Derivatives of 2-oxoalkyl-1-piperazin-2-one, preparation method thereof and therapeutic use of same

Abstract

The present invention relates to derivatives of 4-{2-[phenyl-3,6-dihydropyridin-1-yl]-2-oxoalkyl}-1-piperazin-2-one and 4-{2-[phenyl-2,5-dihydropyrrol-1-yl]-2-oxoalkyl}-1-piperazin-2-one having general formula (I): in which A, B, m, R3 and n are as defined herein. The invention also relates to the preparation thereof and to the therapeutic use thereof.

1 . A method for the prevention or treatment of a condition selected from the group consisting of central and peripheral neurodegenerative diseases, senile dementia, epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's chorea, Down's syndrome, prion diseases, amnesia, schizophrenia, depression, bipolar disorder, amyotrophic lateral sclerosis, multiple sclerosis, cardiovascular conditions, post-ischaemic cardiac damage, cardiomyopathies, myocardial infarction, heart failure, cardiac ischaemia, cerebral infarction, peripheral neuropathies, damage to the optic nerve and to the retina, retinal pigment degeneration, glaucoma, retinal ischaemia, macular degeneration, spinal cord traumas, cranial traumas, atherosclerosis, stenoses, cicatrization disorders, alopecia, cancers, tumours, metastases, leukaemias, respiratory disorders, pulmonary inflammation, allergy, asthma, chronic obstructive pulmonary disease, cutaneous, somatic, visceral, and neurological pain, chronic neuropathic and inflammatory pain, autoimmune diseases, rheumatoid arthritis, ankylosing spondyl arthritis, psoriatic arthritis, plaque psoriasis, bone fractures, bone diseases and osteoporosis, the method comprising administering to a patient in need thereof an effective dose of a compound of formula (I): 
       
         
           
           
               
               
           
         
         in which:
 m is 0 or 1; 
 A is: 
 
       
       
         
           
           
               
               
           
         
         and B is a hydrogen atom 
         or 
         A is a hydrogen atom and B is: 
       
       
         
           
           
               
               
           
         
         
           R1 and R2, which may be identical or different, are independently a hydrogen or halogen atom, a C 1 -C 4  alkyl, C 1 -C 4  fluoroalkyl, C 1 -C 2  perfluoroalkyl or C 1 -C 4  alkoxy group or a trifluoromethoxy group; 
           n is 1 or 2; 
           R3 is a group of formula: 
         
       
       
         
           
           
               
               
           
         
         where R4 and R5, which may be identical or different, are located on any available positions, and are independently a hydrogen or halogen atom, a hydroxyl, a C 1 -C 4  alkyl, C 1 -C 4  fluoroalkyl, C 1 -C 2  perfluoroalkyl, C 1 -C 4  alkoxy group, a trifluoromethoxy group, a cyano group, a COOH, COOalkyl, CONH 2 , CONR6R7 or NHCOR group; and
 R, R6 and R7 are a C 1 -C 6  alkyl; 
 
         in the form of a base or of an acid addition salt. 
       
     
     
         2 . The method according to  claim 1 , wherein for the compound of formula (I), R4 and R5, which may be identical or different, are located on any available positions, and are independently CONH 2 , CONR6R7 or NHCOR;
 in the form of a base or of an acid addition salt.   
     
     
         3 . The method according to  claim 1 , wherein for the compound of formula (I):
 m is 1;   A is:   
       
         
           
           
               
               
           
         
         and B is a hydrogen atom;
 R1 and R2, which may be identical or different, are independently a hydrogen or halogen atom, a C 1 -C 4  alkyl, C 1 -C 4  fluoroalkyl, C 1 -C 2  perfluoroalkyl or C 1 -C 4  alkoxy group or a trifluoromethoxy group; 
 n is 1 or 2; 
 R3 is a group of formula: 
 
       
       
         
           
           
               
               
           
         
         where R4 and R5, which may be identical or different, are located on any available positions and are independently a hydrogen or halogen atom, a hydroxyl, a C 1 -C 4  alkyl, C 1 -C 4  fluoroalkyl, C 1 -C 2  perfluoroalkyl or C 1 -C 4  alkoxy group, a trifluoromethoxy group, a cyano group, or a COOH or COOalkyl group; 
         in the form of a base or of an acid addition salt. 
       
     
     
         4 . The method according to  claim 1 , wherein for the compound of formula (I), R1 is other than H; in the form of a base or of an acid addition salt. 
     
     
         5 . The method according to  claim 1 , wherein for the compound of formula (I), R1 is in position -2-, -3- or -4- and is a chlorine atom or a CF 3  radical, and R2 is a hydrogen or a 3- or 4-Cl; in the form of a base or of an acid addition salt. 
     
     
         6 . The method according to  claim 1 , wherein for the compound of formula (I), R3 is a 2-pyridynyl or a 2-pyrimidinyl, each substituted with R4 and R5 as defined in  claim 1 ; in the form of a base or of an acid addition salt. 
     
     
         7 . The method according to  claim 1 , wherein for the compound of formula (I), n=1; in the form of a base or of an acid addition salt. 
     
     
         8 . The method according to  claim 1 , wherein for the compound of formula (I),
 R1 is 3-CF 3 ;   R2 is 4-chloro;   R3 is a 2-pyridyl residue 5-substituted with a CF 3 ; and   n=1;   in the form of a base or of an acid addition salt.   
     
     
         9 . The method according to  claim 1 , wherein the compound is selected from the group consisting of:
 4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-methylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-oxo-2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-pyridin-2-ylpiperazin-2-one;   4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-2-ylpiperazin-2-one;   4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-2-yl-piperazin-2-one;   4-{2-[4-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(6-chloropyridin-2-yl)piperazin-2-one;   4-{2-[4-(3-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(4-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-3-yl-piperazin-2-one;   1-(6-chloropyridin-3-yl)-4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-2-one;   4-{2-oxo-2-[5-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-oxo-2-[4-(3-trifluoromethoxylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-pyridin-2-ylpiperazin-2-one;   4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-2,5-dihydropyrrol-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(3,5-bistrifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(3-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl)-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-phenyl-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-oxo-2-[5-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one; and   4-{2-oxo-2-[5-(3-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   in the form of a base or of an acid addition salt.   
     
     
         10 . A method for inhibiting p75 NTR  receptor dimerization independently of its ligand, the method comprising administering to a patient in need thereof an effective dose of a compound of formula (I): 
       
         
           
           
               
               
           
         
         in which:
 m is 0 or 1; 
 A is: 
 
       
       
         
           
           
               
               
           
         
         and B is a hydrogen atom 
         or 
         A is a hydrogen atom and B is: 
       
       
         
           
           
               
               
           
         
         
           R1 and R2, which may be identical or different, are independently a hydrogen or halogen atom, a C 1 -C 4  alkyl, C 1 -C 4  fluoroalkyl, C 1 -C 2  perfluoroalkyl or C 1 -C 4  alkoxy group or a trifluoromethoxy group; 
           n is 1 or 2; 
           R3 is a group of formula: 
         
       
       
         
           
           
               
               
           
         
         where R4 and R5, which may be identical or different, are located on any available positions, and are independently a hydrogen or halogen atom, a hydroxyl, a C 1 -C 4  alkyl, C 1 -C 4  fluoroalkyl, C 1 -C 2  perfluoroalkyl, C 1 -C 4  alkoxy group, a trifluoromethoxy group, a cyano group, a COOH, COOalkyl, CONH 2 , CONR6R7 or NHCOR group; and
 R, R6 and R7 are a C 1 -C 6  alkyl; 
 
         in the form of a base or of an acid addition salt. 
       
     
     
         11 . The method according to  claim 10 , wherein for the compound of formula (I), R4 and R5, which may be identical or different, are located on any available positions, and are independently CONH 2 , CONR6R7 or NHCOR;
 in the form of a base or of an acid addition salt.   
     
     
         12 . The method according to  claim 10 , wherein for the compound of formula (I):
 m is 1;   A is:   
       
         
           
           
               
               
           
         
         and B is a hydrogen atom;
 R1 and R2, which may be identical or different, are independently a hydrogen or halogen atom, a C 1 -C 4  alkyl, C 1 -C 4  fluoroalkyl, C 1 -C 2  perfluoroalkyl or C 1 -C 4  alkoxy group or a trifluoromethoxy group; 
 n is 1 or 2; 
 R3 is a group of formula: 
 
       
       
         
           
           
               
               
           
         
         where R4 and R5, which may be identical or different, are located on any available positions and are independently a hydrogen or halogen atom, a hydroxyl, a C 1 -C 4  alkyl, C 1 -C 4  fluoroalkyl, C 1 -C 2  perfluoroalkyl or C 1 -C 4  alkoxy group, a trifluoromethoxy group, a cyano group, or a COOH or COOalkyl group; 
         in the form of a base or of an acid addition salt. 
       
     
     
         13 . The method according to  claim 10 , wherein for the compound of formula (I), R1 is other than H; in the form of a base or of an acid addition salt. 
     
     
         14 . The method according to  claim 10 , wherein for the compound of formula (I), R1 is in position -2-, -3- or -4- and is a chlorine atom or a CF 3  radical, and R2 is a hydrogen or a 3- or 4-Cl; in the form of a base or of an acid addition salt. 
     
     
         15 . The method according to  claim 10 , wherein for the compound of formula (I), R3 is a 2-pyridynyl or a 2-pyrimidinyl, each substituted with R4 and R5 as defined in  claim 10 ; in the form of a base or of an acid addition salt. 
     
     
         16 . The method according to  claim 10 , wherein for the compound of formula (I), n=1; in the form of a base or of an acid addition salt. 
     
     
         17 . The method according to  claim 10 , wherein for the compound of formula (I),
 R1 is 3-CF 3 ;   R2 is 4-chloro;   R3 is a 2-pyridyl residue 5-substituted with a CF 3 ; and   n=1;   in the form of a base or of an acid addition salt.   
     
     
         18 . The method according to  claim 10 , wherein the compound is selected from the group consisting of:
 4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-methylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-oxo-2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-pyridin-2-ylpiperazin-2-one;   4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-2-ylpiperazin-2-one;   4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-2-yl-piperazin-2-one;   4-{2-[4-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(6-chloropyridin-2-yl)piperazin-2-one;   4-{2-[4-(3-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(4-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-3-yl-piperazin-2-one;   1-(6-chloropyridin-3-yl)-4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-2-one;   4-{2-oxo-2-[5-(3-trifluoromethyl phenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-oxo-2-[4-(3-trifluoromethoxylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-pyridin-2-ylpiperazin-2-one;   4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-2,5-dihydropyrrol-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(3,5-bistrifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-(3-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-[4-phenyl-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   4-{2-oxo-2-[5-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one; and   4-{2-oxo-2-[5-(3-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;   in the form of a base or of an acid addition salt.   
     
     
         19 . A compound of formula (IV) 
       
         
           
           
               
               
           
         
         in which A, B, m and n are as defined in  claim 1  and Hal is a halogen atom;
 with the exception of 2-chloro-1-[4-(2-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethanone and 2-chloro-1-[4-(4-bromophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethanone; 
 
         in the form of a base or of an acid addition salt.