Pleuromutilin derivatives for the treatment of diseases mediated by microbes

Abstract

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 (C1-6)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.

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 according to one of the  claims 1  to  6 , 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,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-{[(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-dioxo-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.