Pleuromutilin derivatives for the treatment of diseases mediated by microbes

Abstract

Pleuromutilin derivative compounds of the following formula, and uses thereof for the treatment of diseases mediated by microbes, are disclosed:

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 n is 0 to 4; 
 m is 0 or 1 with the proviso that the sulphur atom and R 3  are in vicinal position (if m=0 then R 3  is in position 2′, and if m=1 then R 3  is on position 1′); 
 R is ethyl or vinyl; 
 R 1  is hydrogen or (C 1-6 )alkyl, 
 R 2  is hydrogen or
 (C 3-6 )cycloalkyl, or 
 unsubstituted (C 1-6 ) alkyl, or 
 (C 1-6 )alkyl substituted by one or more of
 hydroxy; preferably one or two, 
 methoxy, 
 halogen, 
 (C 3-6 )cycloalkyl, or 
 
 
 R 1  and R 2  together with the nitrogen atom to which they are attached form a 5 to 7 membered heterocyclic ring containing at least 1 nitrogen atom or 1 nitrogen and 1 additional heteroatome e.g. selected from N or O, or 
 R 1  is hydroxy and R 2  is formyl; 
 R 3  is OH, OR 4 , a halogen atom, or
 with the proviso that R 3  is bound to 2′ R 3  represents —O—(CH 2 ) p —O— with p is 2 or 3; 
 
 R 4  is unsubstituted (C 1-6 )alkyl or (C 3-6 )cycloalkyl. 
 
     
     
         2 . A compound of formula (II) 
       
         
           
           
               
               
           
         
       
       wherein n, R, R 1 , R 2  and R 3  are as defined in  claim 1 . 
     
     
         3 . A compound of formula (III) 
       
         
           
           
               
               
           
         
       
       wherein n, R, R 1  and R 2  are as defined in  claim 1 . 
     
     
         4 . A compound of formula (IV) 
       
         
           
           
               
               
           
         
       
       wherein n, R 1  and R 2  are as defined in  claim 1 . 
     
     
         5 . A compound of formula (V) 
       
         
           
           
               
               
           
         
       
       wherein n, R 1  and R 2  are as defined in  claim 1 . 
     
     
         6 . A compound of formula (VI) 
       
         
           
           
               
               
           
         
       
       wherein n, R 1  and R 2  are as defined in  claim 1 . 
     
     
         7 . A compound selected from the group consisting of
 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin   14-O-{[(1S,2S,4S)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin   14-O-{[(1R,2R,5S)-5-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin   14-O-{[(1S,2S,5R)-5-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin   14-O-{[(1R,2R,4S)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,4R) diastereomer thereof   14-O-{[(1R,2R,5R)-5-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin   14-O-{[(1S,2S,5S)-5-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin   14-O-{[(1R,2R,3R)-3-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,3S) diastereomer thereof   14-O-{[(1R,2R,4R)-4-Diethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,4S) diastereomer thereof   14-O-{[(1R,2R,4R)-4-Ethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,4S) diastereomer thereof   14-O-{[(1R,2R,55)-5-Ethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,5R) diastereomer thereof   14-O-{[(1R,2R,55)-5-Diethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,5R) diastereomer thereof   14-O-{[(1R,2R,4S)-4-Diethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,4R) diastereomer thereof   14-O-{[(1R,2R,5R)-5-Diethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,5S) diastereomer thereof   14-O-{[(1R,2R,3R)-3-Ethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,3S) diastereomer thereof   14-O-{[(1R,2R,3R)-3-Diethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,3S) diastereomer thereof   14-O-{[(1R,2R,45)-4-(Formyl-hydroxy-amino)-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,4R) diastereomer thereof   14-O-{[(1R,2R,55)-5-(Formyl-hydroxy-amino)-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,5R) diastereomer thereof   14-O-{[(1R,2R,3R/S)-3-(Formyl-hydroxy-amino)-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,3R/S) diastereomer thereof   14-O-{[(1R,2R,5S)-2-Hydroxy-5-methylamino-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,5R) diastereomer thereof   14-O-{[(1R,2R,55)-5-Allylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,5R) diastereomer thereof   14-O-{[(1R,2R,5S)-2-Hydroxy-5-(2-methoxy-ethylamino)-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,5R) diastereomer thereof   14-O-{[(1R,2R,4R*)-2-Hydroxy-4-(2-hydroxy-ethylamino)-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,4S*) diastereomer thereof   14-O-{[(1R,2R,4R*)-4-Cyclohexylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,4S*) diastereomer thereof   14-O-{[(1R,2R,4R*)-4-Cyclopropylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,4S*) diastereomer thereof   14-O-{[(1R,2R,5S*)-4-Cyclopropylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,5R*) diastereomer thereof   14-O-{[(1R,2R,4S*)-4-Cyclopropylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,4R*) diastereomer thereof   14-O-{[(1R,2R,5R*)-2-Hydroxy-5-morpholin-4-yl-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,5S*) diastereomer thereof   14-O-{[(1R,2R,5S*)-2-Hydroxy-5-morpholin-4-yl-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S,5R*) diastereomer thereof 14-O-{[(1R,2R,5S)-5-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-19,20-dihydro-mutilin and the (1S,2S,5R) diastereomer thereof   14-O-{[(1R,2R,55)-5-Ethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-19,20-dihydro-mutilin and the (1S,2S,5R) diastereomer thereof   14-O-{[(1R,2R,5R)-5-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-19,20-dihydro-mutilin and the (1S,2S,5S) diastereomer thereof   14-O-{[(1R,2R)-4-Aminomethyl-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S) diastereomers thereof   14-O-{[5-Amino-2-chloro-cyclohexylsulfanyl]-acetyl}-mutilin   14-O-{[4-Amino-2-chloro-cyclohexylsulfanyl]-acetyl}-mutilin   14-O-[(4-Amino-1-hydroxy-cyclohexylmethylsulfanyl-acetyl]-mutilin   14-O-{[(1R,2R)-2-Hydroxy-5-(3-methylamino-propyl-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S) diastereomers thereof   14-O-{[(1R,2R)-2-Hydroxy-4-(3-methylamino-propyl)-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S) diastereomers thereof   14-O-{[(1R,2R)-5-(3-Amino-propyl)-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S) diastereomers thereof   14-O-{[(1R,2R)-4-(3-Amino-propyl)-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S,2S) diastereomer thereof   14-O-{[(6R,8R)-8-Amino-1,4-dioxa-spiro[4.5]dec-6-ylsulfanyl]-acetyl}-mutilin and the (6S,8S) diastereomer thereof   14-O-{[4-Amino-2-methoxy-cyclohexylsulfanyl]-acetyl}-mutilin   
       and 14-O-{[5-Amino-2-methoxy-cyclohexylsulfanyl]-acetyl}-mutilin 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . A method of treatment of diseases mediated by microbes which comprises administering to a subject in need of such treatment an effective amount of a compound of any one of  claims 1  to  7 . 
     
     
         11 . (canceled) 
     
     
         12 . (canceled)