3-amino-3-arylpropan-1-ol-compounds, their preparation and use

Abstract

3-amino-3-arylpropan-1-ol compounds corresponding to the formula I in which R 1 to R 5 , A and X have the meanings according to claim 1, and their preparation and use as medicaments.

1. A 3-Amino-3-arylpropan-1-ol   3 - amino -   3   - arylpropan -   1   - ol  compound corresponding to formula I 
                 
 
       wherein
 R 1  and R 2  each independently denote C 1-6 -alkyl, or R 1  and R 2  together form a (CH 2 ) 2-6  ring, which can also be benzo-fused or phenyl-substituted;  
 R 3  denotes H or methyl;  
 R 4  and R 5  each independently denote C 1-6 -alkyl, C 3-6 -cycloalkyl, phenyl, benzyl or phenethyl, or R 4  and R 5  together form a (CH 2 ) 3-6  or CH 2 CH 2 OCH 2 CH 2  ring;  
 A denotes a substituted or unsubstituted aryl radical, which optionally contains heteroatoms in the ring system;  
 X denotes a substituted benzyl group corresponding to formula XI 
                 
 
  or a substituted benzoyl group corresponding to formula XII 
                 
 
  wherein 
 R 12  to R 14  each independently denote H, F, Cl, Br, CHF 2 , CF 3 , OR 11 , SR 11   OR 15   , SR   15 , OCF 3 , SO 2 CH 3 , SO 2 CF 3 , C 1-6 -alkyl, phenyl, CN, COOR 11   COOR 15  or NO 2 , where  
 R 11 R 15  denotes H, C 1-6 -alkyl, phenyl, benzyl, or phenethyl;  
 
 
       and diastereomers or enantiomers thereof, or a salt thereof with a physiologically acceptable acid,
   with the proviso that if R 1  and R   2    together form a  ( CH   2 ) 4    ring, R   3    is H, A is a substituted phenyl group corresponding to formula XIII                      
   in which one of R   6    to R   10    is OH and the remainder of R   6    to R   10    are H, and X is a benzyl group corresponding to formula XI in which R   12    to R   14    are all H, then R   4    and R   5    are not both C   1-2 - alkyl .  
 
     
     
       2. A compound according to  claim 1 , wherein R 1  and R 2  together form a (CH 2 ) 6  ring, which can be benzo-fused or phenyl-substituted. 
     
     
       3. A compound according to  claim 1 , wherein R 1   R 1  and R 2  together form a (CH 2 ) 4  ring, which can be benzo-fused or phenyl-substituted. 
     
     
       4. A compound according to  claim 1 , wherein R 3  represents hydrogen. 
     
     
       5. A compound according to  claim 1 , wherein A is a substituted phenyl group corresponding to formula XIII 
                 
 
       wherein
 R 6  to R 10  each independently denote H, F, Cl, Br, I, CF 3 , OH, OR 11 , OCF 3 , SR 11 , SO 2 CH 3 , SO 2 CF 3 , C 1-6 -alkyl, phenyl, CN, COOR 11  or NO 2 , or R 6  and R 7  or R 7  and R 8  together form an OCH 2 O or OCH 2 CH 2 O ring, and  
 R 11  denotes C 1-6 -alkyl, phenyl, benzyl, or phenethyl, or a substituted or unsubstituted thiophene radical or furan radical.  
 
     
     
       6. A compound according to  claim 1 , wherein R 1  and R 2  together form a (CH 2 ) 2-6  ring, which can be benzo-fused or phenyl-substituted, and R 3  denotes hydrogen. 
     
     
       7. A compound according to  claim 5 , wherein R 1  and R 2  together form a (CH 2 ) 4 -ring, which can be benzo-fused or phenyl-substituted, and R 3  represents hydrogen. 
     
     
       8. A compound according to  claim 5 , wherein R 1  and R 2  together form a (CH 2 ) 4 -ring, and R 3  represents hydrogen. 
     
     
       9. A compound according to  claim 1 , characterized in  wherein R 1  and R 2  together form a (CH 2 ) 4  ring, A represents a substituted or unsubstituted thiophene radical, and R 3  represents hydrogen. 
     
     
       10. A compounds  compound according to  claim 1 , wherein R 1  and R 2  together form a (CH 2 ) 4  ring, A represents a substituted or unsubstituted furan radical, and R 3  represents hydrogen. 
     
     
       11. A compounds  compound according to  claim 1 , wherein X represents a substituted benzyl group of formula XI. 
     
     
       12. A compounds  compound according to  claim 1 , wherein said compound is selected from the group consisting of:
 dimethyl-{[2-(2-methylbenzyloxy)cyclohexyl]phenylmethyl}-amine and the corresponding hydrochloride;  
 [2-(dimethylaminophenylmethyl)cyclohexyl]4-trifluoro-methylbenzoate and the corresponding hydrochloride;  
 [2-(dimethylaminophenylmethyl)cyclohexyl]4-methoxybenzoate and the corresponding hydrochloride;  
 {[2-(2-chlorobenzyloxy)cyclohexyl]-(2-chlorophenyl)-methyl}dimethylamine and the corresponding hydrochloride;  
 {[2-(3-fluorobenzyloxy)cyclohexyl]phenylmethyl}-dimethylamine and the corresponding hydrochloride, and  
 {[2-(4-fluorobenzyloxy)cyclohexyl]phenylmethyl}-dimethylamine and the corresponding hydrochloride.  
 
     
     
       13. A pharmaceutical composition comprising at least one compound according to  claim 1 , and a pharmaceutical carrier or adjuvant. 
     
     
       14. A pharmaceutical composition comprising a mixture of enantiomers of a compound according to  claim 1 , wherein said enantiomers are present in unequal molar amounts. 
     
     
       15. A pharmaceutical composition according to  claim 14 , wherein one enantiomer comprises between 5 and 45 wt. % of the enantiomer mixture and the other enantiomer comprises between 55 and 95 wt. % of the enantiomer mixture. 
     
     
       16. A process for preparing a compound 3-Amino-3-arylpropan-1-ol   3 - amino -   3   - arylpropan -   1   - ol  compound corresponding to formula I 
                 
 
       wherein
 R 1  and R 2  each independently denote  denotes C 1-6 -alkyl, or R 1  and R 2  together form a (CH 2 ) 2-6  ring, which can also be benzo-fused or phenyl-substituted;  
 R 3  denotes H or methyl;  
 R 4  and R 5  each independently denote  denotes C 1-6 -alkyl, C 3-6 -cycloalkyl, phenyl, benzyl or phenethyl, or R 4  and R 5  together form a (CH 2 ) 3-6  ring or CH 2 CH 2 OCH 2 CH 2  ring;  
 A denotes a substituted or unsubstituted aryl radical, which optionally contains heteroatoms in the ring system;  
 X denotes a substituted benzyl group corresponding to formula XI 
                 
 
  or a substituted benzoyl group corresponding to formula XII 
                 
 
 wherein  
 R 12  to R 14  each independently denote  denotes H, F, Cl, Br, CHF 2 , CF 3 , OR 11 , SR 11   OR 15   , SR   15 , OCF 3 , SO 2 CH 3 , SO 2 CF 3 , C 1-6 -alkyl, phenyl, CN, COOR 11   COOR 15  or NO 2 , where  
 R 11 R 15  denotes H, C 1-6 -alkyl, phenyl, benzyl, or phenethyl;  
 said process comprising reacting a Mannich base corresponding to formula II 
                 
 
  wherein R 1  to R 5  and A have the meanings given above, 
 with a Grignard compound of formula (H 3 C)Y, wherein Y denotes MgCl, MgBr, or MgI, or MeLi, or  
 with a reducing agent, to give rise to an alcohol corresponding to formula Id 
                 
 
 
  wherein R 1  to R 5  and A have the meanings given above; and 
 then reacting said alcohol of formula Id with HalX, wherein Hal is a halogen selected from the group consisting of F, Cl, Br, and I, and X has the meaning given above in the presence of an inorganic or organic base at a temperature in the range from 0° to 150° C.; or  
 then condensing said alcohol of formula Id with XOH at a temperature in the range from 0° to 150° C.;  
 to obtain said compound of formula I.  
 
 
     
     
       17. A method according to  claim 16 , wherein said reducing agent is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride, diisobutylaluminium hydride, and complex analogues thereof. 
     
     
       18. A method of alleviating pain in a mammal comprising administering to said mammal an effective pain alleviating amount of a compound according to  claim 1 . 
     
     
       19. A method according to  claim 18 , wherein said pain is neuropathic pain. 
     
     
       20. A method according to  claim 18 , wherein said pain is chronic pain. 
     
     
       21. A method of local anaesthesia comprising administering an effective local anaesthesia inducing amount of a compound according to  claim 1 . 
     
     
       22. A method of treating arrhythmia in a mammal comprising administering to said mammal an effective antiarrhythmic amount of a compound according to  claim 1 . 
     
     
       23. A method of antiemetic treatment comprising administering an effective antiemetic amount of a compound according to  claim 1 . 
     
     
       24. A method of nootropic (neurotropic) treatment comprising administering an effective nootropic (neurotropic) amount of a compound according to  claim 1 . 
     
     
       25. A method of treating cardiovascular disease in a mammal comprising administering to said mammal an effective cardiovascular disease alleviating amount of a compound according to  claim 1 . 
     
     
       26. A method of treating urinary incontinence in a mammal comprising administering to said mammal an effective urinary incontinence alleviating amount of a compound according to  claim 1 . 
     
     
       27. A method of treating diarrhea in a mammal comprising administering to said mammal an effective diarrhea inhibiting amount of a compound according to  claim 1 . 
     
     
       28. A method of treating pruritus comprising administering an effective pruritus alleviating amount of a compound according to  claim 1 . 
     
     
       29. A method of treating alcohol dependency in a mammal comprising administering to said mammal an effective alcohol dependency alleviating amount of a compound according to  claim 1 . 
     
     
       30. A method of treating drug dependency in a mammal comprising administering to said mammal an effective drug dependency alleviating amount of a compound according to  claim 1 . 
     
     
       31. A method of treating medicament dependency in a mammal comprising administering to said mammal an effective medicament dependency alleviating amount of a compound according to  claim 1 . 
     
     
       32. A method of treating inflammation comprising administering an effective inflammation inhibiting amount of a compound according to  claim 1 .