Aminopropanol derivatives

Abstract

Compounds of formula I: wherein R 1 , R 2 , n and m are as defined in the specification, processes for their production, their uses and pharmaceutical compositions containing them.

1 . (canceled) 
     
     
         2 . A compound of formula II: 
       
         
           
           
               
               
           
         
       
       wherein 
       each of m and n, independently, is 1, 2 or 3: 
       X is O or a direct bond: 
       R 1  is
 a phenylalkyl wherein alkyl is a straight- or branched (C 6-20 )carbon chain; or 
 a phenylalkyl wherein alkyl is a straight- or branched (C 1-30 )carbon chain wherein said phenylalkyl is substituted at the phenyl residue by 
 a straight- or branched C 6-20  carbon chain optionally substituted by halogen, 
 a straight- or branched (C 6-20 )alkoxy chain optionally substituted by halogen, 
 a straight- or branched (C 6-20 )alkenyloxy, 
 phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, 
 cycloalkylalkyl substituted by C 6-20 alkyl, 
 heteroarylalkyl substituted by C 6-20 alkyl, 
 heterocyclic C 6-20 alkyl or 
 heterocyclic alkyl substituted by C 6-20 alkyl, 
 
       and wherein 
       the alkyl moiety may have
 in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, O, S, sulfinyl, sulfonyl, or NR 5 , wherein R 5  is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and 
 as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyl or carboxy, and 
 
       R 2  is 
       
         
           
           
               
               
           
         
       
       wherein each of R 3  and R 4  independently is H or C 1-4 alkyl, wherein alkyl is optionally substituted by 1, 2 or 3 halogen atoms; or a pharmaceutically acceptable salt thereof; and wherein greater than 70% of the compound by weight is in the form of the R or S enantiomer. 
     
     
         3 . A compound of formula II according to  claim 2  in the form of the substantially pure enantiomer having the following 3-dimensional configuration 
       
         
           
           
               
               
           
         
       
       . 
     
     
         4 . (canceled) 
     
     
         5 . A process for producing a compound as defined in  claim 2 , comprising deprotecting a compound of formula III, IIIa or IIIb, wherein greater than 70% by weight of the compound of formula III, IIIa or IIIb is in the form of the R or S enantiomer: 
       
         
           
           
               
               
           
         
       
       wherein n, m, X, R 1  and R 2  are as defined above, R 6  is an amino protecting group, and R 6 ′ is a simultaneous OH and amino protecting group; 
       and, where required, converting the compounds of formula II obtained in free form into the desired salt form, or vice versa. 
     
     
         6 . A method according to  claim 7 , wherein the HPLC of step (b) is using a chiral ion-exchange phase based on quinine carbamate or quinidine carbamate. 
     
     
         7 . A method for determining the amount of the R and/or S isomers of a compound of formula II present in a sample, comprising 
       (a) reacting the compound of formula II present in the sample with an aromatic 1,2-dicarbaldehyde to form a compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein m, n, x, R 1  and R 2  are as defined in formula II; and 
       (b) separating the R and S isomers of the compound of formula I by HPLC. 
     
     
         8 . (canceled) 
     
     
         9 . A method for preventing or treating acute or chronic transplant rejection or T-cell mediated inflammatory or autoimmune diseases in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a compound as defined in  claim 2 , or a pharmaceutically acceptable salt thereof. 
     
     
         10 . A compound of formula III, IIIa, IIIb: 
       
         
           
           
               
               
           
         
       
       wherein n, m, x, R 1  and R 2  are as defined in  claim 1  and R 6 ′ is a simultaneous OH and amino protecting group; or a pharmaceutically acceptable salt thereof. 
     
     
         11 . A compound of formula II according to  claim 3 , wherein said compound comprises the S enantiomer of phosphoric acid mono-[2-amino-2-hydroxymethyl-4-(4-octyl-phenyl)-butyl]ester. 
     
     
         12 . A compound of formula II according to  claim 2 , wherein greater than 90% of the compound by weight is in the form of the R or S enantiomer. 
     
     
         13 . A compound of formula II according to  claim 2 , wherein greater than 95% of the compound by weight is in the form of the R or S enantiomer. 
     
     
         14 . A compound of formula II according to  claim 2 , wherein greater than 99% of the compound by weight is in the form of the R or S enantiomer.