Derivatives and their use as selective inhibitors of caspase-2

1. A compound of formula (I):

wherein:

Z 1 is a (C 1 -C 6 )alkyl group;

P 5 is selected from the following amino acid residues

P 1 and P 4 , identical or different, are selected from the following amino acid residues

in which Z 2 and Z 3 , identical or different, are selected from a hydrogen atom and a (C 1 -C 6 )alkyl group;

P 3 is selected from the following amino acids residues

R 1 is selected from

and

R 2 is selected from

in which

m is 0, 1 or 2;

p is 1, 2, 3 or 4;

Z 4 is a halogen atom;

q is 0 or 1;

Z 5 is selected from a (C 1 -C 6 )alkyl and a phenyl group, said phenyl group being substituted or not by an amino group;

Z 6 , Z 7 and Z 10 , identical or different, are selected from a hydrogen atom, a (C 1 -C 4 )alkyl, a tetrahydroquinolynyl and a —(CH 2 ) i -aryl group with i being 0, 1 or 2, said aryl group being substituted or not by one, two, three, or four halogen atom(s) or one (C 1 -C 4 ) alkyl group; and

Z 8 and Z 9 , identical or different, are selected from a halogen atom and a (C 1 -C 6 )alkyl group;

or one of its salts;

said compound of formula (I) being in all the possible racemic, enantiomeric and

diastereoisomeric isomer forms.

2. Compound according to claim 1 of formula (II):

wherein:

R 1 , R 2 and Z 1 are as defined in the formula (I) according to claim 1 ;

R 3 is selected from a —CH 3 , a —CH(CH 3 ) 2 , a —CH 2 CH(CH 3 ) 2 and a —CH(CH 3 )CH 2 CH 3 group;

A and B, identical or different, are selected from a nitrogen atom and a —CH— group;

R 5 and R 6 , identical or different, are selected from a hydrogen atom and a (C 1 -C 6 )alkyl group; and

R 4 is selected from a —CH 3 , a —CH(CH 3 ) 2 , a —CH 2 CH(CH 3 ) 2 , a —CH(CH 3 )CH 2 CH 3 and a —(CH 2 ) 2 CO 2 H group;

or one of its salts;

said compound of formula (II) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms.

3. Compound of formula (II) according to claim 2 , wherein at least one of A and B is a —CH group.

4. Compound according to claim 1 of formula (III):

wherein R 1 , R 2 and Z 1 are as defined in the formula (I) according to claim 1 ;

or one of its salts;

said compound of formula (III) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms.

5. Compound according to claim 1 of formula (IV):

wherein R 1 and R 2 are as defined in the formula (I) according to claim 1 ;

or one of its salts;

said compound of formula (IV) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms.

6. Compound according to claim 1 , wherein R 1 is

7. Compound according to claim 1 , wherein R 2 is selected from:

in which Z′ is a fluorine atom and j is 0, 1 or 2.

8. Compound according to claim 1 , having at least one asymmetric carbon atom of (S) configuration.

9. Compound according to claim 1 , selected from:

10. Compound according to claim 1 , for its use as selective Caspase-2 inhibitor.

11. Pharmaceutical composition, comprising at least one compound according to claim 1 and at least one pharmaceutically acceptable excipient, wherein R 2 is selected from

in which m, p, q, Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 and Z 10 are as defined in the formula (I) according to claim 1 .

12. Method for selectively inhibiting caspase-2 activity in a subject in need thereof, comprising the administration to said subject of a compound according to claim 1 ,

wherein R 2 is selected from

in which m, p, q, Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 and Z 10 are as defined in the formula (I) according to claim 1 .

13. Method according to claim 12 for inhibiting caspase-2 mediated cell death in said subject.

14. Method according to claim 12 for treating neonatal brain damage, ischemic brain injuries, ischemic optic neuropathy, glaucoma.

15. Method according to claim 12 for treating metabolic syndrome, nonalcoholic fatty liver disease, or obesity, in said subject.

16. Method according to claim 12 for inducing a neuroprotection in said subject.

17. Method according to claim 12 for inducing a neuroprotection in said subject, wherein the subject is suffering from Alzheimer's disease, Huntington's disease, or Parkinson's disease.

18. Method according to claim 12 for inducing a neuroprotection in said subject, wherein the subject is suffering from neonatal brain damage, traumatic brain injury, stroke-like situations, brain injuries, ischemic optic neuropathy, or glaucoma.

19. Method according to claim 12 for inhibiting neurodegeneration in said subject.

20. Method according to claim 12 , for inhibiting neurodegeneration in a subject suffering from Alzheimer's disease, Huntington's disease, or Parkinson's disease.

21. Method according to claim 12 for treating cognitive decline in said subject, wherein the subject is suffering from Alzheimer's disease.

22. Method according to claim 12 for protecting neuronal cells from Amyloid beta peptides and/or Amyloid-beta oligomers toxicity, wherein the subject is suffering from Alzheimer's disease.

23. Method according to claim 12 , for treating obesity, metabolic syndrome, or nonalcoholic fatty liver disease.