THERAPEUTIC USE OF PLEUROMUTILINS

1 . A method for treating or preventing an inflammatory disease which is not mediated by bacteria 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 , and their pharmaceutically acceptable salts, solvates, prodrugs or metabolites.

3 . The method according to claim 1 , wherein the compound or the pharmaceutically acceptable salt, solvate, prodrug or metabolite thereof is 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-{1[(1R, 2R, 4R)-4-Diethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 4S) diastereomer thereof,

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

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

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

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

14-O-{1[(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-{1[(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-{1[(1R, 2R, 3R/S)-3-(Formyl-hydroxy-amino)-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 3R/S) diastereomer thereof,

14-O-{1[(1R, 2R, 5S)-2-Hydroxy-5-methylamino-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 5R) diastereomer thereof,

14-O-{1[(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-{1[(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-{1[(1R, 2R, 5S*)-4-Cyclopropylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and the (1S, 2S, 5R*) diastereomer thereof,

14-O-{1[(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-{1[(1R, 2R, 5S)-5-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-19,20-dihydro-mutilin and the (1S, 2S, 5R) diastereomer thereof,

14-O-{1[(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-{1[(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,

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 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 or Lefamulin itaconate salt.

7 . The method according to claim 1 , wherein the inflammatory disease is a result of an inappropriate or chronic inflammatory response.

8 . The method according to claim 1 , wherein the inflammatory disease is a condition of over-reacting immune response, a neutrophil-dominated inflammatory disease, an auto-immune disease, an allergy, or a dermatological inflammatory disease.

9 . The method according to claim 8 , wherein the inflammatory disease is a condition of over-reacting immune response selected from acute lung injury (ALI) including acute respiratory distress syndrome (ARDS), sepsis, and cytokine release syndrome including cytokine storm.

10 . The method according to claim 8 , wherein the inflammatory disease is a neutrophil-dominated inflammatory disease selected from chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis including diffuse panbronchiolitis (DPB), bronchiolitis obliterans syndrome, and non-eosinophilic asthma.

11 . The method according to claim 8 , wherein the inflammatory disease is a condition of over-reacting immune response mediated by a virus.

12 . The method according to claim 1 , wherein the inflammatory disease is an inflammatory disease which is not mediated by microbes.

13 . The method according to claim 1 , wherein the inflammatory disease is an inflammatory condition associated with or caused by a viral infection, wherein the compound or the pharmaceutically acceptable salt, solvate, prodrug or metabolite thereof is administered both to treat and/or to prevent the viral infection and to treat and/or to prevent the inflammatory condition.

14 . The method according to claim 13 , wherein the inflammatory condition is a result of an inappropriate or chronic inflammatory response associated with or caused by the viral infection.

15 . The method according to claim 13 , wherein the inflammatory condition is a condition of over-reacting immune response associated with or caused by the viral infection.

16 . The method according to claim 13 for treatment of a patient in need of both a treatment against the viral infection and a treatment against the inflammatory condition.

17 . The method according claim 13 , wherein the viral infection is mediated by a positive- or negative-sense single-stranded RNA virus.

18 . The method according claim 13 , wherein the viral infection is an airborne disease.

19 . The method according to claim 1 , wherein the viral infection is a respiratory disease.

20 .- 33 . (canceled)

34 . Lefamulin in form as an acid addition salt with itaconic acid, optionally Lefamulin itaconate.

35 . The method according to claim 11 , wherein the condition includes a viral sepsis or an acute respiratory disease related to a viral infection.

36 . The method according to claim 35 , wherein the viral infection is selected from Influenza, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and COVID-19.

37 . The method according to claim 17 , wherein the virus is selected from Coronaviridae, Paramyxoviridae, Orthomyxoviridae, Flaviviridae, and Picornaviridae.

38 . The method according to claim 37 , wherein the virus from Coronaviridae is human coronavirus.

39 . The method according to claim 37 , wherein the virus from Paramyxoviridae is from Paramyxovirinae or Pneumovirinae.

40 . The method according to claim 39 , wherein the virus from Paramyxovirinae is Measles virus.

41 . The method according to claim 39 , wherein the virus from Pneumovirinae is Respiratory Syncytial Virus.

42 . The method according to claim 37 , wherein the virus from Orthomyxoviridae is Influenza virus.

43 . The method according to claim 37 , wherein the virus from Flaviviridae is Dengue virus or Zika virus.

44 . The method according to claim 37 , wherein the virus from Picornaviridae is Rhinovirus.