Pleuromutilin derivatives for the treatment of diseases mediated by microbes

Abstract

Pleuromutilin derivative compounds of the following formula (I), 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 from a 5 to 7 membered heterocyclic ring containing at least 1 nitrogen atom or 1 nitrogen and 1 additional heteroatoms 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 3  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 according to one of the  claims 1  to  6 , selected from the group consisting of
 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, 5S)-5-Ethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 5R) diastereomer thereof 
 14-O-{[(1R, 2R, 5S)-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, 4S)-4-(Formyl-hydroxy-amino)-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 4R) diastereomer thereof 
 14-O-{[(1R, 2R, 5S)-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, 5S)-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-{[(1(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, 5S)-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 . The compound according to any of  claims 1  to  7  in the form of a salt and/or solvate. 
     
     
         9 . A compound according to any of  claims 1  to  8  for use as a pharmaceutical drug substance. 
     
     
         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  8 . 
     
     
         11 . A pharmaceutical drug composition comprising a compound of anyone of  claims 1  to  8 , in association with at least one pharmaceutical excipient. 
     
     
         12 . A pharmaceutical drug composition according to  claim 11 , further comprising another pharmaceutically active agent.