Novel compounds and their use as selective inhibitors of caspase-2

Abstract

The present invention relates to a compound of formula (I):wherein P1, P3, P4 and P5 are amino acid residues or amino acid like structures.The invention also relates to a compound of formula (I) for its use as a Caspase-2 inhibitor and for its therapeutical use. It also concerns the use of a compound of formula (I) as activity base probe to selectively detect Caspase-2 activity.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         in which: 
         Z 1  and Z 2 , identical or different are selected from a hydrogen atom, a (C 1 -C 6 )alkyl and a (C 1 -C 6 )alkoxy group; 
         P 5  is selected from the following amino acids residues or amino acid like structures: 
       
       
         
           
           
               
               
           
         
         P 1  and P 4 , identical or different, are selected from the following amino acid like structures: 
       
       
         
           
           
               
               
           
         
       
       in which Z 3  and Z 4 , 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 acid 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 5  is a halogen atom; 
 q is 0 or 1; 
 Z 6  is selected from a (C 1 -C 6 )alkyl and a phenyl group, said phenyl group being optionally substituted by an amino group; 
 Z 7 , Z 8  and Z 11 , 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 optionally substituted by one, two, three, or four halogen atom(s) or one (C 1 -C 4 ) alkyl group; and 
 Z 9  and Z 10 , 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  and R 2  are as defined in the formula (I) according to  claim 1 ; 
 Z 1  and Z 2  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  a —CH(CH 3 )CH 2 CH 3  and a 4-hydroxyphenyl 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, preferably A and B are —CH groups. 
     
     
         4 . Compound according to any one of the preceding claims of formula (III): 
       
         
           
           
               
               
           
         
         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 (III) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms. 
       
     
     
         5 . Compound according to any one of the preceding claims, wherein R 1  is: 
       
         
           
           
               
               
           
         
       
     
     
         6 . Compound according to any one of the preceding claims, wherein R 2  is selected from: 
       
         
           
           
               
               
           
         
         in which Z′ is a fluorine atom and j is 0, 1 or 2; 
         and preferably R 2  is: 
       
       
         
           
           
               
               
           
         
       
     
     
         7 . Compound according to any one of the preceding claims, having at least one, preferably at least three asymmetric carbon atoms of (S) configuration, and more preferably all the asymmetric carbon atoms of (S) configuration. 
     
     
         8 . Compound according to any one of the preceding claims, selected from: 
       
         
           
           
               
               
           
         
       
     
     
         9 . Compound according to any one of the preceding claims, for its use as selective Caspase-2 inhibitor. 
     
     
         10 . Pharmaceutical composition, comprising at least one compound according to any one of the  claims 1  to  8  and at least one pharmaceutically acceptable excipient, wherein R 2  is selected from: 
       
         
           
           
               
               
           
         
         in which m, p, q, Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Z 10  and Z 11  are as defined in the formula (I) according to  claim 1 . 
       
     
     
         11 . Compound according to any one of the  claims 1  to  8 , for its use as a medicament,
 wherein R 2  is selected from: 
 
       
         
           
           
               
               
           
         
         in which m, p, q, Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Z 10  and Z 11  are as defined in the formula (I) according to  claim 1 . 
       
     
     
         12 . Compound according to any one of the  claims 1  to  8 , for its use in the prevention and/or treatment of diseases and/or injuries in which Caspase-2 activity is implicated,
 wherein R 2  is selected from: 
 
       
         
           
           
               
               
           
         
         in which m, p, q, Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Z 10  and Z 11  are as defined in the formula (I) according to  claim 1 . 
       
     
     
         13 . Compound according to  claim 12  for its use in the prevention and/or treatment of pathologies with cell death, particularly in chronic degenerative diseases such as Alzheimer's disease or other tauopathies, Huntington's disease and Parkinson's disease;
 neonatal brain damage in particular neonatal brain ischemia; traumatic brain injury; kidney ischemia; hypoxia-ischemia (H-I) injuries; stroke-like situations brain injuries; heart ischemia; myocardial infarction; amyotrophic lateral sclerosis (ALS); retinal damages; ophthalmic diseases such as blunt ocular injury, ischemic optic neuropathy and glaucoma; skin damages; sterile inflammatory diseases such as diabetes, atherosclerosis, cardiac ischemia, gout, pseudogout, joint loosening, atherosclerosis, syndromes triggered by aluminium salts, non-arteritic ischemic optic neuropathy (NAION), glaucoma and metabolic diseases; non-sterile inflammatory diseases such as bacterial infection in particular with bacteria producing pore-forming toxins, influenza virus infection and single-stranded (ss) RNA Rhabdoviridae infection, such as Maraba virus or vesicular stomatitis virus (VSV); diseases caused by pathogenic bacteria, such as  Brucella, Staphylococcus aureus  and  Salmonella ; dyslipidemias; obesity; metabolic syndrome; and nonalcoholic fatty liver disease. 
 
     
     
         14 . Compound according to  claim 13 , for its use in the prevention and/or treatment of Alzheimer's disease. 
     
     
         15 . Compound according to  claim 12 , for its use in protecting neuronal cells from Aβ-induced dysfunction or toxicity, more particularly against Aβ-induced cell death, Aβ-induced axonal degeneration, Aβ-induced electrophysiological dysfunction, and/or Aβ-induced synapse loss. 
     
     
         16 . Use of a compound according to any one of the  claims 1  to  8  as activity-based probe to selectively detect Caspase-2 activity, wherein R 2  is selected from: