THERAPEUTIC USE OF PLEUROMUTILINS

1 . A method of treatment or prevention of a bacterial infection, wherein the bacterial infection is mediated by spirochetes, comprising administering to a subject in need thereof 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,

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 selected from N or O, or

R 1 is hydroxy and R 2 is formyl;

R 3 is OH, OR 4 , or a halogen atom, or

R 3 is bound to 2′ and R 3 represents —O—(CH 2 ) p —O— with p being 2 or 3; and

R 4 is unsubstituted (C 1-6 )alkyl or (C 3-6 )cycloalkyl,

or a pharmaceutically acceptable salt, solvate, prodrug or metabolite thereof.

2 . The method according to claim 1 , wherein the compound or the pharmaceutically acceptable salt, solvate, prodrug or metabolite thereof is selected from formulae (II), (III), (IV), (V), and (VI)

wherein in each formula, n, R 1 and R 2 are defined as in claim 1 .

3 . A method of treatment or prevention of a bacterial infection, wherein the bacterial infection is mediated by spirochetes, comprising administering to a subject in need thereof a compound or the pharmaceutically acceptable salt, solvate, prodrug or metabolite thereof selected from

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) diastereomer thereof,

14-O-{[(1R, 2R)-2-Hydroxy-4-(3-methylamino-propyl)-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S, 2S) diastereomer thereof,

14-O-{[(1R, 2R)-5-(3-Amino-propyl)-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S, 2S) diastereomer 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, and their pharmaceutically acceptable salts, solvates, prodrugs or metabolites.

4 . The method according to claim 1 , wherein the compound or the pharmaceutically acceptable salt, solvate, prodrug or metabolite thereof is Lefamulin or its pharmaceutically acceptable salts, solvates, prodrugs or metabolites.

5 . The method according to claim 1 , wherein the compound or the pharmaceutically acceptable salt, solvate, prodrug or metabolite thereof is in the form of a salt and/or a solvate.

6 . The method according to claim 1 , wherein the compound or the pharmaceutically acceptable salt, solvate, prodrug or metabolite thereof is Lefamulin in form of Lefamulin acetate salt.

7 . (canceled)

8 . The method according to claim 7 , wherein the bacteria are selected from the order of Spirochaetales or Leptospirales.

9 . The method according to claim 7 , wherein the bacteria are selected from the order of Spirochaetales.

10 . The method according to claim 1 , wherein the bacteria are selected from the genera of Borrelia, Borreliella, Leptospira , or Treponema.

11 . The method according to claim 1 , wherein the bacterial infection is mediated by Treponema.

12 . The method according to claim 11 , wherein the bacterial infection is syphilis, pinta, (treponemal) periodontitis or yaws.

13 . The method according to claim 1 , wherein the bacterial infection is mediated by bacteria of the family of Borreliaceae.

14 . The method according to claim 13 , wherein the bacterial infection is Lyme Disease or relapsing fever.

15 . The method A according to claim 1 , wherein the compound is administered to a human.

16 . (canceled)

17 . The method according to claim 1 , wherein the subject is a human.

18 . The method according to claim 12 , wherein the syphilis includes venereal syphilis and endemic syphilis.

19 . The method according to claim 13 , wherein the bacterial infection is mediated by Borreliella or Borrelia.

20 . The method according to claim 14 , wherein Lyme Disease includes Lyme Borreliosis.