3,3-diphenylpropylamines, their use and preparation

Abstract

The invention relates to 3,3-diphenylpropylamines of formula (I), wherein R 1 signifies hydrogen or methyl, R 2 and R 3 independently signify hydrogen, methyl, methoxy, hydroxy, carbamoyl, sulphamoyl or halogen, and X represents a tertiary amino group of formula (II), wherein R 4 and R 5 signify non-aromatic hydrocarbyl groups, which may be the same or different and which together contain at least three carbon atoms, and wherein R 4 and R 5 may form a ring together with the amine nitrogen, their salts with physiologically acceptable acids and, when the compounds can be in the form of optical isomers, the racemic mixture and the individual enantiomers. The invention also relates to methods for their preparation, pharmaceutical compositions containing the novel compounds, and the use of the compounds for preparing drugs

1. A 3,3-diphenylpropylamine of formula I 
                   
       wherein R 1  represents hydrogen or methyl, R 2  and R 3  independently represent hydrogen, methyl, methoxy, hydroxy, carbamoyl, sulphamoyl or halogen, and X represents a tertiary amino group of formula II 
                 
 
       wherein R 4  and R 5  represent non-aromatic hydrocarbyl groups, which are the same or different and which together contain at least three carbon atoms, and wherein R 4  and R 5  may form a ring together with the amine nitrogen; or a physiologically acceptable acid salt thereof. 
     
     
       2. The 3,3-diphenylpropylamine according to  claim 1 , wherein each of R 4  and R 5  independently represents a saturated hydrocarbyl group. 
     
     
       3. The 3,3-diphenylpropylamine according to  claim 1  wherein at least one of R 4  and R 5  comprises a branched carbon chain. 
     
     
       4. The 3,3-diphenylpropylamine according to  claim 1 , wherein X is a moiety selected from the group consisting of formulas a) to h): 
                       
     
     
       5. The 3,3-diphenylpropylamine according to  claim 1 , wherein the HOCH 2 -group is in the 5-position on the phenyl ring, R 2  is hydrogen and R 3  is hydrogen or hydroxy. 
     
     
       6. The 3,3-diphenylpropylamines according to  claim 1 , selected from N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine, its salts with physiologically acceptable acids, racemates thereof and individual enantiomers thereof. 
     
     
       7. A pharmaceutical composition comprising an effective amount of a 3,3-diphenylpropylamine according to  claim 1  and a compatible pharmaceutical carrier. 
     
     
       8. A method for preparing a 3,3-diphenylpropylamine according to  claim 1 , comprising:
 a) reducing the group R 6 CO of a 3,3-diphenylpropylamine of formula III 
                 
   
       wherein R 1  to R 3  and X are as defined above, R 6  is hydrogen or R 7 O, where R 7  is hydrogen, alkyl, alkenyl, alkynyl or aryl, and any hydroxy groups may be protected, such as by methylation or benzylation, or
 b) reacting a reactively esterified 3,3-diphenylpropanol of formula IV 
                 
 
 
       wherein R 1  to R 3  are as defined above, any hydroxy groups may be protected, and wherein Y is a leaving group, with an amine of formula V
   H—X   V  
 
       wherein X is as defined above, or
 c) reducing a 3,3-diphenylpropionamide of formula VI 
                 
 
 
       wherein R 1  to R 3  and X are as defined above and any hydroxy groups may be protected, or
 d) N-methylating a secondary 3,3-diphenylpropylamine of formula VII 
                 
 
 
       wherein R 1  to R 3  and X are as defined above and any hydroxy groups may be protected, and wherein Z has the same meaning as R 4  and R 5  with the exception of methyl, or
 e) reducing a 3,3-diphenylpropenamine of formula VIIIa or a 3,3-diphenylpropylamine of formula VIIIb 
                 
 
 
       wherein R 1  to R 3  and X are as defined above and any hydroxy groups may be protected, and W signifies a hydroxy group or a halogen atom, or
 f) reacting a diphenylpropylamine of formula IX 
                 
 
 
       wherein R 1  to R 3  and X are as defined above, and Hal is halogen, with formaldehyde or a formaldehyde equivalent, or
 g) oxidizing the methyl group of a diphenylpropylamine of formula X 
                 
 
 
       wherein R 1  to R 3  and X are as defined above, and
 i) when necessary splitting off hydroxy protecting groups in the compounds obtained, if desired after mono- or di-halogenation of one or both of the phenyl rings, and/or  
 ii) if desired converting the obtained bases of formula I into salts thereof with physiologically acceptable acids, or vice versa, and/or  
 iii) if desired separating an obtained mixture of optical isomers into the individual enantiomers, and/or  
 iv) if desired methylating an ortho-hydroxy group in an obtained compound of formula I, wherein R 1  is hydrogen and/or R 3  is hydroxy.  
 
     
     
       9. The 3,3-diphenylpropylamine according to  claim 1 , wherein said compound is in the form of a racemic mixture of optical isomers. 
     
     
       10. The 3,3-diphenylpropylamine according to  claim 1 , wherein said compound is an individual enantiomer. 
     
     
       11. The 3,3-diphenylpropylamine according to  claim 2 , wherein R 4  and R 5  independently represent a C 1-8 -alkyl group or adamantyl and the total number of carbon atoms contained in R 4  and R 5  is at least four carbon atoms. 
     
     
       12. The 3,3-diphenylpropylamine according to  claim 11 , wherein R 4  and R 5  independently represent a C 1-6 -alkyl group. 
     
     
       13. The 3,3-diphenylpropylamine according to  claim 5 , wherein R 3  is in the 2-position on the phenyl ring. 
     
     
       14. A method for treating acetylcholine-mediated disorders which comprises administering to a patient in need thereof an effective amount of a 3,3-diphenylpropylamine as claimed in  claim 1 . 
     
     
       15. The method according to  claim 14 , wherein said disorder is urinary incontinence. 
     
     
       16. A pharmaceutical composition comprising an effective amount of a  3 , 3 - diphenylpropylamine of formula I,                      
       
         wherein R 
         1  
         represents hydrogen or methyl, R 
         2  
         and R 
         3  
         independently represent hydrogen, methyl, methoxy, hydroxy, carbamoyl, sulphamoyl or halogen, and X represents a tertiary amino group of formula II  
         
           
           
               
               
           
         
       
         wherein R   4    and R   5    represent non - aromatic hydrocarbyl groups, which are the same or different and which together contain at least three carbon atoms, and wherein R   4    and R   5    may form a ring together with the amine nitrogen; or a physiologically acceptable acid salt thereof; and a compatible inert pharmaceutical carrier for oral use, for injection or for nasal spray administration.   
     
     
       17. A pharmaceutical composition as claimed in  claim 16 , wherein the  3 , 3 - diphenylpropylamine is selected from N,N-diisopropyl- 3 -( 2 -hydroxy- 5 -hydroxymethylphenyl)- 3 -henylpropylamine, its salts with physiologically acceptable acids, racemates thereof and individual enantiomers thereof.   
     
     
       18. A pharmaceutical composition as claimed in  claim 16 , wherein the  3 , 3 - diphenylpropylamine is selected from(+)-N,N-diisopropyl- 3 -( 2 -hydroxy- 5 -hydroxymethylphenyl)- 3 -phenylpropylamine, and its salts with physiologically acceptable acids.