Phenylethylamines and condensed rings variants as prodrugs of catecholamines, and their use

Abstract

Compounds of the general formula I wherein rings B, C, D and E may be present or not and, when present, are combined with A as A+C, A+E, A+B+C, A+B+D, A+B+E, A+C+E, A+B+C+D or A+B+C+D+E, rings B, C and E being aliphatic whereas ring D may be aliphatic or aromatic/heteroaromatic, and wherein X is —(CH 2 ) m —, in which m is an integer 1-3, to form a ring E or, when E is absent, a group R 1 bound to the nitrogen atom, wherein R 1 is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 3 carbon atoms, cycloalkyl(alkyl) groups of 3 to 5 carbon atoms (i.e. including cyclopropyl, cyclopropylmethyl, cyclobutyl and cyclobutylmethyl) and wherein Y is —(CH 2 ) n —, in which n is an integer 1-3, to form a ring C or when C is absent, a group R 2 bound to the nitrogen atom, wherein R 2 is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 7 carbon atoms, cycloalkyl(alkyl) groups of 3 to 7 carbon atoms, alkenyl or alkylnyl groups of 3 to 6 carbon atoms, arylalkyl, heteroarylalkyl having 1 to 3 carbon atoms in the alkyl moiety, whilst the aryl/heteroaryl nucleus may be substituted, provided that when rings B, C, D and E are absent NR 1 R 2 is different from dimethylamino, N-methyl-N-ethylamino, N-methyl-N-propynyl-amino, N-methyl-N-propylamino and N-hydroxipropyl-N-methylamino, and salts thereof with pharmaceutically acceptable acids or bases are disclosed as well as the use of such compounds for the manufacturing of pharmaceutical compositions for the treatment of Parkinson's disease, psychoses, Huntington's disease, impotence, renal failure, heart failure or hypertension, such pharmaceutical compositions and methods of treating Parkinson's disease and schizophrenia.

The invention claimed is: 
     
       1. Compounds of the following general formula If: 
       
         
           
           
               
               
           
         
       
       wherein m is an integer 1-3 and R 2  is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 7 carbon atoms, cycloalkyl (alkyl) groups of 3 to 7 carbon atoms, alkenyl or alkylnyl groups of 3 to 6 carbon atoms, arylalkyl, heteroarylalkyl having 1 to 3 carbon atoms in the alkyl moiety, in which the aryl/heteroaryl may be substituted; and salts thereof with pharmaceutically acceptable acids or bases. 
     
     
       2. Compounds according to  claim 1 , wherein R 2  is n-propyl. 
     
     
       3. A method of treating Parkinson's disease in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula If as defined in  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
       4. A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein m is an integer 1-3, n is an integer 1-3, R 1  is selected from the group consisting of an alkyl or haloalkyl groups of 1 to 3 carbon atoms, R 2  is selected from the group consisting of an alkyl or haloalkyl groups of 1 to 7 carbon atoms; and
 substantially pure chiral forms and pharmaceutically acceptable salts thereof. 
 
     
     
       5. The compound of claim 4, wherein said compound is 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       6. The compound of claim 4, wherein said compound is Formula Ib having the following substantially pure enantiomeric form: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       7. The compound of claim 4, wherein said compound is 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       8. A compound having a substantially pure enantiomeric form selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein m is an integer 1-3, n is an integer 1-3, R 2  is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 7 carbon atoms; and pharmaceutically acceptable salts thereof. 
     
     
       9. The compound of claim 7, wherein R 1  is n-propyl. 
     
     
       10. The compound of claim 6, wherein R 2  is n-propyl. 
     
     
       11. A compound according to claim 4, which is 3-(1-propyl-piperidin-3-yl)-cyclohex-2-enone; or the pharmaceutically acceptable salt thereof. 
     
     
       12. A pharmaceutical composition which contains a compound, said compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein m is an integer 1-3, n is an integer 1-3, R 1  is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 3 carbon atoms, R 2  is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 7 carbon atoms; and substantially pure chiral forms and pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
       13. A pharmaceutical composition which contains a compound, said compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein m is an integer 1-3, n is an integer 1-3, R 2  is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 7 carbon atoms; and substantially pure chiral forms and pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
       14. A method of treating Parkinson's disease in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein said compound or pharmaceutically acceptable salt thereof is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein m is an integer 1-3, n is an integer 1-3, R 1  is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 3 carbon atoms, R 2  is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 7 carbon atoms; and pharmaceutically acceptable salts thereof. 
     
     
       15. The method of claim 14, wherein said compound is 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof. 
     
     
       16. The method of claim 14, wherein said compound is 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof. 
     
     
       17. The method of claim 15, wherein R 2  is n-propyl. 
     
     
       18. The method of claim 16, wherein R 1  is n-propyl.