Hydroxylamine derivatives

Abstract

This invention is related to hydroxylamino derivatives of the following general formula (I) wherein n is 0, 1 or 2; R 1 and R 2 , independently of each other, are H, OH or OCH 3 ; R 3 is H or CH 3 ; R 4 is H, C 1 -C 3 straight or branched alkyl or, together with R 3 , forms a five to seven-membered carbocyclic ring; and R 5 and R 6 , independently of each other, are H or C 1 -C 5 straight or branched alkyl and the pharmaceutically acceptable salts or prodrug thereof, for the preparation of medicaments useful for the prevention, treatment and diagnosis of CNS degenerative disorders related to protein misfolding and/or misaggregation. The invention also relates to novel compounds included in formula (I), to a method for preparing the compounds and to pharmaceutical compositions containing them.

1 . A compound of the formula: 
     
       
         
         
             
             
         
       
       and pharmaceutically acceptable salts thereof, wherein: 
       is 0, 1 or 2; 
       R 1  and R 2 , independently of each other, are H, OH or OCH 3 ; 
       R 3  is H or CH 3 ; 
       R 4  is H, C 1 -C 3  straight or branched alkyl or, together with R 3 , forms a five to seven-membered carbocyclic ring; 
       and R 5  and R 6 , independently of each other, are H or C 1 -C 5  straight or branched alkyl 
       with the provisos that: 
       R 1  and R 2  cannot be both hydrogen; 
       when n is 0, R 1  and R 2  are both hydroxyl, and R 3  and R 5  are hydrogen, R 4  cannot be CH 3 ; 
       when n is 0, R 3  is H and R 4  is H or CH 3 , R 6  cannot be C 1 -C 3  straight or branched alkyl; 
       and that the compound cannot be:
 1-(4-hydroxyphenyl)-2-hydroxylaminoethane, 
 1-(4-hydroxyphenyl)-2-hydroxylaminopropane, 
 1-(4-methoxyphenyl)-2-hydroxylaminopropane, 
 1-(3,4-dimethoxyphenyl)-2-hydroxylaminopropane, 
 1-(4-methoxyphenyl)-4-hydroxylaminobutane, 
 1-(3-methoxyphenyl)-2-hydroxylaminopropane, 
 1-(3,4-dimethoxyphenyl)-2-hydroxylaminoethane, 
 N-methyl-1-(3,4-dihydroxyphenyl)-2-hydroxylaminopropane, 
 1-(3-methoxy-4-hydroxyphenyl)-2-hydroxylaminopropane, 
 N-methyl-1-(3-methoxy-4-hydroxyphenyl)-2-hydroxylaminopropane, 
 N-methyl-1-(3,4-dimethoxyphenyl)-2-hydroxylaminopropane, and 
 N-ethyl-1-(3-hydroxyphenyl)-2-hydroxylaminoethane. 
 
     
   
   
       2 . A pharmaceutical composition comprising one or more compounds according to  claim 1  in a mixture with suitable excipients and/or carriers. 
   
   
       3 . A pharmaceutical composition comprising one or more compounds according to  claim 1  and a compound for the treatment of central and peripheral nervous system disorders involving protein misfolding and/or misaggregation of beta-amyloid peptide, alpha-synuclein, prion protein and huntingtin selected from Alzheimer's Disease, Lewy body disease, Parkinson's Disease, spongiform encephalopathies, Huntington's Disease and systemic AA amyloidosis, in admixture with suitable excipients and/or carriers.