Title of Invention

"MUTILIN DERIVATIVES AS PHARMACEUTICALS"

Abstract

14-()-|(((C16)Alkoxy-(C1.6)alkyl)-phenylsulfanyl)-acetyl|-mutilins, 14-()-|(((C1-0,)Mono or dialkylamino-(C1.6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-()-|((l lydroxy-(C1.6,)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-|((Formyl-(C0.5)-alkyl)-phenylsullanyl)-acotyl|-mutilins, 14-0-[((Guanidino-imino-(C1-6)alkyl)-phenylsultanyl)-acctyl|-mutilins. 14-O-[((Ureido-imino-(C1-6)alky)-phenylsulfany|-acety|-mutilins. l4-()-|((Thiourcido-imino-(C1-6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, I4-O-|((Isothiourcido-imino-(C6 )alkyl)-phenylsulfanyl)-acetyl]-mutilins and their use as pharmaceuticals.

Full Text

The present invention relates to organic compounds, such as pleuromutiiins. Pleuromutiiin, a compound of formula (Formula Removed) is a naturally occurring antibiotic, e.g. produced by the basidomycetes Pleurotus mutilus and P.passeckerianus, see e.g. The Merck Index, 12th edition, item 7694. A number of further pleuromutiiins containing the ring structure principle of pleuromutiiin and being substituted at the hydroxy group have been developed, e.g. as antimicrobials. We have now found pleuromutiiins with interesting activity. In one aspect the present invention provides a compound, e.g. a pleuromutiiin, selected from the group consisting of 14-O-[(((C1-6)Alkoxy-(C1.6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[(((C1-6)Mono- or dialkylamino-(C1-6alky)-phnenylsulfany)-acetyl]-mutilins, 14-O-[((Hydroxy-(C1.6)-alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Formyl-(C0.5)-alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Guanidino-imino-(C1-8)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Ureido-imino-(C1-6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Thioureido-imino-(C1-6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((lsothioureido-imino-(C1-6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Cyano-(C0-5)-alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Azido-(C0-5)-alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[(((C1.6)Acyloxy-(C1-6)alkyl)-phenylsulfanyl)-acetyll-mutilins, 14-O-[((Benzoyloxy-{C1.6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, wherein the phenyl- or 5- or 6-membered heteroaryl-ring is optionally further substituted by up to four groups independently selected from halogen, (C1.6)alkyl, aryl, aryl(C1-6)- alkyl, (d-6)alkoxy, (C1-6)alkoxy(C1.6)alkyl, halo(C1-6)alkyl, aryl (d.6)alkoxy, hydroxy, nitro, cyano, azido, acyloxy, carbamoyl, mono-or di-N-(C1-6)alkylcarbamoyl, (C1-6)- alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, (C1-6)alkylguanidino, amidino, (d-e) alkylamidino, sulphonylamino, aminosulphonyl, (C1-6) alkylthio, (C1.6)-alkylsulphinyl, (d-e) alkylsulphonyl, heterocyclyl, heteroaryl, heterocyclyl(C1-6)alkyl and heteroaryl(C1-6)alkyl, or two adjacent ring carbon atoms may be linked by a (C3-5) alkylene chain, to form a carbocyclic ring. Preferably, the invention is related to 14-O-[(((C1-6)Alkoxy-(C1.6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[(((d-a)Mono- ordialkylamino-(d-6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[(((C1.5)Acylamino-(C1-6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Hydroxy-(C1.6)-alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Formyl-(C0.5)-alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Guanidino-imino-(C1.6)alkyl)-phenylsulfanyl)-acetyl]-mutilins. More preferably, the present invention provides a compound of formula (Formula Removed) wherein n is 1 to 6; X is oxygen, or NR2 wherein R2 is hydrogen or linear or branched (C1.6)-alkyl, or hydroxy-(d- s)alkyl or (C1-6)alkoxy-(C1-6)alkyl, R, is hydrogen, linear or branched (C1-6)-alkyl, mono- or dihalogenated (C1-6)-alkyl, amino^,. a)-alkyl, hydroxy(C1.6)-alkyl, phenyl(C1.B)-alkyl, (C^-alkylen, furanyl(C1.6)-alkyl, (C3.6)- cycloalkyl and the corresponding ammonium salts, e.g. chlorides, or R1 and R2 together with the nitrogen atom to which they are attached form a 5 to 7 membered heterocycle containing at least one nitrogen atom, or XR1 is0 piperazinyl or morpholinyl. In another aspect the present invention provides a compound of formula (Formula Removed) R4, R5, Rs, R7 are hydrogen, linear or branched d-a alky] or C3.8 cycloalkyl, R8 is C1 alkyl. Preferably, the present invention provides a compound of formula II, wherein Y is NR3l X is NR7, R3 is X 1 and R4 and R7 together with the nitrogen atoms to which they are attached form a 5 to 7 membered heterocyclic ring containing at least 2 nitrogen atoms, whereas R5 and RB are as defined above, or and R5 and R6 together with the nitrogen atoms to which they are attached form a 5 to 7 membered heterocyclic ring containing at least 2 nitrogen atoms, whereas R4 and R7 are as defined above, or and R4 and R5 together with the nitrogen atoms to which they are attached form a 5 to 7 membered heterocyclic ring containing one or more nitrogen atoms, whereas R6 and R7 are as defined above. More preferably, the present invention provides a compound of formula II, wherein Y is NR3, X is NR7, R3is (Formula Removed) R6 and R7 are as defined above, R9 is hydrogen, linear or branched C1-6 alkyl or acyl, e.g. C^acyl. A pleuromutilin provided by the present invention includes a pleuromutilin having the basic structural elements of the mutilin ring system as set out in formula (Formula Removed) wherein RPLEU is vinyl or ethyl and the dotted line is a bond or is no bond. The following numbering system is used in the present application: (Formula Removed) The dotted line between positions 19 an 20 (and between positions 1 and 2) is a bond or is no bond. In a compound of formula A or of formula PLEU a hydrogen atom in positions 4, 7 and/or 8 of the ring system may be replaced by deuterium, and if the dotted line between positions 1 and 2 is no bond (single bond between positions 1 and 2) the ring system may be further substituted in positions 1 and/or 2, e.g. by halogen, deuterium or hydroxy. The group -O- in position 14 is further substituted, preferably by a substituted carbonyl group. It turned out that the antimicrobial activity against clinical relevant bacterial pathogens (Staphylococcus aureus, Enterococcus faecalis, Streptococcus pneumoniae, Moraxella catarrhalis and Escherichia coli, see Table 1 hereinafter) of said pleuromutilin-derivatives is particularly enhanced when the phenyl-ring carries a) a saturated or unsaturated carbon atom in meta position in relation to the sulphur bound to the phenyl ring, or b) a saturated or unsaturated carbon atom in ortho position in relation to the sulphur bound to the phenyl ring, provided that the phenyl ring is further substituted by up to four groups as named in claim 1. Therefore, compounds are preferred, wherein said (CH2)n-group is in meta position in relation to the sulphur bound to the phenyl-ring. Also preferred are compounds, wherein said (CH2)n-group is in ortho position in relation to the sulphur bound to the phenyl-ring, with the proviso that the phenyl-ring is further substituted by up to four groups independently selected from halogen, (C1-6)alky!, aryl, ary(C1-6)- alkyl, (C1-6)alkoxy, (C1-6)alkoxy(C1-6)alkyl, haloC1. 6)alkyl, aryl (C1.6)alkoxy, hydroxy, nitro, cyano, azido, acyloxy, carbamoyl, mono-or di-N-(d. 6)alkylcarbamoyl, (C1-6)- alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, (d. 6)alkylguanidino, amidino, (C1-6) alkylamidino, sulphonylamino, aminosulphonyl, (C1-6) alkylthio, (Ci.6)-alkylsulphinyl, (Ci.6) alkylsulphonyl, heterocyclyl, heteroaryl, heterocycly(C1 6)alkyl and heteroaryl(C1.6)alkyl, or two adjacent ring carbon atoms may be linked by a (C3.5) alkylene chain, to form a carbocyclic ring. In another aspect the present invention provides a compound selected from the group consisting of 14-O-[(3-Hydroxymethyl-phenylsulfanyl)-acetyl]-mutilin, 14-O-[(3-Formyl-phenylsulfanyl)-acetyl]-mutilin, 14-O-[(3-{[(Aminoimino-methyl)-hydrazono]methyl}-phenylsulfanyl)-acetyl]-mutilin, 14-O-[(3-{[2-(lmino-N-piperazinyl-methyl)-2-methyl-hydrazono]methyl}-phenylsulfanyl)- acetyl]-mutilin, 14-O-[(3-[(3-Ethyl-2-methylimino-imidazolidin-1yl-imino)-methyl]-phenylsulfanyl)- acetyl]-mutilin, 14-O-[(3-{[(lmino-N- piperazinyl-methyl)-hydrazono]-methyl}-phenylsulfanyl)-acetyl]-mutilin, e.g. in the form of a salt, such as a hydrochloride. In a further aspect the present invention provides a compound selected from the group consisting of 14-0-[(3-Hydroxymethyl-phenylsulfanyl)-acetyl]-mutilin, 14-0-{[3-(Aminoimino-methyl)-hydrazonomethyl-phenylsulfanyl]-acetyl}-mutilin, 14-0-[{3-[((1-Piperazinoiminomethyl)-methylhydrazono)-methyl]-phenylsulfanyl}-acetyl]- rnutilin, 14-0-[{3-[(3-Ethyl-(2-ethylimino)-imidazolidin-1-ylimino)-methyl]-phenylsulfanyl}-acetyl]- mutilin, 14-O-t{3-[(1-Piperazinoiminomethyl)-hydrazonomethyl]-phenylsulfanyl}-acetyl]-mutilin, 14-O-[{3-[(2-Morpholin-4-yl-ethoxyimino)-methyl]-phenylsulfanyl}-acetyl]-mutilin, 14-O-[3-{[(2-Pyrrolidin-1-yl-ethoxyimino)-methyl]-phenylsulfanyl}-acetyl]-mutilin, 14-O-[(3-Aminomethyl-phenylsulfanyl)-acetyl]-mutilin, 14-O-[(3-Allylaminomethyl-phenylsulfanyl)-acetyl]-mutilin, 14-O-[3-{[(Furan-2ylmethyl)-amino]-methyi}-phenylsulfanyl-acetyl]-mutilin, 14-O-[(3-Cyclopropylaminomethyl-phenylsulfanyl)-acetyl]-mutilin, e.g. in the form of a salt, such as a hydrochloride. A compound provided by the present invention is herein also designated as "compound(s) of (according to) the present invention". A compound of the present invention includes mutilin-14-yl acetic acid esters, e.g. as explicitely defined above, and a compound of formula I or II. A compound of the present invention includes a compound in any form, e.g. in free form, in the form of a salt, in the form of a solvate and in the form of a salt and a solvate. The compounds of the present invention may be in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or a solvate. When some of the compounds of this invention are allowed to crystallise or are recrystallised from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be present in the crystalline product. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. In another aspect the present invention provides a compound of the present invention in the form of a salt. Such salts include preferably pharmaceutical^ acceptable salts, although pharmaceuticaly unacceptable salts are included, e.g. for preparation / isolation / purification purposes. A salt of a compound of the present invention includes a metal salt or an acid addition salt. Metal salts include for example alkali or earth alkali salts; acid addition salts include salts of a compound of the present invention with an acid, e.g. hydrogen fumaric acid, fumaric acid, naphthalin-1,5-sulphonic acid, hydrochloric acid, deuterochloric acid; preferably hydrochloric acid, A compound of the present invention in free form may be converted into a corresponding compound in the form of a salt; and vice versa. A compound of the present invention in free form or in the form of a salt and in the form of a solvate may be converted into a corresponding compound in free form or in the form of a salt in non-solvated form; and vice versa. A compound of of the present invention, if substituted accordingly, may exist in the form of isomers and mixtures thereof; e.g. optical isomers, diastereoisomers, cis/trans conformers. A compound of the present invention may e.g. contain asymmetric carbon atoms and may thus exist in the form of enatiomers or diastereoisomers and mixtures thereof, e.g. racemates. Substituents at any asymmetric carbon atom may be present in the (R)-, (S)- or (R.S)-configuration, preferably in the (R)- or (S)-configuration. E.g., if in a compound of formula I Ri is substituted alkyl and that substituent is attached to a carbon atom of the side chain of such alkyl, the carbon atom to which such substituent is attached is an asymmetric carbon atom and such substiutent may be in the (R)- and (S)-configuration, including mixtures thereof. The configuration of substituents attached to asymmetric carbon atoms of the mutilin-ring is preferably the same as in natural pleuromutilin. Isomeric mixtures may be separated as appropriate, e.g. according, e.g. analogously, to a method as conventional, to obtain pure isomers. The present invention includes a compound of the present invention in any isomeric form and in any isomeric mixture. The present invention also includes tautomers of a compound of the present invention, where tautomers can exist. Any compound described herein, e.g. a compound of the present invention and intermediates in their production may be prepared as appropriate, e.g. according, e.g. analogously, to a method as conventional, e.g. or as specified herein. In another aspect the present invention provides a process for the preparation of l4-0-[(((C1-6)Alkoxy-(C1.6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[(((C1.6)Mono- or dialkylamino-(C1-6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-0-[((Hydroxy-(C1.6)-alkyl)- phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Formyl-(C0-6)-alkyl)-phenylsulfanyl)-acety!]-mutilins, 14-O-[((Guanidino-imino-(Ci-8) alkyl)-phenylsulfanyl)-acetyl]-mutiiins, 14-O-[((Ureido-imino-(C1-6)alky)-phenylsulfany)-acetyll-mutilins, 14-0-[((Thioureido-imino-(C1-6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-0-[((lsothioureido-imino-(C1.6)alkyl)-phenylsulfanyl)-acetyi]-mutilins, 14-O-[(((C1-6)Alkoxy-(C1-6) alkyl)- 5- or 6-membered heteroarylsulfanyl)-acetyl]-mutilins, 14-O-[((Hydroxy-(C1.6)-alkyl)- 5- or 6-membered heteroarylsulfanyl)-acetyl]-mutilins, 14-O-[((Formyl-(C0-5)-aikyl)- 5- or 6-membered heteroarylsulfanyl)-acetyl]-mutilins, 14-0-[((Guanidino-imino-(C1-6)alkyl)- 5- or 6-membered heteroarylsulfanyl)-acetyl]-mutilins, 14-0-[(((C1.6)Alkylguanidino-imino-(C1-6)alkyl)- 5- or 6-membered heteroarylsulfanyl)-acetyl]-mutilins, 14-0-[((Ureido-imino-(C1.6)alkyl)- 5- or 6-membered heteroarylsulfanyl)-acetyl]-mutilins, 14-0-[((Thioureido-imino-(Ci.6)alkyl)- 5- or 6-membered heteroarylsulfanyl)-acetyl]-mutilins, 14-0-[((lsothioureido-imjno-(Ci.6)alkyl)- 5- or 6-membered heteroarylsulfanyl)-acetyl]-mutilins comprising reacting a a. 14-O-Pleuromutilintosylate with a hydroxy-(C-alkyl-thiophenol or 5- or 6-membered hydroxy-(C1-6)-alkyl-thioheteroaryl compound in the presence of a base (if no further transformation is wanted, the final compounds are isolated and purified in a suitable manner), b 1. oxidizing the hydroxy group selectively into a formyl group using an appropriate oxidizing agent (if no further transformation is wanted, the final compounds are isolated and purified in a suitable manner), b2. transforming the hydroxyl group to the corresponding mesylate, cl. condensing the compound bearing the formyl group with a compound having a free amino group c2. Substitution of the mesylate with an azide c2a. Substitution of the mesylate with substituted primary or secondary amines d2. Reduction of the azides to the amines e2. Acylation of the amine. Compounds having substituents which are intended not to participate in the reaction steps may be used in a protected form. Protecting groups may be removed afterwards without disrupting the remainder of the molecule. A compound obtained by a process provided by the present invention may be converted into a corresponding salt, according, e.g. analogously, to a method as conventional, e.g. by treatment with an acid, or, metal base, respectively, to obtain an acid addition salt, or, a metal salt, respectively and vice versa, a compound obtained by a process provided by the present invention in the form of a salt, may be converted into the correpeonding compound in the form of a free base, according, e.g. analogously, to a method as conventional, e.g. by treatment with an acid if a metai salt is obtained and by treating with a metal base, e.g. a metal hydroxide if an acid addition salt is obtained. The compounds of the present invention, e.g. including a phenylsuifanyl- or 5 - 6 membered heteroarylsulfanyl-mutilin provided by the present invention as defined above, and a compound of formula I or II exhibit pharmacological activity and are therefore useful as pharmaceuticals. For example, the compounds of the present invention show antimicrobial, e.g. antibacterial, activity against gram positive bacteria, such as coagulase-positive and coagulase-negative Staphylococci, e.g. Staphylococcus aureus, Styphylococcus epidermis, Staphylococcus haemolyticus, Streptococci, e.g. Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus agalacticae, Enterococci, e.g. Enterococcus faecium and Moraxellaceae, e.g. Moraxella catarrhalis, Pasteurellaceae, e.g. Haemophilus influenzae, as well as against Mycoplasmactaceae, Chlamydiaceae, e.g. Chlamydia trachomatis, Chlamydia pneumoniae and obligatory anaerobes, e.g. Bacteroides fragilis, Clostridium difficile; in vitro in the Agar Dilution Test or Microdilution Test according to the Climical and Laboratory Standards Institute (CLSI, former National Commiteefor Clinical Laboratory Standards (NCCLS) 2006, Document M7-A7 Vol. 26, No. 2: "Methods for dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically- Seventh Edition, Approved Standard"; and in the in vitro determination of the antibacterial activity against anaerobic bacteria according to National Committee for Clinical Laboratory Standards (NCCLS) VOL. 24, No. 2, M11-A5, Methods for Antimicrobal Susceptibility Testing of Anaerobic Bacteria; Approved Standard; Sixth Edition (2004) and in vivo in the septicaemic mouse model against Staphylococcus aureus. Compounds of the present invention are therefore suitable for the treatment and prevention of diseases which are mediated by microbes, e.g. by bacteria. Diseases which also may be treated include e.g. diseases mediated by Helicobacter, such as Helicobacter pylori, and diseases mediated by Mycobacterium tuberculosis, diseases mediated by Legionella pneumophila or Neisseriaceae, diseases which also may be treated include in general inflammatory diseases, where microbes are mediating said inflammation, e.g. including acne. Compounds of the present invention are preferably useful to treat skin and soft tissue infections, for example epidermal infections like impetigo, bullous impetigo or ecthyma, dermal infections like erysipelas, cellulites, erythrasma or necrotizing fasciitis, follicular infections like folliculitis, furunculosis or carbunculosis, other infections like paronychia, dactylitis, botryomycosis, mastitis, secondarily infected skin lesions, secondarily infected dermatoses, for the decolonization of bacterial carriers, e.g. decolonisation of nasal Staphylococcus aureus carriers, and acne, by topical application. Accordingly, in a further aspect the present invention provides the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the preparation of a medicament adapted for topical administration for use in the treatment of skin and soft tissue infections and also in the treatment of acne in humans. The invention also provides the use of a compound of the invention, or a pharmaceutical acceptable derivative thereof, in the manufacture of a medicament for use in the treatment of a skin or soft tissue infection. In another aspect the present invention provides a compound of the present invention for use as a pharmaceutical, preferably as an antimicrobial, such as an antibiotic, e.g. and an anti-anaerobic. In another aspect the present invention provides a compound of the present invention for use in acne treatment. In a further aspect the present invention provides a compound of the present invention for use in the preparation of a medicament for the treatment of diseases, mediated by microbes, such as bacterials, for example -diseases mediated by bacteria, e.g. selected from Staphylococci, Streptococci, Enterococci; - diseases mediated by Helicobacter - diseases mediated by Legionella, Neisseriaceae, Moraxellaceae, Pasteurellaceae, Corynebacteria, - diseases mediated by Mycobacterium tuberculosis, - e.g. diseases mediated by Mycoplasmataceae, Chlamydiaceae and obligatory anaerobes, - for the treatment of acne, and for the decolonization of individuals colonized with bacteria. In a further aspect the present invention provides 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 the present invention e.g. in the form of a pharmaceutical composition. In a further aspect the present invention provides a method of treatment of acne which comprises administering to a subject in need of such treatment an effective amount of a compound of the present invention e.g. in the form of a pharmaceutical composition. Treatment includes treatment and prophylaxis. For antimicrobial and acne treatment, the appropriate dosage will, of course, vary depending upon, for example, the chemical nature and the pharmakokinetic data of a compound of the present invention employed, the individual host, the mode of administration and the nature and severity of the conditions being treated. However, in general, for satisfactory results in larger mammals, for example humans, an indicated daily dosage is in the range from about 0.01 to 3 g of a compound of the present invention conveniently administered, for example, in divided doses up to four times a day. A compound of the present invention may be administered by any conventional route, for example enterally, e.g. including nasal, buccal, rectal, oral, administration; parenterally, e.g. including intravenous, intramuscular, subcutanous administration; or topically, e.g. including epicutaneous, intranasal, intratracheal administration, e.g. in form of coated or uncoated tablets, capsules, injectable solutions or suspensions, e.g. in the form of ampoules, vials, in the form of semi-solid formulations, e.g. ointments, creams, gels, pastes, in the form of inhaler powder, foams, tinctures, lip sticks, concealer sticks, drops, sprays, or in the form of suppositories, e.g. in analogous manner to macrolides, such as erythromycins, e.g. clarithromycin or azithromycin. A compound of the present invention may be administered in the form of a pharmaceutically acceptable salt, e.g. an acid addition salt or metal salt; or in free form; optionally in the form of a solvate. A compound of the present invention in the form of a salt exhibit the same order of activity as the compound in free form; optionally in the form of a solvate. A compound of the present invention may be used for pharmaceutical treatment according to the present invention alone or in combination with one or more other pharmaceutically active agents. Such other pharmaceutically active agents include e.g. other antibiotics and antiinflammatory agents, and, if a compound of the present invention is used in the treatment of acne, other pharmaceutically agents include furthermore agents which are active against acne or used for the decolonization/sterilisation of bacterial carriers. Combinations include fixed combinations, in which two or more pharmaceutically active agents are in the same formulation; kits, in which two or more pharmaceutically active agents in separate formulations are sold in the same package, e.g. with instruction for co¬administration; and free combinations in which the pharmaceutically active agents are packaged separately, but instruction for simultaneous or sequential administration are given. In another aspect the present invention provides a pharmaceutical composition comprising a compound of the present invention, e.g. including a compound of formula I, in free form or in the form of a pharmaceutically acceptable salt; e.g. and/or in the form of a solvate; in association with at least one pharmaceutical, excipient, e.g. carrier or diluent, e.g. including fillers, binders, disintegrators, flow conditioners, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers. In another aspect the present invention provides a pharmaceutical composition according to the present invention, further comprising another pharmaceutically active agent. Such pharmaceutical compositions may be manufactured according, e.g. analogously, to a method as conventional, e.g. by mixing, granulating, coating, dissolving or lyophilizing processes. Unit dosage form may contain, for example, from about 0.01 mg to about 3000 mg, such as 1 mg to about 100 mg. The compounds of the present invention are additionally suitable as veterinary agents, e.g. veterinary active compounds, e.g. in the prophylaxis and in the treatment of microbial, e.g. bacterial diseases, in animals, such as fowl, pigs and calves; e.g. and for diluting fluids for artificial insemination and for egg-dipping techniques. In another aspect the present invention provides a compound of the present invention for use as a veterinary agent. In a further aspect the present invention provides a compound of the present invention for the preparation of a veterinary composition which is useful as a veterinary agent. In another aspect the present invention provides a veterinary method for the prophylaxis and in the treatment of microbial, e.g. bacterial diseases which comprises administering to a subject in need of such treatment an effective amount of a compound of the present invention, e.g. in the form of a veterinary composition. For use of the active compounds of the present invention as a veterinary agent, the dosage will of course vary depending upon the size and age of the animal and the effect desired; for example for prophylactic treatment relatively low doses would be administered over a longer time period, e.g. 1 to 4 weeks. Preferred doses in drinking water are from 0.0125 to 0.05 weight by volume, particularly 0.0125 to 0.025; and in foodstuffs from 20 to 400 g/metric ton, preferably 20 to 200 g/metric ton. It is preferred to administer the active compounds of the present invention as a veterinary agent to hens in drinking water, to pigs in foodstuff and to calves orally or parenterally, e.g. in the form of oral or parenteral preparations. The invention is further described by reference to the following examples. These examples are provided for illustration purposes only and are not intended to be limiting the present invention in any way. Examples Example 1: 14-0-[(3-Hydroxymethyl-phenylsulfanyl)-acetyl]-mutilin Step 1: Pleuromutilintosylate To a solution of 18.63 g (49.2 mmol) of Pleuromutilin and 9.39 g (49.2 mmol) of toluenesulfonylchloride in 1400 mL of methylethylketone a solution of 4.98 g (49.2 mmol) of triethylamine in 300 mL of methylethylketone is slowly added at ambient temperature. The reaction is stirred for 24 h at ambient temperature, the formed precipitate is filtered off and 2800 mL of water is added to the solution. The solution is extracted three times with ethyl acetate, the organic phase is dried with Na2S04 and evaporated to dryness under reduced pressure. The crude product is used for the next step without further purification. 1H-NMR (400 MHz, DMSO-d6, ë, ppm, characteristic signals): 0.49 (d, 3H, J = 7Hz, CH3 -16); 0.8 (d, 3H, J = 7Hz, CH3 - 17); 1.02 (s, 3H, CH3 - 18); 1.29 (s, 3H, CH3 - 15); 2.38 (bs, 1H, H -4); AB-system (uA= 4.75, uB= 4.62, J = 50Hz, CH2 - 22); 5,00 (m, 2H, H - 20); 5.52 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 and 18Hz, H - 19); 7.46 (d, 2H, J = 8Hz, H - 24); 7.79 (d, 2H, J = 8Hz, H - 23). (Formula Removed) Step 2: 14-0-[(3-Hydroxymethyl-phenylsulfanyl)-acetyl]-mutilin To 1.96 g (14 mmol) of (3-Mercapto-phenyl)-methanol [prepared from 3-Mercaptobenzoic acid according to: Chemistry Express, Vol 7, No.11, pp.865-868 (1992)] in 90 mL of absolute ethanol 322 mg (14 mmol) of sodium is added. After stirring the reaction for 30 min at ambient temperature a solution of 7.45 g (14 mmol) of Pleuromutilintosylate in 130 mL of methylethylketone is added and the reaction stirred at ambient temperature for 16h. The reaction mixture is evaporated to dryness under reduced pressure, dissolved in ethyl acetate and extracted three times with water. The organic phase is dried with Na2SO4, evaporated to dryness under reduced pressure and the residue is chromatographed on silica gel using dichloromethane / methanol 100 : 1.5 as mobile phase. The obtained material was cristalline (Fp. 139-141 °C). 1H-NMR (500 MHz, CDCI3, 5, ppm, characteristic signals): 0.68 (d, 3H, J = 7Hz, CH3 -16); 0.88 (d, 3H, J = 7Hz, CH3 -17); 1.12 (s, 3H, CH3 -18); 1.42 (s, 3H, CH3 - 15); 2.06 (bs, 1H, H - 4); 3.32 (t, 1H, J = 6Hz, H -11); 3.59 (s, 2H, CH2 - 22); 4.66 (s, 2H, CH2 - 27); 5.15 and 5.30 (2xm, 2H, H - 20); 5.72 (d, 1H, J = 8Hz, H -14); 6.41 (dd, 1H, J = 11 and 17Hz, H - 19); 7.19 and 7.28 (2xm, 3H, H - 24,25 and 26); 7.38 (s, 1H, H - 23). Example 3:14-0-[(5-Hydroxymethyl-2-fluoro-phenylsulfanyl)-acetyl]-mutilin 1H-NMR (400 MHz, CD3OD, δ, ppm, characteristic signals): 0.67 (d, 3H, J = 7Hz, CH3 - 16); 0.89 (d, 3H, J = 7Hz, CH3 - 17); 1.18 (s, 3H, CH3 - 18); 1.35 (s, 3H, CH3 - 15); 2.29 (bs, 1H, H -4); 3.42 (d, 1H, J = 7Hz, H - 11); AB-system (uA= 3.70, uB= 3.60, J = 39Hz, CH2 - 22); 4.53 (s, 2H, CH2 - 26); 5.07 (m, 2H, H - 20); 5.64 (d, 1H, J = 8Hz, H - 14); 6.19 (dd, 1H, J = 7 and 19Hz, H - 19); 7.08, 7.27 and 7.44 (3xm, 3H, H - 23,24 and 25). The required (4-Fluoro-3-mercapto-phenyl)-methanol is prepared in two steps from 3-Chlorosulfonyl-4-fluoro-benzoic acid following the procedure for the preparation of (3-Mercapto-phenyl)-methanol described in Chemistry Express, Vol 7, No.11, pp.865 - 868). (Formula Removed) Example 4:14-0-[(2-Hydroxymethyl-4-fluoro-phenylsulfanyl)-acetyl]-mutilin 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.51 (d, 3H, J = 7Hz, CH3 - 16); 0.78 (d, 3H, J = 7Hz, CH3 - 17); 0.97 (s, 3H, CH3 - 18); 1.27 (s, 3H, CH3 - 15); 2.34 (bs, 1H, H -4); 3.37 (d, 1H, J = 7Hz, H - 11); AB-system (uA= 3.78, uB= 3.70, J = 29Hz, CH2 - 22); 4.56 (d, 2H, J = 5Hz, CH2 - 26); 4.92 (m, 2H, H - 20); 5.45 (d, 1H, J = 8Hz, H - 14); 6.19 (dd, 1H, J = 11 and 18Hz, H -19); 7.02 and 7.44 (2xm, 2H, H - 24 and 25); 7.20 (m, 1H, H - 23). The required (5-Fluoro-2-mercapto-phenyl)-methanol is prepared from 5-Fluoro-2-mercapto-benzoic acid following the procedure for the preparation of (3-Mercapto-phenyl)-methanol described in Chemistry Express, Vol 7, No.11, pp.865 - 868). (Formula Removed) Example 5: 14-0-[(3-Cyano-phenylsulfanyl)-acetyl]-mutilin 1H-NMR (400 MHz, DMSO-de, δ, ppm, characteristic signals): 0.55 (d, 3H, J = 7Hz, CH3 - 16); 0.78 (d, 3H, J = 7Hz, CH3 - 17); 0.97 (s, 3H, CH3 - 18); 1.28 (s, 3H, CH3 - 15); 2.35 (bs, 1H, H -4); 3.36 (t, 1H, J = 6Hz, H - 11); AB-system (uA = 4.00, uB= 3.93, J = 31 Hz, CH2 - 22); 4.97 (m, 2H, H - 20); 5.48 (d, 1H, J = 8Hz, H - 14); 6.01 (dd, 1H, J = 11 and 18Hz, H - 19); 7,45 - 7.86 (3xm, 4H, H - 23,24,25 and 26). The required 3-Mercapto-benzonitrile is prepared from 3-Cyano-benzenesulfonyl chloride following the procedure for the preparation of 3-Mercaptobenzoic acid described in Journal of Heterocyclic Chemistry (1982), 19(4), 961 - 5. (Formula Removed) Example 6:14-0-[(4-Hydroxymethyl-phenylsulfanyl)-acetyl]-mutilin 'H-NMR (400 MHz, CDCI3, 5, ppm, characteristic signals): 0.68 (d, 3H, J = 7 Hz, CH3 -16); 0.86 (d, 3H, J = 7Hz, CHa-17); 1.12 (s, 3H, CH3 - 18); 1.40 (s, 3H, CH3 - 15); 2.06 (bs, 1H, H - 4); 3.32 (dd, 1H, J = 7 and 11 Hz, H- 11); 3.56 (s, 2H, CH2 - 22); 4.66 (d, 2H, J = 4Hz, CH2 - 25); 5.16 and 5.30 (2xm, 2H, H - 20); 5.73 (d, 1H, J = 8Hz, H - 14); 6.41 (dd, 1H, J = 11 and 17Hz, H - 19); 7.28 and 7.38 (2xd, 4H, J = 8Hz, H - 23 and 24); 9.91 (s, 1H, H - 25). The required (4-Mercapto-phenyl)-methanol was prepared from 4-Mercapto-benzoic acid following the procedure for the preparation of (3-Mercapto-phenyl)-methanol described in Chemistry Express, Vol 7, No.11, pp.865 - 868). (Formula Removed) Example 7:14-0-t(2-Hydroxymethyl-phenylsulfanyl)-acetyl]-mutilin 1H-NMR (500 MHz, CDCI3, δ, ppm, characteristic signals): 0.60 (d, 3H, J = 7 Hz, CH3 -16); 0.85 (d, 3H, J = 7 Hz, CH3 - 17); 1.09 (s, 3H, CH3 - 18); 1.39 (s, 3H, CH3 - 15); 2.04 (bs, 1H, H - 4); 3.30 (t, 1H, J = 7Hz, H - 11); AB-system (uA= 3.62, uB= 3.58, J = 21 Hz, CH2 - 22); AB-system (uA = 4.82, uB = 4.78, J = 19Hz, CH2 - 27); 5.12 and 5.28 (2xm, 2H, H - 20); 5.67 (d, 1H, J = 8Hz, H - 14); 6.35 (dd, 1H, J = 11 and 18Hz, H -19); 7.24 and 7.42 (2xm, 4H, arom-H). The required (2-Mercapto-phenyl)-methanol is prepared from 2-Mercapto-benzoic acid following the procedure for the preparation of (3-Mercapto-phenyl)-methanol described in Chemistry Express, Vol 7, No.11, pp.865 - 868). (Formula Removed) Example 8:14-0-[(2-Hydroxy-5-hydroxymethyl-phenylsulfanyl)-acetyl]-mutilin 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.57 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 -17); 0.99 (s, 3H, CH3 -18); 1.29 (s, 3H, CH3 - 15); 2.34 (bs, 1H, H -4); 3.36 (t, 1H, J = 6Hz, H - 11); AB-system (uA= 3.70, uB= 3.59, J = 26Hz, CH2 - 22); 4.32 (d, 2H, J = 5Hz, CH2 - 26); 4.95 (m, 2H, H - 20); 5.47 (d, 1H, J = 8Hz, H - 14); 6.03 (dd, 1H, J = 11 and 18Hz, H - 19); 6.75 (d, 1H, J = 8Hz, H - 25); 6.98 (dd, 1H, J = 2 and 8Hz, H - 24); 7.11 (d, 1H, J = 2Hz, H-23). (Formula Removed) The required 4-Hydroxymethy1-2-mercapto-phenol is prepared from 3-Chlorosulfonyl-4-hydroxy-benzoic acid following the procedure for the preparation of (3-Mercapto-phenyl)-methanol described in Chemistry Express, Vol 7, No.11, pp.865 - 868). Example 9: 14-0-[(3-Formyl-phenylsulfanyl)-acetyl]-mutiIin To 2.38 g (4.75 mmol) of 14-0-[(3-Hydroxymethyl-phenylsulfanyl)-acetyl]-mutilin in 70 mL of dichloromethane is added 2.02g (4.75 mmol) of Dess-Martin reagent. After stirring the reaction for 60 min at ambient temperature the reaction mixture is filtered, evaporated to dryness under reduced pressure and chromatographed on silica gel using dichloromethane / methanol 100 : 1 as mobile phase. 1H-NMR (400 MHz, CDCI3, δ, ppm, characteristic signals): 0.68 (d, 3H, J = 7Hz, CH3 -16); 0.86 (d, 3H, J s 7Hz, CH3 - 17); 1.11 (s, 3H, CH3 - 18); 1.39 (s, 3H, CH3 - 15); 2.06 (bs, 1H, H - 4); 3.32 (m, 1H, H- 11); 3.64 (s, 2H, CH2 - 22); 5.12 and 5.26 (2 x m, 2H, H - 20); 5.74 (d, 1H, J = 8Hz, H - 14); 6.36 and 6.40 (dd, 1H, J = 11 and 17Hz, H - 19); 7.45 (t, 1H, J = 8Hz, H - 25); 7.62 (m, 1H, H-26); 7.71 (m, 1H, H -24); 7.85 (m, 1H, H - 23); 9.97 (s, 1H.H-27). The following compounds are prepared in a similar fashion: Example 10:14-0-[(2-Formylphenylsulfanyl)-acetyl]-mutil!n 1H-NMR (400 MHz, DMSO-d6, 5, ppm, characteristic signals): 0.54 (d, 3H, J = 7 Hz, CH3 - 16); 0.79 (d, 3H, J = 7 Hz, CH3 - 17); 0.97 (s, 3H, CH3 - 18); 1.32 (s, 3H, CH3 - 15); 2.35 (bs, 1H, H -4); 3.37 (t, 1H, J = 6Hz, H - 11); AB-system (uA= 3.95, uB= 3.88, J = 21 Hz, CH2 - 22); 4.92 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H -14); 6.02 (dd, 1H, J = 11 and 18Hz, H -19); 7.38 and 7.57 (2xt, 2H, J = 8Hz, H - 24 and 25); 7.50 and 7.89 (2xd, 2H, J = 8Hz, H - 23 and 26); 10.19 (s, 1H, H-27). (Formula Removed) Example 11:14-0-[(4-Formylphenylsulfanyl)-acetyl]-mutilin 1H-NMR (500 MHz, DMSO-d6, δ, ppm, characteristic signals); 0.57 (d, 3H, J = 7 Hz, CH3 -16); 078 (d, 3H, J = 7 Hz, CH3 - 17); 0,96 (s, 3H, CH3 -18); 1,30 (s, 3H, CHS - 15); 2.36 (bs, 1H, H -4); 3.37 (t, 1H, J = 6Hz, H - 11); AB-system (uA= 4.03, uB= 3.98, J = 24Hz, CH2 - 22); 4.95 (m, 2H, H - 20); 5.51 (d, 1H, J = 8Hz, H -14); 6.02 (dd, 1H, J = 11 and 18Hz, H - 19); 7.49 and 7.78 (2xd, 4H, J = 8Hz, H - 23 and 24); 9.91 (s, 1H, H - 25). (Formula Removed) Example 12:14-0-{[3-(Aminoimino-methyl)-hydrazonomethyl-phenylsulfanyl]-acetyl}-mutilin hydrochloride To 381 mg (0.61 mmol) of 14-0~[(3-Formyl-phenylsulfanyl)-acetyl]-mutilin in 4 mL of N,N-dimethylacetamide is added 83 mg (0.61 mmol) of aminoguanidine-dihydrocarbonate and 0.61 ml of 2N HCI. After stirring the reaction for 12h at ambient temperature the reaction mixture is evaporated to dryness under reduced pressure and chromatographed on silica gel using dichloromethane / methanol / isopropylether 4:1:1 containing 1% acetic acid as mobile phase. 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.55 (d, 3H, J = 7Hz, CH3 - 16); 0,78 (d, 3H, J = 7Hz, CH3 - 17); 0.95 (s, 3H, CH3 - 18); 1.27 (s, 3H, CH3 - 15); 2.33 (bs, 1H, H -4); 3.36 (t, 1H, J = 6Hz, H - 11); AB-system (uA= 3.94, uB= 3.85, J = 36Hz, CH2 - 22); 4.90 (m, 2H, H - 20); 5.48 (d, 1H, J = 8Hz, H - 14); 6.00 (dd, 1H, J = 11 and 18Hz, H - 19); 7.32 (m, 1H, H - 25); 7.32 and 7.58 (2 x m, 2H, H - 24 and 26); 7.83 (s, 1H, H - 23); 8.05 (s, 1H, H - 27). The following compounds were prepared in a similar fashion: Example 13: 14-0-[{3-[((1-Piperazinoiminomethyl)-methylhydrazono)-methyl]-phenylsulfanyl}-acety!]-mutilin hydrochloride 1H-NMR (500 MHz, CD3OD, δ, ppm, characteristic signals): 0.65 (d, 3H, J = 7Hz, CH3 - 16); 0.89 (d, 3H, J = 7Hz, CH3 - 17); 1.03 (s, 3H, CH3 - 18); 1.37 (s, 3H, CH3 - 15); 3.34 (s, 3H, N-CH3); 3.41 - 3.58 (m, 8H, N-CH2); AB-system (uA= 3.78, uB = 3.73, J = 24Hz, CH2 - 22); 5.01 (m, 2H, H - 20); 5.64 (d, 1H, J = 8Hz, H - 14); 6.15 (dd, 1H, J = 11 and 18 Hz, H - 19); 7.40, 7,48 and 7,64 (3 x m, 3H, H - 24, 25 and 26); 7.86 (s, 1H, H - 23); 8.14 (bs, 1H, H - 27). (Formula Removed) Example 14: 14-0-[{3-[(3-Ethyl-(2-ethylimino)-imidazolidin-1-ylimino)-methyl]-phenylsulfanyl}-acetyl]-mutilin hydrochloride 1H-NMR (400 MHz, CDCI3, 5, ppm, characteristic signals): 0.66 (d, 3H, J = 7Hz, CH3 -16); 0.87 (d, 3H, J = 7Hz, CH3 - 17); 1.10 (s, 3H, CH3 - 18); 1.32 (t, 3H, J = 7Hz, CH3 - 31); 1.39 (s, 3H, CH3 -15); 2.06 (bs, 1H, H - 4); 3.46 (d, 3H, J = 5Hz, CH3 - 32); 3.62 (s, 2H, CH2 - 22); 3.85 and 4.05 (2 x m, 4H, CH2 - 28 and 29); 3.97 (q, 2H, J = 7Hz, CH2 - 30); 5.12 and 5.25 (2x m, 2H, H -20); 5.70 (d, 1H, J = 8Hz, H - 14); 6.37 (dd, 1H, J = 11 and 17 Hz, H - 19); 7.30 - 7.55 (3xm, 3H, H - 24, 25 and 26); 7.56 (s, 1H, H - 23); 7.64 (s, 1H, H - 27). (Formula Removed) Example 15:14-0-[{3-[(1-Piperaz«noimlnomethyl)-hydrazonomethyl]-phenylsulfanyl}-acetyl]-mutilin hydrochloride - 1H-NMR (500 MHz, CDCI3, δ, ppm, characteristic signals): 0.63 (d, 3H, J = 7Hz, CH3 -16); 0.87 (d, 3H, J = 7Hz, CH3 - 17); 1.04 (s, 3H, CH3 - 18); 1.35 (s, 3H, CH3 - 15); 2.25 (bs, 1H, H - 4); 3.05 (m, 4H, N-CH2); 3.64 (m, 6H, N-CH2, H - 22); 5.02 and 5.12 (2xm, 2H, H - 20); 5.65 (d, 1H, J = 8Hz, H - 14); 6.21 (dd, 1H, J = 11 and 17Hz, H - 19); 7.31 (t, 1H, H - 25); 7.38 and 7.52 (2xm, 2H, H - 24 and 26); 7.77 (bs, 1H, H - 23); 8.26 (s, 1H, H - 27). (Formula Removed) Example 16:14-0-[{3-[(2-Morpholin-4-yl-ethoxyimino)-methyl]-phenylsuIfanyl}-acetyl]-mutilin hydrochloride 1H-NMR (400 MHz, DMSO-d6) 5, ppm, characteristic signals): 0.55 (d, 3H, J = 7 Hz, CH3 - 16); 0.78 (d, 3H, J = 7 Hz, CH3 - 17); 0.95 (s, 3H, CH3 -18); 1.28 (s, 3H, CH3 - 15); 2.34 (bs, 1H, H -4); 2.40 (m, 4H, CH2 - 30); 2.60 (t, 2H, J = 6Hz, CH2 - 29), 3.42 (t, 1H, J = 6Hz, H - 11); 3.55 (t, 4H, J = 5Hz, CH2 - 31); AB-systern (uA= 3.88, uB = 3.70, J = 30Hz, CH2 - 22); 4.21 (t, 2H, J = 6Hz, CH2 - 28); 4.90 (m, 2H, H - 20); 5.48 (d, 1H, J = 8Hz, H - 14); 6.00 (dd, 1H, J = 11 and 18Hz, H - 19); 7.30 -7.90 (m, 4H, H - 23,24,25 and 26); 8.17 (s, 1H, H-27). Example 17: 14-0-{3-{[(2-Pyrrolidin-1-yl-ethoxyimino)-methyl]-phenylsulfanyl}-acetyl]-mutilin hydrochloride 1H-NMR (500 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.55 (d, 3H, J = 7 Hz, CH3 - 16); 0.78 (d, 3H, J = 7 Hz, CH3 -17); 0.96 (s, 3H, CH3 - 18); 1.28 (s, 3H, CH3 - 15); 2.34 (bs, 1H, H -4); 2.60 - 3.00 (bm, 10H, CH2 - 29,30 and 31); 3.36 (t, 1H, J = 6Hz, H - 11); AB-system (uA = 3.88, uB= 3.70, J = 35Hz, CH2 - 22); 4.26 (t, 2H, J = 6Hz, CH2 - 28); 4.90 (m, 2H, H - 20); 5.48 (d, 1H, J = 8Hz, H - 14); 6.00 (dd, 1H, J = 11 and 18Hz, H - 19); 7.30 - 7.43 (m, 3H, H - 24,25 and 26); 7.58 (s, 1H, H - 23); 8.19 (s, 1H, H - 27). (Formula Removed) Example 18:14-0-t{4-[(1-Piperazinoiminomethyl)-hydrazonomethyl}-phenylsulfanyl}-acetyl]-mutilin hydrochloride 1H-NMR (400 MHz, DMSO-d8, δ, ppm, characteristic signals): 0.51 (d, 3H, J = 7 Hz, CH3 - 16); 077 (d, 3H, J = 7 Hz, CH3 - 17); 0.97 (s, 3H, CH3 - 18); 1.24 (s, 3H, CH3 - 15); 2.33 (bs, 1H, H -4); 3.18 (m, 4H, CH2 - 29); 3.36 (t, 1H, J = 6Hz, H - 11); 3.81 (m, 4H, CH2 - 28); AB-system (uA = 3.90, uB=3.81, J = 34Hz, CH2 - 22); 4.91 (m, 2H, H - 20); 5.47 (d, 1H, J = 8Hz, H - 14); 6.00 (dd, 1H, J = 11 and18Hz, H-19); 7.10- 7.51 (m, 5H, H - 23,24,25,26 and 27). (Formula Removed) Example 19:14-0-[{2-[(Aminoiminomethyl)-hydrazonomethyl]-phenylsulfanyl}-acetyl]-mutilin hydrochloride 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.52 (d, 3H, J = 7 Hz, CH3 - 16); 0.75 (d, 3H, J = 7 Hz, CH3 - 17); 0.96 (s, 3H, CH3 - 18); 1.27 (s, 3H, CH3 - 15); 2.33 (bs, 1H, H -4); 3.36 (t, 1H, J = 6Hz, H - 11); AB-system (uA= 3.87, uB= 3.78, J = 26Hz, CH2 - 22); 4.92 (m, 2H, H - 20); 5.47 (d, 1H, J = 8Hz, H - 14); 5.99 (m, 1H, H - 19); 7.25 (m, 2H, H - 24 and 25); 7.44 and 7.96 (2xm, 2H, H - 23, and 26); 8.54 (s, 1H, H - 27). (Formula Removed) Example 20:14-0-[{4-[(Aminoiminomethyl)-hydrazonomethyl]-phenylsulfanyl}-acetyl]-mutilin hydrochloride 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.56 (d, 3H, J = 7 Hz, CH3 - 16); 0.79 (d, 3H, J = 7 Hz, CH3 - 17); 0.97 (s, 3H, CH3 - 18); 1.30 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H -4); 3.37 (t, 1H, J = 6Hz, H - 11); AB-system (uA= 3.94, uB= 3.88, J = 24Hz, CH2 - 22); 4.96 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.03 (dd, 1H, J = 11 and 18Hz, H -19); 7.38 and 7.78 (2xd, 4H, J = 8Hz, H - 23 and 24); 8.10 (s, 1H, H - 25). Example 21: 14-0-[{4-[(1-PiperazinoJminomethyl)-hydrazonomethyl]-phenylsulfanyl}-acetyl]-mutilin hydrochloride 1H-NMR (400 MHz, DMSO-d8, δ, ppm, characteristic signals): 0.56 (d, 3H, J = 7 Hz, CH3 - 16); 0.78 (d, 3H, J = 7 Hz, CH3 - 17); 0.98 (s, 3H, CH3 - 18); 1.29 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H -4); 3.22 (m, 4H, CH2 - 27); 3.37 (t, 1H, J = 6Hz, H - 11); 3.85 (m, 4H, CH2-26); AB-system (uA = 3.95, uB= 3.89, J = 24Hz, CH2 - 22); 4.94 (m, 2H, H - 20); 5.49 (d, 1H, J = 8Hz, H - 14); 6.03 (dd, 1H, J = 11 and 18Hz, H - 19); 7.40 and 7.79 (2xd, 4H, J = 8Hz, H - 23 and 24); 8.54 (s, 1H, H - 25). (Formula Removed) Example 22:14-0-[{4-[(1-Piperazinoiminomethyl)-methylhydrazonomethyl]-phenylsulfanyl}-acetyl]-mutilin hydrochloride iminomethyl-hydrazine (WO 9635692). (Formula Removed) Example 24:14-O-[(3-Acetoxymethyl-phenylsulfanyl)-acetyl]-mutilin To a solution of 1g (2 mmol) of 14-0-[(3-Hydroxymethyl-phenylsulfanyl)-acetyl]-mutilin in 10 mL of CH2CI2 are added 351 µL {3.2 mrnol) of N-methylmorpholine and 302 uL (3.2 mmol) of acetic anhydride together with a catalytic amount of 4-dimethylaminopyridine. The reaction mixture was allowed to stand for 16h at ambient temperature, concentrated under reduced pressure and chromatographed on silica using CH2CI2 / MeOH 100 : 0.5 ►lOO : 1 as mobile phase. 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 -17); 0.98 (s, 3H, CH3 - 18); 1.30 (s, 3H, CH3 - 15); 2.05 (s, 3H, CH3 -28); 2.35 (bs, 1H, H - 4); 3.37 (t, 1IH, J = 6Hz, H - 11); AB-system (uA = 3.85, uB= 3.78, J = 29Hz, CH2 - 22); 4.97 (m, 2H, H - 20); 5.00 (s, 2H, CH2 - 27); 5,49 (d, 1H, J = 8Hz, H - 14); 6.03 (dd, 1H, J = 11 and 18Hz,H- 19); 7.13 - 7.28 (m, 3H, H - 24,25, and 26); 7.33 (bs, 1H, H - 23). (Formula Removed) Example 25:14-0-{[3-(2-Hydroxyphenylcarbonyl)-hydroxymethyl-phenylsulfanyl]-acetyl}-mutilin To 276 mg (2 mmol) of salicylic acid suspended in 15 mL of CH2CI2 122 mg (1 mmol) of 4-dimethylaminopyridine, 500 mg (1 mmol) of l4-0-[(3-Hydroxymethy!-phenylsulfanyl)-acetyl]-mutilin and 515 mg (2.5 mmol) of dicyclohexylcarbodiimide are added. The reaction mixture is allowed to stand for 24h at ambient temperature. After concentrating under reduced pressure, water and ethyl acetate are added and the organic phase is washed several times with water and brine. After concentration under reduced pressure the residue is chromatograped on silica using CH2CI2/ MeOH 100 : 1 as mobile phase. 1H-NMR (400 MHz, DMSO-d8, δ, ppm, characteristic signals): 0.53 (d, 3H, J = 7Hz, CH3 - 16); 0.77 (d, 3H, J = 7Hz, CH3 - 17); 0.95 (s, 3H, CH3 - 18); 1.27 (s, 3H, CH3 - 15); 2.30 (bs, 1H, H -4); 3.34 (t, 1H, J = 6Hz,' H - 11); AB-system (uA= 3.88, uB= 3.79, J = 26Hz, CH2 - 22); 4.92 (m, 2H, H - 20); 5.46 (d, 1H, J = 8Hz, H - 14); 6.02 (m, 1H, H - 19); 6.88 - 7.80 (m, 8H, arom-H). (Formula Removed) Example 26:14-0-[(3-Mercaptomethyl-phenylsulfanyl)-acetyl}-mutilin Step 1:14-0-[(3-W!ethanesulfonyIoxymethyl-phenylsulfanyl)-acetyl]-mutilin Step 2: 14-0-[(3-Tritylsulfanylmethyl-phenylsulfanyl)-acetyl]-mutilin To 118 mg (1.73 mmol) of NaOEt in 5mL of absolute ethanol 478 mg (1.73 mmol) of triphenylmethanethiol in 8 mL of absolute ethanol is added and the resulting solution stirred at ambient temperature. After 45 minutes 1g (1.73 mmol) of 14-0-[(3-Methanesulfonyloxymethyl-phenylsulfanyl)-acetyl]-mutilin in 9 mL of acetone is added and the reaction is kept at ambient temperature for 3h. After concentrating under reduced pressure, water and ethyl acetate are added and the organic phase is washed several times with water and brine. After concentration under reduced pressure the crude product is used for the next step without further purification. (Formula Removed) Step 3: 14-0-[(3-Mercaptomethyl-phenylsulfanyl)-acetyl]-mutilin To 600 mg (0.79 mmol) of 14-0-[(3-Tritylsulfanylmethyl-phenylsulfanyl)-acetyl]-mutilin dissolved in 15 mL of a 1:1 mixture of TFA / CH2CI2 630 uL (3.95 mmol) of triethylsilane is added. The reaction mixture is allowed to stand at ambient temperature for 2h. After concentrating at reduced pressure, the residue is chromatographed on silica using cyclohexane / ethyl acetate 7 : 3 as mobile phase. 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.57 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.98 (s, 3H, CH3 - 18); 1.30 (s, 3H, CH3 - 15); 2.37 (bs, 1H, H -4); 3.38 (t, 1H, J = 6Hz, H - 11); 3.66 (d, 2H, J = 8Hz, CH2 - 27); AB-system (uA = 3.84, uB = 3.77, J = 27Hz, CH2 - 22); 4.95 (m, 2H, H - 20); 5.49 (d, 1H, J = 8 Hz, H - 14); 6.03 (dd, 1H, J = 11 and 18 Hz, H -19); 7.12 - 7.26 (m, 3H, H - 24,25 and 26); 7.31 (bs, 1H, H-23). (Formula Removed) Example 27:14-0-[(3-Acetylthiomethyl-phenylsulfanyl)-acetyl]-mutilin To 579 mg (1mmol) of 14-0-[(3-Methanesulfonyloxymethyl-phenylsulfanyl)-acetyl]-mutilin in 100 mL of THF 114 mg of potassium thioacetate is added. After stirring for 24 h at ambient temperature, the reaction mixture is concentrated under reduced pressure. Ethyl acetate and water are added and the organic phase is washed several times with water and brine. After concentrating under reduced pressure, the residue is chromatographed on silica using CH2CI2 / MeOH 100 : 1 as mobile phase. 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.55 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.98 (s, 3H, CH3 -18); 1.29 (s, 3H, CH3 -15); 2.33 (s, 3H, CH3 -28); 2.35 (bs, 1H, H - 4); 3.37 (t, 1H, J = 6Hz, H - 11); AB-system (uA= 3.82, uB = 3.76, J = 26Hz, CH2 - 22); 4.04 (s, 2H, CH2 - 27); 4.94 (m, 2H, H - 20); 5.49 (d, 1H, J = 8 Hz, H - 14); 6.03 (dd, 1H, J = 11 and 18 Hz, H - 19); 7.08 (m, 1H, H - 25); 7.22 (m, 2H, H - 24 and 26); 7.26 (bs, 1H, H-23). (Formula Removed) Example 28:14-0-[(3-Azidomethyl-phenylsulfanyl)-acetyl]-mutilin To 1g (1.73 mmol) of 14-0-[(3-Methanesulfonyloxymethyl-phenylsulfanyl)-acetyl]-mutilin in 10 mL of DMF 449 mg of NaN3 is added. The resulting suspension is stirred for 4.5h at 50°C and left overnight at ambient temperature. Water and ethyl acetate are added and the organic phase washed several times with water and brine. After concentrating under reduced pressure, the residue is chromatographed on silica using CH2CI2 / MeOH 100 : 1 as mobile phase. 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 1.00 (s, 3H, CH3 - 18); 1.30 (s, 3H, CH3 - 15); 2.34 (bs, 1H, H -4); 3.37 (t, 1H, J = 6Hz, H - 11); AB-system (uA= 3.85, uB= 3.78, J = 27Hz, CH2 - 22); 4.39 (s, 2H, CH2-27); 4.95 (m, 2H, H -20); 5.49 (d, 1H, J = 8Hz, H- 14); 6.04 (dd, 1H, J = 11 and 18 Hz, H -19); 7.18 (m, 1H, H - 25); 7,32 (m, 2H, H - 24 and 26); 7,34 (bs, 1H, H - 23). (Formula Removed) Example 29:14-0-[(3-Aminomethyl-phenylsulfanyl)-acetyl]-mutilin hydrochloride 1g (1.9 mmol) of 14-0-[(3-Azidomethyl)-phenylsulfanyl-acetyl]-mutilin is dissolved in 30 mL of THF, 900 mg of Lindlar-catalyst is added and the reaction mixture hydrogenated for 6h. The reaction mixture is filtered through celite, concentrated under reduced pressure and the residue is chromatographed on silica using CH2CI2 / MeOH 10 : 1 as mobile phase. The hydrochloride was obtained by dissolving 125 mg of 14-0-[(3-Aminomethyl)-phenylsulfanyl-acetyl]-mutilin in 3 mL of CH2CI2 and adding 2 mL of HCI-saturated Et20. After 45 minutes the reaction was evaporated to dryness under reduced pressure. 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.57 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 1.00 (s, 3H, CH3 - 18), 1.31 (s, 3H, CH3 - 15); 2.38 (bs, 1H, H -4); 3.38 (t, 1H, J = 6Hz, H - 11); AB-system (uA= 3.89, uB= 3.82, J = 26Hz, CH2 - 22); 3.95 (s, 2H, CH2 - 27); 4.98 (m, 2H, H - 20); 5.51 (d, 1H, J = 8Hz, H - 14); 6.05 (dd, 1H, J = 11 and 18Hz, H - 19); 7,30 (m, 3H, H - 24,25 and 26); 7,48 (s, 1H, H - 23). (Formula Removed) Example 30: 14-0-[(3-Acetylaminomethyl-phenylsulfanyI)-acetylJ-mutilin To 300 mg (0.6 mmol) of 14-0-[(3-Aminomethyl)-phenylsulfanyl-acetyl]-mutilin in 3 mL of CH2CI2 106 uL (0.96 mmol) of N-methylmorpholine, 91 µL (0.96 mmol) of acetic anhydride and a catalytic amount of 4-dimethylaminopyridine are added. The resulting solution is allowed to stand for 5h at ambient temperature. After evaporation to dryness under reduced pressure, the residue is chromatographed on silica using CH2Cl2 / MeOH 100 :1 ► lOO : 1,2 as mobile phase. 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 -17); 0.99 (s, 3H, CH3 - 18); 1.30 (s, 3H, CH3 - 15); 1,85 (s, 3H, CH3 -28); 2.35 (bs, 1H, H - 4); 3.38 (t, 1H, J = 6Hz, H - 11); AB-system (uA = 3.82, uB = 3.75, J = 28Hz, CH2 - 22); 4,18 (d, 2H, J = 6Hz, CH2 - 27); 4.95 (m, 2H, H - 20); 5.49 (d, 1H, J = 8Hz, H -14); 6.04 (dd, 1H, J = 11 and 19Hz, H - 19); 7.03 - 7.26 (m, 4H, H - 23,24,25 and 26). (Formula Removed) Using acetic formic anhydride, the following example is prepared in a similar fashion: Example 31: 14-0-[(3-Formylaminomethyl-phenylsulfanyl)-acetyl]-mutilin Vl-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.57 (d, 3H, J = 7Hz, CH3 - 16); 0.80 (d, 3H, J = 7Hz, CH3 - 17); 1.00 (s, 3H, CH3 - 18); 1.30 (s, 3H, CH3 - 15); 2.35 (bs, 1H, H -4); 3.37 (t, 1H, J = 6Hz, H - 11); AB-system (uA= 3.85, uB= 3.77, J =26 Hz, CH2 - 22); 4,24 (d, 2H, J = 6Hz, CH2 - 27); 4.95 (m, 2H, H - 20); 5.49 (d, 1H, J = 8Hz, H - 14); 6.05 (dd, 1H, J = 11 and 19Hz, H - 19); 7,03 - 7.38 (m, 4H, H - 23,24,25 and 26), 8.11 (s, 1H, H - 28). (Formula Removed) Example 32:14-0-[{3-[(2-Hydroxy-ethylamino)-methyl]-phenylsulfanyl}-acetyl]-mutilin hydrochloride To 579 mg (1mmol) of 14-0-[(3-Methanesulfonyloxymethyl-phenylsulfanyl)-acetyl]-mutilin in 20 mL of THF 112 mg (2mmol) of 2-Amino-ethanol are added and the reaction is stirred at ambient temperature for 16h. After concentration under reduced pressure ethyl acetate and water are added and the organic phase is washed several times with water and brine. The organic phase is dried with anhydrous sodium sulfate, evaporated under reduced pressure and the residue chromatographed on silica using CH2CI2 / MeOH / aqu. NH3100 : 5 : 0.05 as mobile phase. The hydrochloride was obtained as exemplified for example 29. 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.57 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.98 (s, 3H, CH3 - 18); 1.30 (s, 3H, CH3 - 15); 2.35 (bs, 1H, H -4); 2.53 (t, 2H, J = 6Hz, CH2 - 28); 3.38 (m, 5H, H - 11, CH2 - 28 and 29); 3.44 (q, 2H, J = 6 and 10 Hz, CH2 - 29); 3.65 (S, 3H, CH2 - 27); AB-system (uA= 3.82, uB= 3.74, J = 27Hz, CH2 - 22); 4.95 (m, 2H, H - 20); 5.49 (d, 1H, J = 8Hz, H -14); 6.04 (dd, 1H, J = 11 and 18Hz, H -19); 7.18 (m, 3H, H- 24,25 and 26); 7.29 (s, 1H, H - 23). (Formula Removed) The following compounds are prepared in a similar fashion: Example 33: 14-0-[{3-[(3-Amino-propylamino)-methyl]-phenylsulfanyl}-acetyl]-mutilin hydrochloride 'H-NMR (400 MHz, DMSO-d6, 5, ppm, characteristic signals): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.98 (s, 3H, CH3 - 18); 1.30 (s, 3H, CH3 - 15); 2.35 (bs, 1H, H -4); 2.48 and 2.57 (2xm, 4H, CH2 - 28 and 30); 3.36 (t, 1H, J = 6Hz, H - 11); 3.60 (s, 2H, CH2 -27); AB-system (uA= 3.81, uB= 3.743, J = 28Hz, CH2 - 22); 4.95 (m, 2H, H - 20); 5.49 (d, 1H, J = 8Hz, H - 14); 6.03 (dd, 1H, J = 11 and 17Hz, H - 19); 7.10 - 7.23 (m, 3H, H- 24,25 and 26); 7.28 (s, 1H, H -23). (Formula Removed) Example 34: 14-0-[(3-{[3-(3-Amino-propylamino)-propylamino]-methyl}-phenylsulfanyl)-acetyl]-mutilin hydrochloride 1H-NMR (400 MHz, DMSO-d6, 5, ppm, characteristic signals): 0.57 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 1.00 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.38 (s, 1H, H -4); 2.86 - 3.05 (m, 8H, CH2 - 28,30,31 and 33); 3.76 (bt, 1H, J = 6Hz, H - 11); AB-system (uA = 3.92, uB = 3.84, J = 27Hz, CH2 - 22); 4.06 (bs, 2H, CH2- 27); 4.97 (m, 2H, H - 20); 5.51 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 and 18Hz, H - 19); 7,36 (m, 3H, H - 24,25 and 26); 7,60 (s, 1H.H-23). (Formula Removed) Example 35:14-0-[{3-[(2,2-Difluoro-ethylamino)-methyl]-phenylsulfanyl}-acetyl]-mutilin hydrochloride 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.55 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.97 (s, 3H, CH3 - 18); 1.29 (s, 3H, CH3 - 15); 2.34 (bs, 1H, H -4); 2.79 (bt, 2H, J = 16Hz, CH2 - 28); 3.48 (t, 1H, J = 6Hz, H - 11); 3.68 (s, 2H, CH2 - 27); AB-system (uA= 3.83, uB= 3.77, J = 30Hz, CH2- 22); 4.94 (m, 2H, H - 20); 5.49 (d, 1H, J = 8Hz, H -14); 5,97 (tt, 1H, J = 4 and 56Hz, H - 29); 6.03 (dd, 1H, J = 11 and 18Hz, H - 19); 7,10 - 7.28 (m, 3H, H - 24,25 and 26); 7,30 (s, 1H, H - 23). (Formula Removed) Example 36:14-0-[(3-Benzylaminomethyl-phenyIsulfany|)-acetyl]-mutilin hydrochloride 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 1.00 (s, 3H, CH3 - 18); 1.30 (s, 3H, CH3 - 15); 2.35 (bs, 1H, H -4); 3.37 (t, 1H, J = 6Hz, H - 11); 3.54 (d, 2H, J = 7Hz, CH2 - 28); AB-system (uA = 3.90, uB = 3.83, J = 26Hz, CHZ- 22); 4.04 (s, 2H, CH2- 27); 4.97 (m, 2H, H - 20); 5.43 (m, 2H, H - 30); 5.50 (d, 1H, J = 8Hz, H - 14); 5,90 (m, 1H, H - 29); 6.04 (dd, 1H, J = 11 and 18Hz, H - 19); 7,35 (m, 3H, H - 24,25 and 26); 7,53 (d, 1H, J = 1Hz, H - 23). (Formula Removed) Example 38: 14-0-{[3-(2-Methoxy-ethylamino)-methyl-phenylsulfanyl]-acetyl}-mutilin hydrochloride 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.57 (d, 3H, J = 7Hz, CH3 - 16); 0.80 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.30 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H -4); 3,01 (t, 2H, J = 5Hz, CH2 - 28); 3.28 (s, 3H, CH3 - 30); 3.38 (t, 1H, J = 6Hz, H - 11); 3.59 (t, 2H, J = 5Hz, H - 29); AB-system (uA= 3.89, uB = 3.83, J = 26Hz, CH2 - 22); 4.07 (s, 2H, CH2 -27); 4.97 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H -14); 6.04 (dd, 1H, J = 10 and 21Hz, H - 19); 7,34 (m, 3H, H - 24,25 and 26); 7,56 (bs, 1H, H - 23). Example 39: 14-0-[(3-{[2-(2-Amino-ethylamino)-ethylamino]-methyl}-phenylsulfanyl)-acetylj-mutilin hydrochloride 1H-NMR (500 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.57 (d, 3H, J = 7Hz, CH3- 16); 0.79 (d, 3H, J = 7Hz, CH3- 17); 1.00 (s, 3H, CH3- 18); 1.31 (s, 3H, CH3- 15); 2.37 (bs, 1H, H -4); 3,13 - 3,36 (m, 8H, CH2- 28,29,30 and 31); 3.37 (t, 1H, J = 6Hz, H - 11); AB-system (uA = 3.92, uB = 3.84, J = 32Hz, CH2 - 22); 4.15 (s, 2H, CH2- 27); 4.96 (m, 2H, H - 20); '5.52 (d, 1H, J = 8Hz, H - 14); 6.06 (dd, 1H, J = 11 and 18Hz, H - 19); 7,37 (m, 3H, H - 24,25 and 26); 7,59 (s, 1H, H-23). (Formula Removed) Example 40:14-0-[3-{[(Furan-2ylmethyl)-amino]-methyi}-phenylsulfanyl-acetyl]-mutilin hydrochloride Example 41:14-0-[(3-Methylaminomethyl-phenylsulfanyl)-acetyl]-mutilin hydrochloride 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals); 0.56 (d, 3H, J = 7Hz, CH3- 16); 0.79 (d, 3H, J = 7Hz, CH3- 17); 0.99 (s, 3H, CH3- 18); 1.29 (s, 3H, CH3- 15); 2.35 (bs, 1H, H -4); 2.98 - 3.23 (m, 4H, CH2 - 28 and 31); 3.35 (t, 1H, J = 6Hz, H -11); 3.70 - 3.96 (m, 6H, CH2 -22,29 and 30); 4,27 (m, 2H, CH2 - 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6,03 (dd, 1H, J = 11 and 19Hz, H-19); 7.40 (m,3H,H-24,25 and 26), 7.63(s, 1H, H - 28). (Formula Removed) Example 44: 14-0-[(3-Piperazin-1-ylmethyl-phenylsulfanyl)-acetyl]-mutilin hydrochloride 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.56 (d, 3H, J = 7Hz, CH3- 16); 0.79 (d, 3H, J = 7Hz, CH3-17); 1,00 (s, 3H, CH3-18); 1.28 (s, 3H, CH3-15); 2.23 and 2.66 (m, t, 8H, J = 5Hz, CH2- 28,29,30 and 31); 2.34 (bs, 1H, H - 4); 3.35 (m, 3H, H-11, CH2-27); AB-system (uA= 3.80, uB= 3.73, J = 24Hz, CH2 - 22); 4,27 (m, 2H, CH2 - 27); 4.95 (m, 2H, H - 20); 5.49 (d, 1H, J = 8Hz, H - 14); 6.02 (dd, 1H, J = 11 and 18Hz, H - 19); 7.08 - 7.27 (m, 4H, H -23,24,25 and 26). (Formula Removed) Example 45: 14-0-{3-[(2-Dimethylamino-ethylamino)-methyl]-phenylsulfanyI-acetyl}-mutilin hydrochloride 1H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.56 (d, 3H, J = 7Hz, CH3- 16); 0.79 (d, 3H, J = 7Hz, CH3- 17); 1.00 (s, 3H, CH3- 18); 1.31 (s, 3H, CH3- 15); 2.37 (bs, 1H, H -4); 2.82 (s, 6H, CH3 - 30 and.31); 3.38 (m, 5H, H -11, CH2 - 28 and 29); AB-system (uA= 3.92, uB = 3.83, J = 27Hz, CH2 - 22); 4,13 (m, 2H, CH2 - 27); 4.97 (m, 2H, H - 20); 5.51 (d, 1H, J = 8Hz, H - 14); 6.05 (dd, 1H, J = 11 and 18Hz, H - 19); 7.38 (m, 3H, H- 24,25 and 26); 7.59 (s, 1H, H-23). (Formula Removed) Example 46:14-0-{3-t(2-Amino-ethylamino)-methyl]-phenylsulfanyl}-acetyl]-mutilin hydrochloride 'H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.56 (d, 3H, J = 7Hz, CH3- 16); 0.80 (d, 3H, J = 7Hz, CH3- 17); 0.97 (s, 3H, CH3- 18); 1.30 (s, 3H, CH3- 15); 2.35 (bs, 1H, H -4); 2.45 and 2.58 (2xm, 4H, CH2 - 28 and 29); 3.34 (d, 1H, J = 6Hz, H - 11); 3.62 (s, 2H, CH2 -27); AB-system (uA= 3.82, uB= 3.73, J = 27Hz, CH2 - 22); 4.95 (m, 2H, H - 20); 5.49 (d, 1H, J = 8Hz, H - 14); 6.03 (dd, 1H, J = 11 and 18Hz, H - 19); 7.18 (m, 3H, H- 24,25 and 26); 7.29 (s, 1H. H -23). (Formula Removed) Example 47: 14-0-[(3-{[Bis-(2-hydroxy-ethyl)-amino]-methyl}-phenylsulfanyl)-acetyl]-mutilin hydrochloride 1H-NMR (400 MHz, DMSO-d8, δ, ppm, characteristic signals): 0.56 (d, 3H, J = 7Hz, CH3- 16); 0.79 (d, 3H, J = 7Hz, CH3- 17); 0.99 (s, 3H, CH3-18); 1.30 (s, 3H, CH3-15); 2.36 (bs, 1H, H -4); 2.53 (t, 2H, J = 6Hz, CH2 - 28); 3.13 and 3.23 (2xm, 4H, CH2 - 28 and 30); 3.38 (bt, 1H, H -11, J = 6Hz); 3.78 (m, 4H, CH2 - 29 and 31); AB-system (uA= 3.92, uB = 3.84, J = 31 Hz, CHa -22); 4.48 (bd, 2H, J = 4Hz, CH2 - 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 and 18 Hz, H - 19); 7.38 (m, 4H, arom-H). (Formula Removed) Example 48:14-0-[(3-Dimethylaminomethyl-phenylsulfanyl)-acetyl]-mutilin hydrochloride 29 'H-NMR (400 MHz, DMSO-d6, δ, ppm, characteristic signals): 0.55 (d, 3H, J = 7Hz, CH3- 16); 0.79 (d, 3H, J = 7Hz, CH3- 17); 0.97 (s, 3H, CH3- 18); 1.29 (s, 3H, CH3- 15); 2.11 (s, 6H, CH3 -28 and 29); 2.36 (bs, 1H, H - 4); 3.31 (s, 2H, CH2 - 27); 3.37 (t, 1H, H -11, J = 6Hz); AB-system (uA = 3.80, uB = 3.74, J = 25Hz, CH2 - 22); 4.95 (m, 2H, H - 20); 5.49 (d, 1H, J = 8Hz, H - 14); 6.03 (m, 1H, H -19); 7.08 and 7.22 (2xm, 4H, arom-H). (Formula Removed) \Antimicrobial activity of novel pleuromutilin-derivatives: The antibacterial activity expressed as minimal inhibitory concentration (MIC) was determined according to the approved standard reference recommendations of CLSI (former NCCLS). Compound of Example 1 and the other claimed compounds exhibited very good activity against at least one of the clinical relevant bacterial pathogens Staphylococcus aureus, Enterococcus faecalis, Streptococcus pneumoniae, Moraxella catarrhalis and Escherichia coli (see Table 1). This in vitro activity was significantly better than that of the comparator compound 2, as the MICs of Example 1 were by at least a factor of 2 lower against at least one of the strains shown in Table 1 than the MICs of Example 2 (see Table 1). Table 1. Antimicrobial activity of Example 1 and the comparator compound Example 2 against selected bacterial pathogens shown as minimal inhibitory concentration (MIC, [ug/ml]). Species ATCC number Strain MIC [ug/ml] Example 1 Example 2 (Table Removed) WE CLAIM: 1. A compound selected from the group consisting of 14-0-[(((C1-6)Alkoxy-(C1-6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-0-[(((C1-6)Mono-ordialkylamino-(C1-6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[(((C1-6)Acylamino-(C1-6)alkyl]-phenylsulfany)-acetyll-mutilins, 14-O-[((Hydroxy-(C1-6)-alkyl]-phenylsulfany)-acetyl)-mutilins, 14-O-[((Formyl-(C0-5)-alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Guanidino-imino-(C1-6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Ureido-imino-(C1.8)alkyl)-phenylsulfanyl)-acetyl)-mutilins, 14-O-[((Thioureido-imino-(C1-6)aikyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((lsothioureido-imino-(C1-5)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Cyano-(C0-5)-alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Azido-(C0-5)-alkyl)-phenylsulf anyl)-acetyl]-mutilins, 14-O-[(((C1-6)Acyloxy-(c)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-O-[((Benzoyloxy-( C1-6)alkyi)-phenylsulfanyl)-acetyl]-mutilins, wherein the phenyl-ring is optionally further substituted by up to four groups independently selected from halogen, (C1-6)alkyi, aryl, aryl(C1-6)- alkyl, (C1-6)alkoxy, (C1- 6)alkoxy(C1-6)alkyl, halo(C1-6)alkyl, aryl (C1-6alkoxy, hydroxy, nitro, cyano, azido, acyloxy, carbamoyl, mono-ordi-N-( C1-6)alkylcarbamoyl, (C1-6)- alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, (C1-6alkylguanidino, amidino, (C1-6) alkylamidino, sulphonylamino, aminosulphonyl, (Ci.6) alkylthio, (C1-6)-alkylsulphinyl, (C1-6) alkylsulphonyl, heterocyclyl, heteroaryl, heterocyclyKd^alkyl and heteroaryKC^alkyl, or two adjacent ring carbon atoms may be linked by a (C3-5) alkylene chain, to form a carbocyclic ring. 2. A compound according to claim 1 which is selected from the group consisting of 14-0-[((( C1-6)Alkoxy-(C1-6)alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-0-[(((C1-6)Mono- or dialkylamino- C1-6alky)-phenylsulfanyl]-acetyl]-mutilins, 14-0-[((Hydroxy-( C1-6)-alkyl)-phenylsulfanyl)-acetyl]-mutilins, 14-0-[((Formyl-(CQ-5)-alkyl)-phenylsulfanyl)-acetyl]-mutilins, M-O-KCGuanidino-imino-( C1-6)alkyl]-phenylsulfanyl]-acetyll-mutilins. 3. A compound of formula (I) (Formula Removed) wherein n is 1 to 6; X is oxygen or NR2 wherein R2 is hydrogen or linear or branched (C-i-e)-alkyl, or hydroxy-(C1-6)alkyl or (C1-6)alkoxy-(C1-6)alkyll R, is hydrogen, linear or branched ( C1-6)-alkyl, mono- or dihalogenated ( C1-6)-alkyl, amino( C1-6)-alkyl, hydroxy( C1-6)-alkyl, phenyl( C1-6)-alkyl, ( C1-6)-alkylen, furanyl( C1-6)-alkyl, (C3.6)-cycloalkyl, and the corresponding ammonium salts, e.g. chlorides, or R-l and R2 together with the nitrogen atom to which they are attached form a 5 to 7 membered heterocycle containing at least one nitrogen atom, or XR1 is piperazinyl or morpholinyl. 4. A compound of formula (II) (Formula Removed) wherein n is 0 to 5, Y is oxygen or NR3, ; X is oxygen, sulfur, NH or NR3 (Formula Removed) or (Formula Removed) together with a corresponding anion, e.g. chloride, F\4, R5, R6, R7 are hydrogen, linear or branched C1-6alkyl or C3.8cycloalkyl, R8 is Chalkyl. 5. A compound according to claim 4, wherein YisNR3, XisNR7, R3 is X (Formula Removed) and R4 and R7 together with the nitrogen atoms to which they are attached form a 5 to 7 membered heterocyclic ring containing at least 2 nitrogen atoms, whereas R5 and R6 are defined as in claim 4, or and R5 and R6 together with the nitrogen atoms to which they are attached form a 5 to 7 membered heterocyclic ring containing at least 2 nitrogen atoms, whereas R4 and R7 are defined as in claim 4, or and R4 and R5 together with the nitrogen atoms to which they are attached form a 5 to 7 membered heterocyclic ring containing one or more nitrogen atoms, whereas R8 and R7 are defined as in claim 4. A compound according to claim 5, wherein Y is NR3, X is NR7, R3 is (Formula Removed) R6 and R7 are defined as in claim 4, R9 is hydrogen, linear or branched Ci.6alkyl or acyl, e.g. C-i^acyl. 7. A compound according to one of claims 3, 4, 5 and 6, wherein said (CH2)n-group is in meta position in relation to the sulphur bound to the phenyl-ring. 8. A compound according to one of claims 3, 4, 5 and 6, wherein said (CH2)n-group is in ortho position in relation to the sulphur bound to the phenyl-ring, with the proviso that the phenyl-ring is further substituted by up to four groups independently selected from halogen, (C1-8)alkyl, aryl, aryl (C1-6)- alkyl, (C1-6)alkoxy, (C1-6)alkoxy(C1-6)alkyl, halo (C1-6)alkyl, aryl (C^alkoxy, hydroxy, nitro, cyano, azido, acyloxy, carbamoyl, mono-or di-N-(C1-6)alkylcarbamoyl, (C1-6)- alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, (C1-6)alkylguanidino, amidino, (C1-6) alkylamidino, sulphonylamino, aminosulphonyl, (C1-6) alkylthio, (C1-6)-alkylsulphinyl, (C1-6) alkylsulphonyl, heterocyclyl, heteroaryl, heterocycly (C1-6)alkyl and heteroaryl (C1-6)alkyl, or two adjacent ring carbon atoms may be linked by a (C3-5) alkylene chain, to form a carbocyclic ring. 9. A compound selected from the group consisting of 14-0-[(3-Hydroxymethyl-phenylsulfanyl)-acetyl]-mutilin, 14-0-{[3-(Aminoimino-methyl)-hydrazonomethyl-phenylsulfanyl]-acetyl}-mutilin, 14-0-[{3-[((1-Piperazinoiminomethyl)-methylhydrazono)-methyl]-phenylsulfanyl}-acetyl]-mutilin, 14-0-[{3-[(3-Ethyl-(2-ethyUmino)-imidazoHdin-l-ylimino)-methyl]-pheiiyIsulfanyl}-acetyl]- mutilin, 14-0-[{3-[(l-Piperazinoiminomethyl)-hydrazonome'thyl]-phenyLsulfanyl}-acetyl-mutilin, l4-0-[{3-|(2-Morpholin-4-yl-ethoxyimino)-methyl]-;phenylsulfanyl)-acetyl[-mutilin. 14-0-(3-{l(2-PyrroIidin-l-yl-ethoxyimino)-methyl|-phenylsulfanyI}-acetyl]-mutilin, 14-0-[(3-Aminomethyl-phenylsulfanyl)-acetyl]-mutilin, 14-0-[(3-Allylaminomethyl-phenylsulfanyl)-acetyl]Mmitilin, 14-0-[3-{(Furan-2yImethyl)-amino|-methyl}-phenylsulfanyl-acetyl|-mutilin. 14-0-[(3-Cyclopropylamiiiomethyl-phenylsulfanyl)-acetyl]-mutiIin. 10. A compound of any one of claims 1 to 9, in the form of a salt. 11. A compound of anyone of claims 1 to 10, for use as a pharmaceutical. 12. 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 11. 13. Use of a compound according to anyone of claims 1 to 11 for the preparation of a medicament for the treatment of diseases mediated by microbes. 14. Use according to claim 13 wherein the microbial infection is a skin or soft tissue infection. 15. A pharmaceutical composition comprising a compound of anyone of claims 1 to 11, in association with at least one pharmaceutical excipient.] 16. A pharmaceutical composition according to claim 15 further comprising anotiu'. pharinaceiitically active agent. 17, A compound as defined in any one of claims 1 to 11 for use in the preparation of a medicament for the treatment of acne. 18. A compound for use in the preparation of a medicament for the decolonization of bacterial carriers. 19. A compound, a method of treatment, use of a compound, a pharmaceutical composition and a compound for use in the preparation of a medicament, substantially as hereinbefore described and illustrated with reference to the foregoing examples and accompanying drawings.

Documents:

5764-delnp-2008-Abstract-(16-06-2014).pdf

5764-delnp-2008-abstract.pdf

5764-delnp-2008-Claims-(02-12-2014).pdf

5764-delnp-2008-Claims-(16-06-2014).pdf

5764-delnp-2008-claims.pdf

5764-delnp-2008-Correspondence Others-(02-12-2014).pdf

5764-delnp-2008-Correspondence Others-(10-12-2014).pdf

5764-delnp-2008-Correspondence Others-(16-06-2014).pdf

5764-DELNP-2008-Correspondence-Others-(31-12-2009).pdf

5764-delnp-2008-correspondence-others.pdf

5764-delnp-2008-description (complete).pdf

5764-delnp-2008-form-1.pdf

5764-DELNP-2008-Form-18-(31-12-2009).pdf

5764-delnp-2008-Form-2-(16-06-2014).pdf

5764-delnp-2008-form-2.pdf

5764-delnp-2008-Form-3-(16-06-2014).pdf

5764-delnp-2008-form-3.pdf

5764-delnp-2008-form-5.pdf

5764-delnp-2008-GPA-(16-06-2014).pdf

5764-delnp-2008-Marked-Claims-(02-12-2014).pdf

5764-delnp-2008-pct-101.pdf

5764-delnp-2008-pct-105.pdf

5764-delnp-2008-pct-210.pdf

5764-delnp-2008-pct-220.pdf

5764-delnp-2008-pct-237.pdf

5764-delnp-2008-pct-301.pdf

5764-delnp-2008-pct-304.pdf

5764-delnp-2008-pct-306.pdf

5764-delnp-2008-pct-308.pdf

Form 13.pdf

Letter to IPO.pdf

Petition 137.pdf

Petition.pdf