Pleuromutilin derivatives for use in the treatment of diseases mediated by microbes

1. A compound selected from the group consisting of N-unsubstituted, N-alkylated, and N-acylated

14-O-[(amino(C 0-4 )alkyl-hydroxy-cyclobutylsulfanyl)-acetyl]-mutilins,

14-O-[(amino(C 0-4 )alkyl-hydroxy-cyclopentylsulfanyl)-acetyl]-mutilins,

14-O-[(amino(C 0-4 )alkyl-hydroxy-cycloheptylsulfanyl)-acetyl]-mutilins,

14-O-[(amino(C 0-4 )alkyl-hydroxy-cyclooctylsulfanyl)-acetyl]-mutilins, and

14-O-[(amino(C 0-4 )alkyl-hydroxy-bicycloalkylsulfanyl)-acetyl]-mutilins,

wherein bicycloalkyl is a group of formula

 wherein o is 0, 1, 2, 3, or 4, and p is 0, 1, 2, 3, or 4.

2. A compound according to claim 1 which is an N-unsubstituted, N-alkylated, or N-acylated 14-O-[amino(C 0-4 )alkyl-hydroxy-cyclopentylsulfanyl)-acetyl]-mutilin or an N-unsubstituted, N-alkylated, or N-acylated 14-O-[amino(C 0-4 )alkyl-hydroxy-bicycloalkylsulfanyl)-acetyl]-mutilin,

wherein one ring of the bicyclic alkyl is a cyclopentyl ring.

3. A compound of formula (I)

or of formula (II)

wherein

m is 0, 1, 2, 3 or 4;

n is 0, 1, 3 or 4;

o is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

R is ethyl or vinyl;

R 1 is hydrogen or (C 1-6 )alkyl;

R 2 is hydrogen, (C 3-6 )cycloalkyl, unsubstituted (C 1-6 )alkyl, or (C 1-6 )alkyl substituted by one or more of hydroxy, methoxy, halogen, or (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 heteroatom, or

R 2 is a group of formula

 wherein

R 3 is hydrogen, straight chain or branched (C 1-8 )alkyl or (C 3-8 )cycloalkyl, or

R 3 is that part of a natural amino acid in D or in L form which remains if the carboxylic acid group is split off, or

R 3 is that part of a non natural amino acid in D or in L form which remains if the carboxylic acid group is split off.

4. A compound according to claim 3 of formula (III)

or of formula (IV)

wherein m, n, o, p, R 1 and R 2 are as defined in claim 3 .

5. A compound according to claim 3 of formula (V)

or of formula (VI)

or of formula (VII)

or of formula (VIII)

wherein m, R 1 and R 2 are as defined in claim 3 .

6. A compound according to claim 1 , selected from the group consisting of

14-O-{[(1R, 2R, 4R)-4-Amino-2-hydroxy-cyclopentylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 4S) diastereomer thereof,

14-O-{[(1R, 2R, 4S)-4-Amino-2-hydroxy-cyclopentylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 4R) diastereomer thereof,

14-O-{[(1R, 2R, 4R)-4-Aminomethyl-2-hydroxy-cyclopentylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 4S) diastereomer thereof,

14-O-{[(1R, 2R, 4S)-4-Aminomethyl-2-hydroxy-cyclopentylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 4R) diastereomer thereof,

14-O-{[(1R, 2R, 4S)-4-[(2,2-Dimethyl-propylamino)-methyl]-2-hydroxy-cyclopentylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 4R) diastereomer thereof,

14-O-{[(1R, 2R, 4S)-2-Hydroxy-4-[(2,2,2-trifluoro-acetylamino)-methyl]-cyclopentylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 4R) diastereomer thereof,

14-O-{[(1R, 2R, 3S)-2-Hydroxy 3-[2-(2,2,2-trifluoro-acetylamino)-ethyl]-cyclopentylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 3R) diastereomer thereof,

14-O-{[(1R, 2R, 3S)-3-(2-Amino-ethyl)-2-hydroxy-cyclopentylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 3R) diastereomer thereof,

14-O-{[(1R, 2R, 5R)-5-Hydroxy-2-[2-(2,2,2-trifluoro-acetylamino)-ethyl]-cyclopentylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 5S) diastereomer thereof,

14-O-{[(1R, 2R, 5R)-2-(2-Amino-ethyl)-5-hydroxy-cyclopentylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 5S) diastereomer thereof,

14-O-{[(1R, 2R, 5R)-2-[2-(2,2-Dimethyl-propylamino)-ethyl]-5-hydroxy-cyclopentylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 5S) diastereomer thereof,

14-O-{[(1R, 2R, 5R)-5-Amino-2-hydroxy-cycloheptylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 5S), (1R, 2R, 5S)-(1S, 2S, 5R) diastereomers thereof,

14-O-{[(1R, 2S, 3S, 5R, 6S)-6-Amino-2-hydroxy-bicyclo[3.2.0]hept-3-ylsulfanyl]-acetyl}-mutilin and the (1S, 2R, 3R, 5S, 6R) diastereomer thereof,

14-O-{[(1R, 2S, 3S, 5R, 6S)-6-Formylamino-2-hydroxy-bicyclo[3.2.0]hept-3-ylsulfanyl]-acetyl}-mutilin and the (1S, 2R, 3R, 5S, 6R) diastereomer thereof,

14-O-{[(1R, 2S, 3S, 5R, 6S)-6-(2-Amino-acetylamino)-2-hydroxy-bicyclo[3.2.0]hept-3-ylsulfanyl]-acetyl}-mutilin and the (1S, 2R, 3R, 5S, 6R) diastereomer thereof,

14-O-{[(1R, 2S, 3S, 5R, 6S)-6-Cyclopropylamino-2-hydroxy-bicyclo[3.2.0]hept-3-ylsulfanyl]-acetyl}-mutilin and the (1S, 2R, 3R, 5S, 6R) diastereomer thereof, and

14-O-{[4-Acetylamino-6a-hydroxy-octahydropentalen-1-ylsulfanyl]-acetyl}-mutilin.

7. A compound according to claim 1 in the form of a salt and/or solvate.

8. A pharmaceutical drug composition comprising a compound of claim 1 , in association with at least one pharmaceutical excipient.

9. A pharmaceutical drug composition according to claim 8 , further comprising another pharmaceutically active agent.

10. A compound according to claim 3 , wherein R 2 is (C 1-6 )alkyl substituted by one hydroxy.

11. A compound according to claim 3 , wherein R 2 is (C 1-6 )alkyl substituted by two hydroxy.

12. A compound according to claim 3 , wherein R 1 and R 2 together with the nitrogen atom to which they are attached form a 5 to 7 membered heterocyclic ring containing 1 nitrogen and 1 additional heteroatom selected from the group consisting of nitrogen and oxygen.