Method of enhancing cellular production of molecular chaperone, hydroxylamine derivatives useful for enhancing the chaperone production and the preparation thereof

Abstract

A method of increasing expression of a molecular chaperon by a cell and/or enhancing the activity of a molecular chaperon in cells is provided. The method comprises treating a cell that is exposed to a physiological stress which induces expression of a molecular chaperon by the cell with an effective amount of a certain hydroxylamine derivative to increase the stress. Alternatively, an hydroxylamine derivative can be administrated to a cell before it is exposed to a physiological stress which induces expression of a molecular chaperon by the cell. Preferably, the cell to which an hydroxylamine derivative is administered is an eukaryotic cell. The hydroxylamine derivative corresponds to the formulae (I) or (II). The invention also provides novel hydroxylamine derivatives falling within the scope of the formulae (I) and (II) as well as pharmaceutical and/or cosmetical compositions comprising the said compounds.

1 . A method of increasing expression of a molecular chaperon by an eukaryotic cell comprising:
 treating an eukaryotic cell of a living mammalian organism that is exposed to a physiological stress accompanying allergic diseases, immune diseases, autoimmune diseases, diseases of viral or bacterial origin, tumorous, skin and/or mucous diseases, epithelial disease of renal tubulus, atherosclerosis, coronarial disease, pulmonary hypertonia, cerebrovascular ischemia, stroke, or traumatic head injury with an effective amount of a chemical compound to increase the expression of the molecular chaperon by the cell beyond the amount induced by the physiological stress, wherein the chemical compound is one or more of a hydroxylamine derivative represented by formula (I″),   
       
         
           
           
               
               
           
         
       
       or a salt thereof or any optically active streoisomer thereof, wherein 
       R″ is alkyl or substituted alkyl, 
       A is unsubstituted or substituted aryl or heteroaryl, and 
       R 1  is H, unsubstituted or substituted straight or branched alkyl, cycloalkyl, aralkyl, or aralkyl substituted in the alkyl and/or aryl moiety. 
     
     
         2 . The method according to  claim 1  wherein the cell is treated before the physiological stress. 
     
     
         3 . The method according to  claim 1  wherein the cell is treated after the physiological stress. 
     
     
         4 . The method of  claim 1  wherein the cell is a neuronal cell, muscle cell, vessel wall cell, epithelial cell or a cell of the immune system. 
     
     
         5 . The method of  claim 1  wherein the physiological stress is metabolic, oxidative or local mechanical stress or a stress caused by hypoxia, heat shock, radiation or toxic materials. 
     
     
         6 . The method of  claim 1  wherein the physiological stress causes an increase of reactive free radicals or a cytokine present in the area surrounding the cell. 
     
     
         7 . The method of  claim 1  wherein one or more of the skin or mucosal disease is caused by dermatosis or ulcerous disease of the gastrointestinal system provoked by physiological stress. 
     
     
         8 . The method of  claim 1  wherein the molecular chaperon is a heat shock protein (hsp). 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein R″ is ω-amino-alkyl which may be substituted on the amino and/or alkyl chain, and wherein the alkyl chain has 1 to 5 carbon atoms. 
     
     
         11 . The method of  claim 10  wherein R″ is an ω-amino-alkyl mono- or disubstituted on the amino, and wherein the amino substituent or substituents, independently, are one or two straight or branched alkyl or cycloalkyl, or the two amino substituents, together with the nitrogen atom attached thereto, form a 3 to 7-membered saturated hetero ring, which may contain additional hetero atoms. 
     
     
         12 . The method of  claim 1  wherein A is
 phenyl, phenyl substituted with one or more alkyl, halo, alkoxy, haloalkyl or nitro, or naphtyl or N-containing heteroaryl which may be condensed with a benzene ring, or an S-containing or O-containing heteroaryl.   
     
     
         13 . A method of increasing activity of a molecular chaperon in an eukaryotic cell of a living mammalian organism that is exposed to a physiological stress comprising:
 treating the cell that is exposed to a physiological stress accompanying allergic diseases, immune diseases, autoimmune diseases, diseases of viral or bacterial origin, tumorous, skin and/or mucous diseases, epithelial disease of renal tubulus, atherosclerosis, coronarial disease, pulmonary hypertonia, cerebrovascular ischemia, stroke, or traumatic head injury with an effective amount of a chemical compound to increase the activity of the molecular chaperon in the cell beyond the amount induced by the physiological stress, wherein the chemical compound is one or more of a hydroxylamine derivative represented by formula (I″),   
       
         
           
           
               
               
           
         
       
       or a salt thereof or an optically active stereoisomer thereof, 
       wherein R″ is alkyl or substituted alkyl, 
       A is unsubstituted or substituted aryl or heteroaryl, and 
       R 1  is H, unsubstituted or substituted straight or branched alkyl, cycloalkyl, aralkyl, or aralkyl substituted in the alkyl and/or aryl moiety. 
     
     
         14 . The method of  claim 13 , wherein the mammalian cell is a human cell. 
     
     
         15 . The method of  claim 13  wherein the physiological stress is metabolic, oxidative or local mechanical stress or a stress caused by hypoxia, heat shock, radiation or toxic materials. 
     
     
         16 . The method of  claim 13  wherein the physiological stress causes an increase of reactive free radicals or a cytokine present in the area surrounding the cell. 
     
     
         17 . The method of  claim 13  wherein one or more of the skin or mucosal disease is caused by dermatosis or ulcerous disease of the gastrointestinal system provoked by physiological stress. 
     
     
         18 . The method of  claim 13  wherein the molecular chaperon is a heat shock protein (hsp). 
     
     
         19 - 22 . (canceled) 
     
     
         23 . Hydroxylamine derivatives of the formula (I″), 
       
         
           
           
               
               
           
         
         wherein
 A is phenyl or phenyl substituted with halo or nitro or an N-containing heteroaryl group, 
 R′ is H and 
 R″ is ω-aminoalkyl which is mono- or disubstituted on the amino group, wherein the alkyl chain has 1 to 5 carbon atoms and the amino substituent or substituents may be independently one or two straight or branched alkyl or cycloalkyl, or the two amino substituents, when taken together with the N-atom attached thereto, form a 3 to 7-membered heterocyclic ring, or the N—C 1-4  alkyl-quaternary derivative or the N-oxide thereof, with the proviso, that 
 when A is 3-pyridyl, R″ is other than 1-piperidinyl-methyl. 
 
       
     
     
         24 . The hydroxylamine derivatives of  claim 23  wherein A is pyridyl. 
     
     
         25 . Pharmaceutical composition, and said composition's pharmaceutically acceptable carriers and auxiliaries, for the treatment of cardiovascular, vascular, cerebral, allergic, immune, autoimmune diseases, diseases caused by viral or bacterial infections, tumorous, skin or mucosal diseases, wherein composition contains 0.5 to 99.5% by weight of a hydroxylamine compound of  claim 23 .