. A compound of formula (Ia), according to claim 1 wherein R 5 is an alkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyl or heteroaralkyl group, all of which groups may be substituted.
9. A compound of formula (Ia), according to claim 1 wherein R 5 is selected from the following groups: C 1 -C 6 alkyl; heteroalkyl containing 1-6 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and N; heteroalkylcycloalkyl comprising a C 1 -C 4 alkyl group or a C 1 -C 4 heteroalkyl group and an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N; heteroaralkyl comprising a C 1 -C 4 alkyl group or a C 1 -C 4 heteroalkyl group and an optionally substituted heteroaryl group containing 5 or 6 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N; optionally substituted heteroaryl containing 5 or 6 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N; and optionally substituted heterocycloalkyl containing 5 or 6 ring atom and 1, 2 or 3 heteroatoms selected from O, S and N.
10. A compound of formula (Ia), according to claim 1 wherein R 6 is hydrogen or C 1 -C 4 alkyl.
11. A compound of formula (Ia), according to claim 1 wherein R 5 and R 6 together are part of an optionally substituted heterocycloalkyl ring containing 4, 5, 6 or 7 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N.
12. A compound of formula (Ia), according to claim 1 wherein R 5 and R 6 together are part of an optionally substituted piperazine or piperidine ring.
13. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable ester or salt thereof, optionally in combination with a pharmaceutically acceptable carrier.