Title of Invention	A NOVEL PLEUROMUTILIN DERIVATIVE
Abstract	A method of preventing or treating diseases caused by Mycobacterium, comprising administering to a subject in need of such treatment an effective amount of a pleuromutilin.

Full Text

The present invention relates to tuberculosis treatment, such as treatment of diseases mediated by Mycobacterium, e.g. Mycobacterium tuberculosis, with pleuromutillns. Tuberculosis is a chronic infectious disease mediated by infection with Mycobacterium tuberculosis. Tuberculosis is a major disease in developing countries, as well as an increasing problem in developed areas of the world. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If untreated, serious complications and death typically result. Tuberculosis may be generally controlled by antibiotic therapy, such as by treatment with Isoniazid, see e.g. The Merck Index, 12th edition, item 5203; Rifampin (Rifampicin®), see e.g. The Merck Index, 12th edition, item 8382, Streptomycin, see e.g. The Merck Index, 12th edition, item 8983; but a major problem is the development of strain drug resistance against such antibiotics. We have now found a compound class which shows surprisingly activitiy in the treatment of diseases caused by Mycobacterium, such as Mycobacterium tuberculosis, e.g. even against dnjg resistant strains. In one aspect the present invention provides the use of a pleuromutilin in the preparation of a medicament for the treatment of diseaeses mediated by Mycobacterium. In another aspect the present invention provides a method of treating diseases mpdiated by Mycobacterium, comprising administering to a subject in need of such treatment an effective, e.g. an anti-mycobacterium effective; amount of a pleuromutilin. Mycobacterium includes M. tuberculosis. Diseaeses mediated by Mycobacterium include mycobacterium infections. A pleuromutilin for treatment includes one or more pleuromutillns, e.g. a combination of different pleuromutillns. Treatment includes treatment and prophylaxis. A pleuromutilin for use according to the present invention or for treating diseases according to the present invention is designated hereinafter as "a pleuromutilin(s) of (according to) the present invention". A pleuromutilin of the present invention includes a pleuromutiiln in the form of a free base, and, where existing, in the form of a salt, in the form of a solvate and in the form of a salt and a solvate, e.g. and in the form of a complex, such as a cyclodextrin complex. A pleuromutilin of the present invention may exist in the form of isomers and mixtures thereof, e.g. including diastereoisomers and mixtures thereof. Isomeric mixtures nnay be separated as appropriate, e.g. according to a method as conventional, to obtain pure isomers. The present invention includes a pleuromutilin according to the present invention in any isomeric form and in any isomeric mixture, such as described in patent literature cited below, which patent literature is introduced herein by reference with respect to isomeric forms of pleuromutlins. Preferably the cofiguration in the mutilin ring is the same as in a naturally produced mutilin. Pleuromutilin, a compound of formula is a naturally occurring antibiotic, e.g. produced by the basidomycetes Pleurotus mutilus and pTpasseckerianus, see e.g. The Merck Index, 12th edition, item 7694. A number of further pleuromutiiins having the principle ring structure of pleuromutilin and having e.g. antibacterial activity, have been developed. A pleuromutilin of the present invention includes a pleuromutilin having the basic structural elements as set out in formula wherein R 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: 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 -0- in position 14 is further substituted, preferably by a substituted carbonyl group. Examples of pleuromutilins according to the present invention includes e.g. wherein R is CH3-(CH2)7-CH=CH-(CH2)7-COO-, CH3-(CH2)4-CH=CH-CH2-CH=CH-(CH2)r C00-, CH3-(CH2)9-CH=CH-(CH2)7-COO- or hydrogen; wherein X, Y and Z are as defined in any one of the following groups: a. X is -CO-CH2-R1, wherein R- is H, CI, Br, I, thiocyanato, azido, (N,N-tetramethylene-thiocarbamoyl)-mercapto, dithiocarbonic acid-0-(Ci.3)alkyl, -S-phenyl, S-phenyl substituted by carboxyl or by one or two OH, -S-pyridyt, -S-benzyi, -S-(Ci^)alkyl, or -S-(Ci.5)all b. X is -CO-CO-OH, Y is vinyl and Z is H; c. X is -COCH3, Y is vinyl and Z is H; d. X is COCH2NH2, Y is ethyl and Z is H; wherein Ri is vinyl or ethyl, n is an integer from 2 to 5, X is sulphur or a group -Y-phenylene-Z- or a group =NR4, Y and Z are both sulphur or one of Y and Z is sulphur and the other is oxygen, R4 is H or a second mutilin ring of formula I-US4278674, wherein Ri is as defined above and attached via a -O-CO-CH2- group in position 14; each of R2 and R3 are (independently of each other) (Ci.io)alkyl. or R2 and R3 together with the nitrogen atom form pyrrolidine, piperidino, morpholino, thiomorpholino, or 1-hexahydro-1H-azepino, orR2 and R3 together with the nitrogen atom form piperazinyl, the second nitrogen atom of which is substituted by (Ci.5)alkyl, (CM)hydroxyalkyl, (C2.5)alkynoyloxy{Ci^)alkyl, or benzoyloxy(Ci^)alkyl, or Ri is as defined above, n = 2, R3 is (Ci.io)alkyl, (Ci^)hydroxyalkyl, (C2-5)alkynoyloxy-(Ci^)alkyl, or ben2oyloxy(Ci-»)alkyl, X is =NR'4 and R2 together with R'4 fonns an ethylene bridge between both nitorgen atoms; such as ■ 14-Desoxy-14[(2-diethylaminoethyl)mercaptoacetoxy]mutilin, e.g. also known as tiamulin of formula wherein R is ethyl or vinyl, Ri is selected from a- or p-anomers of hexopyranoses, hexofuranoses, pentopyranoses, pentofuranoses, pyranose and furanose aminosugars, disaccharides, trisaccharides and Rz is H, benzoyl or (C2^)alkanoyi; or Ri is 2-deoxy-2-(hydroxyimino)-3,4,6-tri-0-acetyl-a-D-glucopyranosyl or -gaiactopyranosyl, 2-deoxy-2-(hydroxyimino)-a-D-galactopyranosyl, 2-deoxy-2-amino-4,6-di-0-acetyl-a-D-glucopyranosyl, or 2-deoxy-2-acetamido-3,4,6-tri-0-acetyl-a-D-glucopyranosyl and R2 is H; and the 19,20-dihydro derivative thereof and the tetra (C2^)alkanoyl derivatives thereof; - A compound as disclosed in EP0013768, e.g. of formula R2 and R3 together form an optionally substituted cyclic group of 3 to 8 ring atoms, optionally containing one additional lieteroatom selected from N, 0 and S, and optionally fused to a liydrocarbon ring, a heterocyclic group or an aromatic group; or R2 is one of the above monovalent groups and R3 is a group selected form SO2R4, COR5, OR5 and NReRy," wherein R4 is optionally substituted, - saturated or unsaturated (Ci^)hydrocarbon or (C3-8)cyclic hydrocarbon, - heterocyclyl, aryl, (Ci^)alkylamino or arylamino; R5 is optionally substituted - saturated or unsaturated (Ci^) hydrocarbon or (C3^)cyclic hydrocarbon, - heterocyclyl or aryl, Re and R7 independently of each other are H, or optionally substituted - saturated or unsaturated (Ci^) hydrocarbon or (C3^)cyclic hydrocarbon, - heterocyclyl or aryl, or Rg and R7 together with the nitrogen atom to which they are attached form an optionally substituted (C3.8)cyclic group, optionally containing one additional heteroatom selected from N, O or S, and optionally fused to a hydrocarbon ring, a heterocyclic ring or an aromatic group; wherein Ri is vinyl or ethyl, and R2 is a group R3, R4CH2-, or R5R6CH=CH-, wherein , each of R3 and R4 is an azabicyclic ring system, or R5 and Re together with the carbon atom to which they are attached fonri an azabicyclic ring system; - A compound of W09821855; e.g. of fomiula or R-X-CH2CO2, wherein X is 0, S or NR' and R and R' are indpendently of each other an aliphatic or aromatic group, preferably R2COO- is a carbamoyl group, such as a group R3R4NCO2-wherein R3 and R4 have various meanings (e.g. R3 and R4have the meaning as disclosed for the meaning of R2 and Rain WO9725309); - A compound as disclosed in WO0027790, e.g. a compound of fonnula wherein Ri is an optionally substituted heteroaryl group which comprises a 5-membered heteroaromatic ring which has at least one N-atom, e.g. a pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, indole, benzimidazole, t>enzotriazole, 2-aza-indole or6-aza-indole; and which is linl e.g. pyridine, pyridazine, pyrimidine, pyrazine, isoxazole, thiazoie, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, benzimidazole, 3-oxo-3,4-dihydropyrido[2,3-b]pyrazine, or pyrazolo[1,5-a]pyrimidine; and R2 is vinyl or ethyl; - A compound as disclosed in WO0204414, e.g. a compound selected from 14-0-[(cycloall wherein Ri is: - a 5- or 6-membered aromatic or heteroaromatic ring attached via a ring carbon atom, preferably pyridyl, and comprising a substituent selected from halo, R7O-, R7S- or RsRgN- on a ring carbon adjacent to the carbon of attachment; or - a 5- or 6-membered dihydro heteroaromatic ring attached via a ring carbon atom and comprising one oxygen or one or two nitrogen atoms and optionally fused to phenyl, a 5- or 6-membered heteroaryl ring comprising one or two nitrogen atoms or a 5- or 6- membered heterocyclyl ring comprising a sulphur, oxygen or nitrogen atom and further comprising a substituent selected from 0x0 or thioxo on a ring carbon adjacent to the carbon of attachment; - a 6-membered tetrahydro heteroaromatic ring attached via a ring carbon atom comprising one or two nitrogen atoms and further comprising two substituents independently selected from 0x0 or thioxo wherein one of the substituents is on a ring carbon adjacent to the carbon of attachment; or - a bicyclic heteroyaryl ring attached via a ring carbon atom and comprising nine or ten ring atoms and from one to four nitrogen atoms; wherein the ring of Ri may be optionally further substituted; R2 is vinyl or ethyl; R3 is H, OH or F and R4 is H, or R3 is H and R4 is F; and R5 and Re together fomi an 0x0 group; or R3 and R4 is each H and R5 is H, or OH and Re is H, or R5 is H and Re is H or OH; R7 is optionally substituted (Ci^)alkyl; and Ra and Rg are independently selected from hydrogen or optionally substituted (Ci^)alkyl. - A compound as disclosed in WO0222580, of formula wherein Rap, R'sp, Rep, Ryp and Rap are, index-number correspondingly, as defined for a compound of formula I-WO0222530 for R3, R'3, Re, R? and Re; and Rsp is hydrogen or one or more substituents, and If the group attached to the piperidine ring via the sulphur atom is in position 3 of said piperidine ring and Rsp is hydrogen, then the group attached to the sulphur atom is either in the (S)-configuration or in the (R)-configuration; wherein Rss, R'ss, R4s, Rss, R/s and Res, respectively, are, index-number correspondingly, as defined for a compound of formula I-WO0222580 for R3, R'3, R4, Re, Rr and Re; Rss is hydrogen or one or more substituents, preferably hydrogen; and Ris is that part of an amino acid which remains if the carboxylic group is splitt off; e.g. wherein in a compound of formula U the group attached to the piperidine ring via the sulphur atom is either in the (S)-configuration or in the (R)-configuration; e.g. wherein In a group Ris the amine group of the amino acid residue is either in the (S)-configuration or in the (R)-configuration. Furthermore we have found novel pleuromutilins which show antibacterial activity and activity against Mycobacterium tuberculosis. A novel compound of the present invention includes a compound in any fonn, e.g. in free fomn, in the fonn of a salt, in the form of a solvate and in the form of a salt and a solvate. In another aspect the present invention provides a novel compound of the present invention in the form of a salt. A salt of a novel compound of the present invention includes a pharmaceutically acceptable salt, e.g. including 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 formula I with an acid, e.g. hydrogen fumaric acid, fumaric acid, naphthalin-1,5-sulphonic acid, phosphoric acid, tartaric acid, citric acid, hydrochloric acid, deuterochloric acid; preferably hydrochloric acid. A novel 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 novel 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 unsolvated form; and vice versa. A novel compound of the present invention 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 diastereoisomeres and mixtures thereof, e.g. racemates. For example a novel compound of the present invention may comprise the residue of an amino acid. In such amino acid residue the carbon atom to which the amino group is attached may be an asymmetric carbon atom and the amino group attached may thus be in the R- or S-configuration. A novel compound of the present invention may comprise a cycloalkyi, e.g. attached to the sulfanyl group, which cycloalkyi may be further substituted, and said substitutents may exist in the cis or in the trans conformation. E.g., the carbon atom of a cycloalkyi group to which the sulfanylgroup is attached may be asymmetric, e.g. if said cycloalkyi is further substituted, and substitutents attached to said cycloalkyi group may be in the R- or in the S-configuration. E.g., a novel compound of the present invention also may comprise an oxime group. The hydroxgroup attached to the imino group may be in syn- or in anti-configuration. 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 novel compound of the present invention in any isomeric form and in any isomeric mixture. The present invention also includes tautomers of a novel compound of the present invention where such tautomers can exist. Any compound described herein, e.g. a novel compound of the present invention, may be prepared as appropriate, e.g. according to a method as conventional, e.g. analogously, e.g. or as specified herein. wherein Rp is as defined above, in a reactive form, e.g. a mesylate or a tosylate, optionally in a protected form, to obtain a compound of formula Ip (i.e. novel compound of the present invention ), or to obtain a pre-form of a compound of formula Ip, c. optionally further reacting a pre-form obtained in step b. to obtain a compound of formula Ip, e.g. introducing deuterium to obtain a compound of formula Ip wherein the subsitutents are as defined above, and d. isolating a compound of formula Ip obtained in step b. or in step c. from the reaction mixture. Rpis - substituted (C4^)cycloalkyl, - substituted phenyl, - substituted aliphatic heterocyclyl, having 4 to 8 ring members and comprising as a heteroatom 1 or 2 nitrogen atoms, - alkyl, substituted by (substituted) amino, - alkyl substituted by heterocyclyl, or - substituted, bicyclic aliphatic heterocyclyl, comprising in each ring 5 ring members and one oxygen heteroatom, e.g. including the meanings of of RP in the novel pleuromutilins of the present invention, e.g. such as set out in patent claims 6 to 11. A process provided by the present invention may e.g. be carried out analogously to processes as set out in any of the patent references cited herein, e.g. analogously to a process for the production of compounds as described in patent literature cited herein, such as in WO0109095, WO0204414 and WO0222580, or as described herein. All patent references cited herein are introduced by reference, especially with respect to the claim scopes and meanings of the substituents, e.g. including the preferred meanings of the substitutents, and with respect to production processes. A pleuromutilin of the present invention includes the novel compounds of the present invention of fomriula Ip. A pleuromutilin of the present invention includes one or more, preferably one, pleuromutilins of the present invention, e.g. one pleuromutilin or a combination of different pleuromutilins of the present invention. We have found that novel compounds of the present invention, including compounds of formula Ip, exhibit pharmacological activity similar to pleuromutilins in similar indications as described in WO0109095, WO0204414 and WO0222580, e.g. in test systems similar as "described in WO0109095, WO0204414 and WO0222580, and additionally in test systems described herein. Compounds of formula Ip are therefore useful as pharmaceuticals. In another aspect the present invention provides a compound of formula Ip for use as a phannaceutical, preferably as an antimicrobial, such as an antibiotic, e.g. and as an anti-anaerobic, including the use as a phannaceutical in the treatment of diseases mediated by Mycobacterium, such as Mycobacterium tuberculosis In another aspect the present invention provides a compound of fomnuia Ip for use in the preparation of a medicament for the treatment of microbial diseases, for example of diseases mediated by bacteria, e.g. selected from Staphylococci, Streptococci, Enterococd, Mycobacterium, e.g. Mycobacterium tuberculosis; e.g. and of diseases mediated by Mycoplasms, Chlamydia and obligatory anaerobes. In another aspect the present invention provides a method of treatment of microbial diseases, for example of diseases mediated by bacteria, e.g. selected from Staphylococci, Streptococci, Enterococd, Mycobacterium, e.g. Mycobacterium tuberculosis; e.g. and of diseases mediated by Mycoplasms, Chlamydia and obligatory anaerobes, which method comprises administering to a subjeui in neea or sucn treatment an effective amount of a noveel compound of tine present invwention, e.g. including a compound of formula Ip; e.g. in the form of a pharmaceutical composition. Treatment includes treatment and prophylaxis. For such treatment, the appropriate dosage will, of course, vary depending upon, for example, the chemical nature and the phamnakokinetic 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 0.05 g to about 5.0 g, of a novel compound of of the present invention; conveniently administered, for example, in divided doses up to four times a day. For treatment of diseases mediated by Mycobacterium with a pleuromutilin of the present invention similar considerations apply. A novel 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 fonn of creams, gels, pastes, inhaler powder, foams, tinctures, lip sticks, drops, sprays, or in the fomi of suppositories. For administration of a pleuromutilin of the present invention in diseases mediated by Mycobacterium, similar considerations apply, with the exception of topical administration. The novel compounds 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 fomri of a solvate. The novel compounds of the present invention in the form of a salt exhibit the same order of activity as the novel compounds of the present invention in free form; optionally in the fomi of a solvate. For administration of a pleuromutilin of the present invention in diseases mediated by Mycobacterium similar considerations apply. A novel compound of the present invention mav be used for Dharmanputirfli trpatmont according to the present invention alone, or in combination with one or more other pharmaceutjcaliy active agents. Such other pharmaceutically active agents e.g. include other antimicrobials, e.g. including antibiotics, e.g. cephalosporins, penicillins, erythromycins, tetracyclines. Similar considerations apply for a pleuromutilin of to the present invention in diseases mediated by Mycobacterium, but appropriate other pharmaceutically active agents includes agents known to be active in the treatment of diseases mediated by Mycobacterium, such as Rifampicin (Rifampicin®), Streptomycin (Streptomycin®), Ethambutol (Ethambutol®), Pyrizinamid (Pyrizinamid®). 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 novel compound of the present invention, e.g. a compound of formula Ip, in association with at least one pharmaceutical excipient, e.g. appropriate earner and/or diluent, e.g. including fillers, binders, disintegrators, flow conditioners, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emuisifiers, solubilizers, salts for regulating osmotic pressure and/or buffers; e.g. further comprising another pharmaceutically active agent. Pharmaceutical composition comprising pleuromutilins of the present invention for administration in diseases mediated by Mycobtarium may comprise similar excipient as described above. In another aspect the present invention provides a pharmaceutical composition comprising a pleuromutilin of the present invention in association with at least one phamriaceutical excipient, and further comprising another phannaceutically active agent useful in the treatment of Mycobacterium, e.g. M.tuberculosis, infections, such as Rifampicin (Rifampicin®), Streptomycin (Streptomycin®), Ethambutol (Ethambutol®), Pyrizinamid (Pyrizinamid®). Such 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 fomns may contain, for example, from about 0.5 mg to about 1500 mg, such as 1 mg to about 500 mg. Pleuromutilins of the present invention for administration in diseases mediated by Mycobtarium tuberculosis may be administered in a similar mode and in similar dosages as Rifampicin or Streptomycin. A pleuromutilin of the present invention is preferably selected from the group consisting of a compound of formula I-US4278674, a compound of formula I-EP0153277, a compound of formula I-WO0109095, a compound of formula I-WO0204414, a compound of formula I-WO0222580, a compound of TABLE 1, a compound of formula IB, or a of formula ID; e.g. including e.g. in the form of a hydrochloride. Activity against strains of Mycobacterium, e.g. M.tuberculosis nnay be determined according to the following General Test Procedure: General Test procedure Is carried out according to the known and appropriate Agar Dilution Test. Agar is used as a substrate. Shortly before solidifaction of the Agar TEST COMPOUNDS in different concentrations are added and mixed into the still liquid agar mass (according to the Agar dilution test). Controls without TEST COMPOUNDS are also prepared for determination of strain growth ability. The thus prepared agars are inoculated after solidification with Mycobacterium tuberculosis strains. Incubation is carried out in normal incubators at ZT'C. As a nutrition medium Middlebrook 7H10 + OADC (Oleic, Albumin, Dextrose, Catalase) Enrichment (pH 6.71- 6.73) is used. The minimum inhibition concentration (MIC) which is the compound concentration in the agar which inhibits 99% of strain growth, is detemnined after 3 weeks, 4 weeks and 5 weeks after inoculation. Pleuromutilins of the present invention show activity against strains of Mycobacterium, e.g. M.tubercuiosis and are thus useful in the treatment of infectios caused by Mycobacterium. Pleuromutilins of the present invention surprisingly are even active against resistant and multiresistant M.tuberculosis strains, e.g. strains which are resistant against treatment with known pharmaceuticals useful in the treatment of tuberculosis, e.g. Isoniacid, Rifampicin, Streptomycin. In the following Examples all temperatures are in degree Centigrade and are uncorrected. The following abbreviations are used: BOC: tert.butoxyxcarbonyl DCC: dicyclohexylcarbodiimide DMF: N,N-dimethylfonnamide DMSO: dimethylsulfoxide EDC: N-(3-dimethylaminopropyl)-N '-ethylcarbodiimide hydrochloride EtAc: ethyl acetate EtOH: ethanol HOST: 1-hydroxybenzotriazole MeOH: methanol MS: mass spectroscopy RT: room temperature TBAF: tetra-n-butylammonium fluoride TFA: trifluoroacetic acid THF: tetrahydrofurane Chromatography is carried out on silica gel. Preparation Examples I. Preparation of (novel) pleuromutiilns of the present invention Example l-A 14-0-[(N-{3-IVIethyl-2(R)-amino-butyryl)-piperidine-3-yl)-sulfanyiacetyl]-mutilln intiie form of a hydrocliloride l-AA) 14-0-r(N-BOC-Piperidin-3f S)-vl)-sulfanvlacetvl1-mutilin Method 1: 532 mg of 22-0-tosyl-pleuromutilin are added to a solution of 217 mg of N-BOC-piperidine- 3(S)-tliiol and 112 mg potassium tert. butylate in 10 ml of THF, the mixture obtained is stirred forer 3 hours, the mixture obtained is distributed between EtAc and brine, the organic phase obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to chromatography. 14-0-[(N-BOC-Piperidin-3(S)-yl)-sulfanylacetyl]-mutilin is obtained. Method 2: A solution of 1.97 g of 22-mercapto-pleuromutilin, 1.39 g of N-BOC-3(R)-methyisulfonyloxy- piperidine and 0.12 g of sodium in 50 ml of EtOH is heated to 90° for 12 hours, from the mixture obtained solvent is evaporated and the evaporation residue is subjected to chromatography. 14-0-[(N-BOC-piperidin-3-yl)-sulfanyiacetyl]-mutilin is obtained. 'H-MR(CDCl3):6.45,5.35,5,2(3xm,Hi9,H20,H2i),5.74(d,1H,5,2Hz,Hi4),3.35(d,1H,Hii,J=5.2Hz), AB-system: 3.12,3.18, J=14.7Hz,H22), 3.2,2.95,2.65,2.6(4xm,CH2NCH2), 2.85 (m,1H, SCH),1.18,1.45 (2xs,(CH3)i5,(CH3)i8). 0.75,0.88(2xd,(CH3)i6, (CH3)i7,J=5.4Hz) l-AB) 14-0-r(N-(3-Methvl-2(RVamlno-butvrvn-piDeridine-3-vn-sulfanvlacetvn-mutilin in the form of a hvdrochloride A solution of 280 mg of 14-O-[{N-B0C-piperidin-3-yl)-sulfanylacetyl]-mutilin in 20 ml of CH2CI2 and 1 ml of TFA is stin-ed at RT for 30 minutes and from the mixture obtained solvent is evaporated. The evaporation residue obtained is treated with 40 ml of CH2CI2, 55 mg of N-methyl-morpholine, 110 mg of N-BOC-(R)-valine and 105 mg of DCC are added and the mixture obtained is stirred for 3 hours. From the mixture obtained precipitated dicyclohexylurea is filtered off and the filtrate obtained is subjected to chromatography. Purified 14-0-[(N-(3-Methyl-2(R)-amino-butyryl)-piperidine-3-yl)-sulfanylacetyl]-mutilin obtained is treated with TFA in CH2CI2, solvent is evaporated and the evaporation residue obtained is treated with etheric HCI. 14-0-[(N-(3-Methyl-2(R)-amino-butyryl)-piperidine-3-yl)- sulfanylacetylj-mutilin in the form of a hydrochloride is obtained. ^H-NMR(d-6-DMSO,330K): 6.45,5.35,5,2(3xm,Hi9,H2o,H2i), 5.74 (d,1H,5,2Hz,Hi4), 5.45 (d,1H,NH,J=7.8Hz), 4.1 (m,1H,NHCHC0), 3.35 {d,1H,Hii,J=5.2Hz), AB-system: 3.12,3.18, J=14.7Hz,H22), 3.2, 2.95, 2.65 ,2.6 (4xm,CH2NCH2), 2.8 (m,1H,SCH), 1.18,1.45 (2xs,(CH3)i5,(CH3)i8), 0.75,0.88 (2xd,(CH3)i6,(CH3)i7,J=5.4Hz), 0.78.0.84 (2xd, (CH3)2CHJ=6.8Hz) Example l-B 14-0-[{N-{3-MethyI-2(R)-amino-butyryl)-piperidin6-3(S)-yl)-sulfanylacetyl]-2{S)-fluoro-mutilin in the form of a hydrochloride IBA) 14-0-(Tosvloxvacetvl)-2(S)-fluoro-mutilin To a solution of 500 mg of 14-0-(hydroxyacetyl)-2{S)-fluoro-mutilin (see e.g. Vyplel H., et al J Fluorine Chem; 23, 482 (1983)), in 5 ml of CHzClj 450 mg of toluene sulfonic acid anhydride and 0.21 ml of pyridine are added and the mixture obtained is stirred for 4 hours at RT. The mixture obtianed is diluted with CH2CI2 and extracted with IN HCI, aqueous NaHCOa and H2O. The organic phase obtained is dried, solwent is evaporated and the evaporation residue is subjected to chromatography. 14-0-[tosyloxyacetyl]-2(S)-fluoro- mutilin is obtained. IBB) 14-0-r(N-(3-Methvl-2fR)-amino-butvrvl)-piperidine-3(S)-vn-sulfanvlacetvn-2(S)-fluoro- mutilin in the form of a hvdrochloride is obtained starting from 14-0-[tosyloxyacetyl]-2(S)-fluoro-mutilin analogously to the method of Example lAB). Characterisation data see TABLE 1, Example 12. Example l-C 14-0-[(3-Guanidino-phenylsulfanyl)-acetyl]mutll!n in the form of a hydrochloride ICA) 14-Q-[(3-Amino-phenvlsulfanvlVacetvn-mutilin A solution of 0.92 g of sodium and 5g of 3-amino-thiophenol in 100 ml of dry EtOH is added to a solution of 21.3 g of 22-0-tosyl-pleuromutilin (see e.g. H.Egger et al., J.Antibiotics 29, 923 (1976)) in 250 ml of ethylmethylketone at 25° under careful temperature control. The mixture obtained is kept for 15 hours at 25°, filtered and the filtrate obtained is concentrated under reduced pressure and subjected to chromatography. 14-0-[(3-Amino-phenylsulfanyl)-acetyl]-mutilin is obtained. 'H-NMR(CDCl3): 0.58(d, 3H, H16, J=7.2Hz), 0.81 (d, 3H, H17, J=7.3Hz),1.02 (s, 3H, His), 1-32 (s, 3H, H15), ABX-system(vA= 1.2, VB= 1.88, Hi3a,Hi3b, J=16.1Hz, J=9.1Hz), 2.08(d,1H, H4, J=2.1Hz), ABXY-system(vA= 2.23, VB= 2.19, Hza.Hzb, J=16.2Hz, J=9.1Hz, J=1.8Hz), 2.3(m,1H,Hio), 3.4 (d,1H,Hii, J=5.98Hz), AB-system (VA= 3.81. VB= 3.89, 2H, H22, J=14.1Hz), 5.18(dd,1H, Hzoa, J=17.5Hz, J=1.6Hz). 5.29(dd,1H, Hzob, J=11Hz, J=1.6Hz),5.51 (d,1H, H14, J=8.3Hz), 6.05 (dd,1H,Hi9, J=11Hz, J=17.5Hz), 7.0 (m,1H, arom.H), 7.18 (m2H, arom.H), 7.3t,1H, arom.Hs, J=8Hz). ICB) 14-0-f(3-Guanidino-phenvlsulfanvn-acetvl1mutilin in the form of a hydrochloride A solution of 2.4 g of 14-0-[(3-amino-phenylsulfanyl)-acetyl]mutilin, 1.5 g of cyanamide and 0.44 ml of HCI cone, in 20 ml of dioxane is stirred at room temperature for 28 hours. 14-0-[{3-Guanidino-phenylsulfanyl)-acetyl]mutilin in the form of a hydrochloride in crystalline form is obtained. Characterisation data see in TABLES above. Exmple l-D 14-0-[(3R*-Hydroxypiperidin-4-(R*)yl) -sulfanyi-acetyl]mutllln and 14-0-[(3S*-Hydroxypiperidln-4-(S*)yl) -sulfanyl-acetyl]mutilin in the form of a hydrochloride (diastereoisomeric mixture) 1.06 g of pleuromutilin-22-O-tosylate dissolved in 1 ml of 2-butanone are slowly added to a solution of 466 mg of N-BOC-3-hydroxy-piperidin-4-thiol and 224 mg of potassium-tert. butyiate in 20 ml of THF, the mixture obtained is stirred for 2 hours, the mixture obtained is distributed between brine and EtAc, extracted with 0.1N HCI, and the phases obtained are spearated. The organic phase obtained is dried,and the evaporation residue obtained is subjected to chromatography. A mixture of 14-0-[(3R*-Hydroxypiperidin-4-(R*)yl) -sulfanyl-acetyOmutilin and 14-0-[(3S*-Hydroxypiperidin-4-(S*)yl) -sulfanyl-acetyl]mutilin is obtained which is treated with etheric HCI to obtain the corresponding hydrochloride. Characterisation data see in TABLE 5, Example 42. Example l-E 2,2,4-Trldeutero-14-0-[((3-(S*)-hydroxy-plperidine-4-(S*)-yl)sulfanyl)-acetyl]mutlllnln the form of a deuterochloride A solution of 300 mg of the compound obtained in Example ID in 30ml dioxane with 5 ml of DCI (20% in D2O) is kept for 6 days at 25°. From the mixture obtained solvent is evaporated and the concentration resiue is subjected to lyophilization. 2,2,4-Trideutero-14-0-[((3-(S*)-hydroxy-piperidine-4-(S*)-yl) sulfanyl)-acetyl]mutiiin in the form of a deuterochloride is obtained. Characterisation data see TABLE 5, Example 41. Example l-F 14-0-[3-(R*)-((N-BOC-(R)-Valyl-amino-cyclohexan-1-(R*)-yl)sulfanyl)-acetyl]mutllin(a) 14-0-[3-(S*)-{(N-BOC-{R)-Valyl-amino-cyclohexan-1-{S*)-yl)sulfanyl)-acetyl]mutilin (b) 14-0-[3-{S*)-((N-BOC-(R)-Valyl-amino-cyclohexan-1-{R*)-yl)sulfanyl)-acetyl]mutllln (c) 14-0-[3-{R*)-((N-BOC-(R)-Valyl-amino-cycIohexan-1-(S*)-yl)sulfanyl)-acetyl]mutilin (d) 2.66 g of pleuromutilin-22-O-tosylate dissolved in 10ml THF are slowly added to a solution of 1.65 g of 3-(N-BOC-(R)-valyl-amino)-cyclohexane-(R/S)-thiol and 560 mg of potassium-tert. butylate in 25nnl of THF, the mixture obtained is stirred for 2 hours and distributed between brine and EtAc. The mixture obtained is extracted with 0.1 N HCI, the organic phase obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to chromatography. Pure (a) 14-0-[3-(R*)-((N-BOC-(R)-Valyl-amino-cyclohexan-1-(R*)-yl)sulfanyl)-acetyl]mutilin (b) 14-0-[3-(S*)-((N-BOC-{R)-Valyl-amino-cyclohexan-1 -(S*)-yl)sulfanyl)-acetyl]mutilin (c) 14-0-[3-(S*)-{(N-BOC-(R)-Valyl-amino-cyclohexan-1-(R*)-yl)sulfanyl)-acetyl]mutilin, and (d) 14-0-[3-{R*)-((N-BOC-(R)-Vaiyi-amino-cyclohexan-1 -{S*)-yl)sulfanyl)-acetyl]mutilin is obtained. 'H-NMR(d6-DMS0): (a): 6.5(d,1H,NH,J=8.1Hz), 6.15, 5.1 (2xm,Hi9,H2o,H2i), 5.52(d,1H,J=5,2Hz,Hi4). 3.4(m,1H, Hii.), 3.55 (m,1H,CHN), 3.7 (m,a-valyl), 3.2 (m,2H,H22), 2.7 (m,1H,SCH), 1.4 (s,9H, tert.butyl), 1.18,1.45(2xs,(CH3)i5,(CH3)i8), 0.75,0.88 (2xd,(CH3)i6,(CH3)i7,J=5.4Hz). (b): 6.15, 5.1 (2xm,Hi9,H2o.H2i), 5.52(d,1H,J=5,2Hz,Hi4), 3.4(m,1H,Hii,), 3.55 (m,1H,CHN), 3.70 (m,a-valyl), 3.2 (m,2H,H22), 2.7 (m,1H,SCH), 1.4 (s,9H,tert.butyl), 1.18,1.45(2xs, (CH3)i5,(CH3)i8), 0.75,0.88 (2xd,(CH3)i6,(CH3)i7,J=5.4Hz). (c): 6.15, 5.1 (2xm,Hi9,H2o,H2i), 5.52(d,1H,J=5,2Hz,Hi4), 3.4(m,1H,Hii,), 3.9 (m.lH.CHN), 3.75 (m,a-valyl), 3.2 (m,2H,H22). 3.15 (m.lH.SCH), 1.4 (s,9H,tert.butyl). 1.18,1.45'(2xs, (CH3)i5,(CH3)i8), 0.75,0.88 (2xd.(CH3)i6.(CH3)i7.J=5.4Hz). (d): 6.15. 5.1 (2xm.Hi9,H2o.H2i), 5.52(d,1H,J=5,2Hz,Hi4). 3.4(m.1H,Hii,). 3.9 (m.lH.CHN), 3.70 (m.a-valyl), 3.2 (m,2H,H22), 3.15 (m,1H,SCH), 1.4 (s,9H,tert.butyl), 1.18.1.45(2x3, (CH3)i5,(CH3)i8), 0.75,0.88 (2xd,(CH3)i6,(CH3)i7,J=5.4Hz). Example l-G 14-0-[3-(R*)-{(R)-Valyl-amlno-cyclohexan-1-(R*)-yl)-sulfanyl)-acetyl]-mutllln and 14-0-[3-(S*}-({R)-Valyl-amino-cyclohexan-1-{S*)-yl)-sulfanyl)-acetyl]-mutilin in the form of a hydrochloride (mixture of trans-diastereoisomers) 620 mg of a 1:1 mixture of 14-0-[3-(R*)-((N-BOC-(R)-valyl-amino-cyclohexan-1-(R*)-yl)sulfanyl)-acetyl]mutilin and 14-0-[3-(S*)-((N-BOC-(R)-valyl-amino-cyclohexan-1 -(S*)-yl sulfanyl)- acetyl]mutilin are dissolved in a mixture of 10 ml of dry etheric HCI and 10 ml of CH2CI2. The mixture is stirred for 5 liours and a mixture of trans-diastereoisomers of 14-0-[3-(R*)-((R)-valy!-amino-cyclohexan-1 -(R*)-yl)-sulfanyl)-acetyl]-mutiiin of 14-0-[3-(S*)-((R)-valyl-amino-cyclohexan-1-(S*)-yl)-sulfanyl)-acetyl]-mutilin in the form of a hydrochloride is obtained and isolated. ^H-NMR(d6-DIVIS0,): Rotamer. 8.4 (m,1H,C=0NH), 8.15 (b.SH.NHa*), 6.15. 5.1 (2xm,Hi9,H2o,H2i), 5.52(d,1H,J=5,2Hz,Hi4), 3.95 (mlH, CHNH3', 3.4(m,1H,Hii,), 3.55 (m,a-valyl), 3.2-3.3 (m,2H,H22), 3.18 (m.lH.SCH), 1.18,1.45(2xs,(CH3)i5,(CH3)i8), 0.9 {m,6H,CH(CH3)2), 0.75,0.88 (2xd,(CH3)i6,(CH3)i7.J=5.4Hz) Example l-H 14-0-[3-{R*)-{(R)-Valyl-amlno-cyclohexan-1-(S*)-yl)-sulfanyl)-acetyl]-muti!inand 14-0-[3-{S*)-((R)-Valyl-amino-cyclohexan-1-{R*)-yl)-sulfanyl)-acetyl]-mutllin In the form of a hydrochloride (mixture of cis-diastereolsomers) is obtained analagosouly to the method of Example l-G, but using a 1:1 mixture of 14-0-[3-(R*)-((N-BOC-(R)-valyl-amino-cyclohexan-1-(S*)-yl)sulfanyl)-acetyl]mutilinand 14-0-[3-(S*)-((N-BOC-(R)-valyl-amino-cyclohexan-1-(R*)-yl sulfanyl)-acetyl]mutiiin as a starting material. 'H-NMR(d6-DMS0): Rotamers. 8.52 (m,1H,C=0NH), 8.2 (b,3H,NH3*), 6.15, 5.1 (2xm,Hi9, H2o,H2i), 5.52(d,1H,J=5,2Hz.Hi4), 3.58 (mlH, CHNH3*, 3.4(m,1H,Hii,), 3.48 (m,a-valyl), 3.2-3.3 (m,2H,H22), 2.75 (m,1H,SCH), 1.18,1.45(2xs,(CH3)i5,(CH3)i8), 0.9 (m,6H,CH(CH3)2), 0.75,0.88 (2xd,(CH3)i6.(CH3)i7,J=5.4Hz) Example l-l 14-0-[({N-(R)-Valyl-azepan-4-{R/S)-yl)-sulfanyl acetyl)]-mutllln In the form of a hydrochloride l-IA) 4-(R/S)-f2.4.6-Trimethvl-benzvl-sulfanvn- azeDan-2-one A solution of 828 mg of 3-(R/SH2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexanone-oxime and 570 mg of toluenesulfonylchloride in 5 ml of pyridine is stin-ed at RT for 4 hours and additional 2 hours at 60°. The mixture obtained is distributed between diluted sulfuric acid (2 ml H2SO4 cone, in 15ml H2O) and CH2CI2, the organic phase obtained is dried, solvent is evaporated and the evaporation residue is subjected to chromatography. 4-(R/S)-(2,4,6-Trimethyl-benzyl-sulfanyl)- azepan-2-one is obtained. ^H-NMR(d-6-DMS0): 7.5 (m.lH.NHCO), 6.8 (s,2H,arom.H), 3.75 (s,2H,C6H5CH2S-),3.2 (m, IH.CHN), 3.1(m,3H, CH2NH,CHS) AB-system: VA= 2.72 VB=2.65( 2H,CH2C=0, J=13.4Hz, J=4.5H2) 2.13 2.15,2.3( 9H, 3XCH3) l-IB)4-(R/SW2.4.6-Trimethvl-benzvl-sulfanvn-azeDane 3.3 g of 4-(R/S)-{2,4,6-trimethyl-benzyl-sulfanyl)-azepan-2-one are added to a mixture of 15 ml of a 1M-solution of LiAIHs and 50 ml THF are added. The mixture obtained is lieated for 1 hour at 80°, poured into 200 ml of a 20% aqueous NH4CI-solution and the mixture obtained is extracted with EtAc. The organic phase obtained is dried and solvent is evaporated. 4-{R/S)-(2,4,6-Trimethyl-benzyl-sulfanyl)-azepane is obtained. I-IC) N-BOC-(4-(R/S)-f2,4,6-Trimethvl-benzvl-sulfanvnVazeDane A solution of 2.63 g of 4-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-azepane, 2.18 g of BOC- anhydride and 1 g of triethylamine in 100 ml of THF is stin-ed at 25° for 12 hours and from the mixture obtained solvent is evaporated. The evaporation residue obtained is distributed between CH2CI2 and 1M HCI. Solvent from the organic phase obtained is evaporated and the evaporation residue is subjected to chromatography. N-BOC-(4-(R/S)-(2,4,6-trimethyl- benzyl-sulfanyl))- azepane is obtained. ^H-NMR(d6-DMS0): 6.8 (s,2H,arom.H), 3.75 (s,2H,C6H5CH2S-),3.2 -3.5(m,4H.CH2NHCH2), 2.9(m,1H,CHS), 2.13 2.15,2.3( 9H, SxCHa) I-IC) N-BOC-4-(R/S)-Azepan-thiol is obtained analogously to the method of Example ll-D, but using appropriate starting materials. 1-ID) 14-0-r((N-BOC-AzeDan-4-(R/SVvn-sulfanvl acetvm-mutilin A solution of 1.06 g of pleuromutilin-22-O-tosylate dissolved in 10 ml THF is slowly added to a solution of 420 mg of N-BOC-(4-(R/S)-azepane-thiol and 220 mg of potassium-tert.butylate in 25 ml of THF and the mixture obtained is stirred for 2 hours. The mixture obtained is distributed between brine and EtAc, the mixture obtained is extracted with 0.1 N HCI, the organic phase obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to chromatography. 14-0-[((N-BOC-azepan-4-(R/S)-yl)-sulfanyl acetyl)-mutilin is obtained. ^H-NMR(d6-DIVlS0): 6.15, 5.1 (2xm,Hi9,H2o,H2i), 5.52(d,1H,J=5,2Hz,Hi4). 4.52 (d,1H,OH,J=6.2Hz)3.4(t,1H,Hii,J=6.2Hz), 3.1-3.4 (m,6H,H22.CH2NCH2), 2.9 (m.lH.SCH), 1.4 (s,9H,tert.butyl), 1.18,1.45(2xs,(CH3)i5,(CH3)i8), 0.75,0.88 (2xd,(CH3)i6.(CH3)i7,J=5.4Hz) l-IE) 14-0-f((Azepan-4-fR/SVvlV-sulfanvl acetvDI-mutilin in the fonn of a hydrochloride - 400 mg of 14-0-[((N-BOC-azepan-4-(R/S)-yl)-sulfanyl-acetyl)-mutilin are dissolved in a mixture of 10 ml of dry etheric HCI and 10 ml of CH2CI2. The mixture obtained is stirred for 5 hours and 14-0-[((azepan-4-(R/S)-yl)-sulfanyl acetyl)]-mutilin in the fomri of a hydrochloride is isolated. Characterisation data see TABLE 1, Example 14. I-IF) 14-0-rffN-(R)-Valvl-azepan-4-(R/S)-vn-sulfanvl acetvOI-mutilin in the form of a hydrochloride A mixture of 245 mg 14-0-[({azepan-4-(R/S)-yl)-suIfanyl acetyl)]-mutilin in the form of a hydrochloride, 110 mg of BOC-R-valin, 95 mg of EDC and 100 mg of triethylamine in 10ml THF is stirred at RT for 2 hours. The mixture obtained is distributed between brine and EtAc, the organic phase obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to chromatography. 14-0-[((N-BOC-(R)-Valyi-azepan-4-(R/S}-yI)-sulfanylacetyl)]-mutilin-hydrochlorideis obtained. The BOC-protecting group is cleaved by treatment with 5 ml of etheric HCI and 14-0-[((N-(R)-Valyl-azepan-4-(R/S)-yl)-sulfanyl acetyl)]-mutilin in the form of a hydrochloride is obtained. Characterisation data see TABLE 1, Example 15. Example l-J 14-0-[{(Azepan-2-one-4-(R/S)-yl)-sulfanyl acetyl)]-mutilin is obtained analagously to the method of Example lAB), starting from 4-(R/S)-mercapto-azepan-2-one. Characterisation data see TABLE 5, Example 43. Example l-K 14-0-{[(3-Oxo-cyclopentan-(R/S)-yl)-sulfanyl]-acetyl}-mutllln A solution of 3.95 g of 14-mercapto-acetyl-mutilin in 5 ml of pyridine is treated with 0.81 g of cyclopent-2-enone and a catalytical amount of triethylamine. The mixture obtained is stirred for 3 hours at room temperature, diluted with EtAc and extracted with 1N HCI and H2O. The organic phase obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to chromatography. 14-0-{[(3-oxo-cyclopentan-{R/S)-yl}-sulfanyl]-acetyl}-mutilin is obtained. Characterisation data see in TABLE 5, Example 44. Example l-L 14-0-{[(3-Hydroxylmlno-cyclopentan-{R/S)-yl)-sulfanyi]-acetyl}-mutilln (syn and anti forms) 3.88 g of 14-0-{[(3-oxo-cyclopentan-(R/S)-yl)-sulfanyl]-acetyl}-mutilin are stin-ed overnight with 566 mg of hydroxylamine hydrochloride and 1.13 ml of triethylamine in 40 ml of DMF. From the mixture obtained solvent is distilled off, the distillation residue obtained is taken up in EtAc and the mixture obtained is extracted with 0.1 N HCI and brine. The organic phase obtained is dried and solvent is evaporated. A mixture of 14-0-{[(3-hydroxyimino-cyclo-pentan-(R/S)-yl)-sulfanyl]-acetyl}-mutilin in the syn*- and in the anti*-form is obtained which mixture is either separated by chromatography to obtain the pure syn- and the pure anti- forms, or is used in the form of the mixture obtained in further reaction steps. Characterisation data see TABLE 3, Example 24. Example l-M 14-0-{[(3-(2-Diethylamino-€thoxyim!no)-cyclopentan-(RyS)-yl)-sulfanyl]-acetyl}-mutilin In the form of a hydrochloride 200 mg of 14-0-{[(3-hydroxyimino-cyclopentan-(FR/S)-yl)-sulfanyl]-acetyl}-mutilln and 70 mg of diethylamlnoethylchloride hydrochloride are stirred in 5 ml of CH2CI2, 90 mg of potassium tert butoxide are added and stirring Is continued for 2 days at RT. From the mixture obtained solvent is evaporated, the evaporation residue is subjected to chromatography, the relevant chromatographic fractions obtained are distributed between Et20 and 0.1 N HCI and the aqueous layer is lyophillzed. 14-0-{[(3-(2-dlethylamino-ethoxyimino)-cyclopent-(R/S)-yl)-sulfanyl]-acetyl}-mutilin hydrochloride (syn/anti mixture) is obtained. Characterisation data see TABLE 3, Example 26. Example l-N 14-0-[(2-(R*)-((R)-Valyl)-amino-cyclohexan-1 -(R*)-yl)-sulfanyl acetyl)]-mutllln- hydrochloride l-NA)14-0-fa2-fR*VAminocvclohexan-1-(R*)-vlVsulfanvlacetvl)1-mutilin 1.06 g of pleuromutilln-22-O-tosylate dissolved in 5ml of THF are slowly added to a solution of 334 mg of 2-(R*)-aminocyclohexan-(R*)-thiol in the form of a hydrochloride (see e.g. G.Kavadias and R.Droghini, Can.J.Chem. 1978,56, 2743) and 92 mg sodium in 50 ml of EtOH, the mixture obtained is stin-ed for 2 hours, distributed between brine and EtAc, extracted with 0.1 N HCI and dried. From the mixture obtained solvent is evaporated and the evaporation residue is subjected to chromatography. 14-0-[((2-(R*)-aminocyclohexan-1-(R*)- yl)-sulfanyl acetyl)]-mutilin is obtained. ■'H-NMR(d6-DMS0): 6.15, 5.1 (2xm,Hi9,H2o.H2i), 5.52(d.1H,J=5,2Hz,Hi4), 2.45(m,1H,CHNH), 3.21 (s,2H,H22), 3.4(d,1H, Hii,J=5Hz), 2.55(m,1H,CHS), 1.18,1.45 (2xs,(CH3)i5,(CH3)i8), 0.9 (m,6H,CH(CH3)2), 0.75,0.88 (2xd,(CH3)i6.(CH3)i7.J=5.4Hz). I-NB) 14-0-rf2-fR*W(RVValvn-amino-cvclohexan-1-(R*)-vn-sulfanvl acetvni-mutilln in the form of a hydrochloride A mixture of 245 mg of 14-0-[((2-(R*)-aminocyclohexan-1-(R*)-yl)-sulfanyl acetyl)]-mutilin, 110 mg of BOC-(R)-valin, 95 mg of EDC and 68mg of HOST in 10 ml of THF is stin-ed at RT for 2 hours. The mixture obtained is distributed between brine and EtAc, the organic phase obtained is dried, solvent is evaporated and the evaporation resiude is subjected to chromatography. 14-0-[({2-(R*)-(N-BOC-(R)-Valyl)-amino-cyclohexan-1-(R*)-yl)-sulfanyl acetyl)]-mutiiin is obtained. The BOC-protecting group is cleaved by treatment with 5 ml of etheric HCi and 14-0-[(2-(R*)-((R)-valyi)-amino-cyclohexan-1-(R*)-yl)-sulfanyl acetyl)]-mutilin in the form of a hydrochloride is obtained. 'H-NMR(d6-DMS0): Diastereoisomers):8.45(m, 1H, NHC=0),8.1(b,3H,NH3*), 6.15, 5.1 (2xm,Hi9,H2o,H2i), 5.52(d,1H,J=5,2Hz,Hi4), 3.55 (m,1H, a-H-valyl),3.60(m,1H,CHNH), 3.26-3.35 (m,2H,H22),3.4(m,1H, Hn), 4.5 (d,1H,0H, J=6.2Hz), 2.6,2.75(2xm,1H,CHS), 1.25 (b,3H,CH3CS), 1.18,1.45(2XS,(CH3)I5,(CH3)IB), 0.9 (m,6H,CH(CH3)2), 0.75,0.88 (2xd.(CH3)i6,(CH3)i7,J=5.4Hz) Example 1-0 14-0-{[(3S,3aS,6S,6aR)-6-Amino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilin hydrochloride l-OA) Toluene-4-sulfonic acid (3R, 3aS. 6R. 6aR)-6-hvdroxv-hexahvdro-furof3.2-b1furan-3-vl ester A solution of 5 g of (3R, 3aS, 6R, 6aR)-hexahydro-furo[3,2-b]furan-3,6-diol in 50 ml of pyridine is stirred for 16h with 7.8 g of toluenesulfonylchloride. From the mixture obtained solvent is distilled off and the distillation residue obtained is dissolved in EtAc and extracted with IN HCI, saturated aqueous NaHC03-solution and H2O. The organic layer obtained is dried, solvent is evaporated and the evaporation residue is subjected to chromatography. Toluene-4-sulfonic acid (3R, 3aS, 6R, 6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester is obtained. ^HNMRCDMSO-de): 7.8 (d,2H,Ar-H,J=8.6Hz), 7.5 (d,2H,Ar-H,J=8.6Hz). 4.8-4.9 (m,2H,H-3, 6-OH), 4.4 {dd.1H,H-3a,J=4.7 and 5.0Hz), 4.2 (dd,1H.H-6a,J=4.7 and 4.8Hz). 3.9-4.0 (m,1H,H-6), 3.7-3.8 (m.2H,H-2 and H-5). 3.6 (d,1H,H-2,J=9.3 and 7.1Hz), 3.2 - 3.4(m,1H.H-5), 2.4 (s, 3H, Ar-CHa). I-OB) f3R. 3aR. 6S. 6aRV6-Azido-hexahvdro-furor3.2-b1furan-3-ol A solution of 2.5 g of toluene-4-sulfonic acid (3R, 3aS, 6R, 6aR)-6-hydroxy-hexahydro- furo[3,2-b]furan-3-yl ester in 30 ml of DMF is heated with 0.8 g of sodium azide under reflux for 2 hours, solvent is distilled off and the distillation residue obtained is dissolved in EtAc and extracted with H2O. The organic phase obtained is dried and solvent is evaporated. (3R, 3aR, 6S, 6aR)-6-azido-hexahydro-furo[3,2-b]furan-3-ol is obtained. I-OC) ((3S, 3aR, 6R. 6aR)-6-Hvdroxv-hexahvdro-furor3.2-blfuran-3-vll-carbamic acid tert- butvl ester To a solution of 1.5 g of (3R, 3aR, 6S, 6aR)-6-azido-hexahydro-furo[3,2-b]furan-3-ol in 25 ml of dioxane 75 mg of palladium on charcoal (10%) are added and the mixture obtained is subjected to hydrogenation. The mixture obtained is filtered and stin-ed overnight with 3.2 ml of ethyldiisopropylamine and 4.1 g of (B0C)20. From the mixture obtained solvent is evaporated. The evaporation residue obtained is dissolved in EtAc and extracted with saturated aqueous sodium NaHCOa-solution, 1N HCI and brine. The organic phase obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to chromatography. {(3S, 3aR, 6R, 6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl}-carbamic acid tert-butyl ester is obtained. ^HNMR(DMS0-d6): 7.1 (bs.lH.NH), 4.8 (d,1H,6-OH,J=10Hz), 4.3 (dd,1H,H-6a,J=4.6 and 4.3 Hz), 4.27 (d,1H,H-3a,J=4.3Hz), 4.0-4.1 (m,1H,H-6), 3.2-3.85 (m,5H,2xH-2. H-3, 2xH-5), 1.4 (s,9H,tert.butyl). I-OD) Toluene-4-sulfonic acid (3R. 3aS. 6S. 6aR)-6-tert-butoxvcarbonvlamino-hexahvdro-furor3,2-b1furan-3-vl ester A solution of 700 mg of {(3S, 3aR, 6R, 6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl}-carbamic acid tert-butyl ester in 10 ml of pyridine is stirred for 16 hours with 785 mg of toluolsulfonylchloride, solvent is distilled off and the distillation residue is dissolved in EtAc and extracted with IN HCI, saturated aqueous NaHCOs-solution and H2O. The organic layer obtained is dried and solvent is evaporated. Toluene-4-sulfonic acid (3R, 3aS, 6S, 6aR)-6-tert-butoxycarbonylamino-hexahydro-furo[3,2-b]furan-3-yl ester is obtained. I-OE) 14-0-irf3S.3aS.6S.6aRV6-tert-Butoxvcarbonvlamino-hexahvdro-furor3.2-b1furan-3-ylsulfanvll-acetvll-mutilin 267 mg of potassium tert.butoxide are added to a solution of 950 mg of toluene-4-sulfonic acid (3R, 3aS, 6S, 6aR)-6-tert-butoxycarbonylamino-hexahydro-furo[3,2-b]furan-3-yl ester and 1032 mg of 14-mercapto-acetyl-mutilin in 20 ml of DMSO, The mixture obtained is stin-ed at 70° for 1 hour and distributed between EtAc and brine. The organic phase obtained is washed with H2O, dried and solvent is evaporated. The evaporation residue obtained is subjected to chromatography. 14-0-{[(3S,3aS,6S,6aR)-6-tert-butoxycarbonyl-amino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilin is obtained. ^HNMR(DMS0-d6): 7.1 (bs,1H,NH), 6.1, 5.05, 5.0 (3xm,Hi9,H2o.H2i), 5.55 (d.lH.H^, J=8.2Hz), 4.5 (m,2H,HirOH,H-3a'), 4.4 (d, 1H, H-6a'. J=4Hz), 3.3-4.0 (m,9H,H-2',H-3',H-5-,H-6',Hii,H22), 1.36 (s,9H,tert-butyl), 1.34, 1.05 (2xs, (CH3)i5, (CH3)i8). 0.8. 0.62 (2xd (CH3)i6, (CH3)i7,J=6.8Hz). I-OF) 14-0-(rf3S.3aS.6S.6aRV6-Amino-hexahvdro-furor3,2-b1furan-3-vlsulfanvn-acetvf)-mutilin 950 mg of 14-0-{[(3S,3aS,6S,6aR)-6-tert-butoxycarbonylamino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilin are dissolved in 20 ml of CH2Ci2 and the mixture obtained is stirred for 2 hours with 3 ml of TFA. The mixture obtained is diluted with EtAc and extracted with saturated aqueous NaHCOa-solution. The organic phase obtained is dried and solvent is evaporated. 14-0-{[(3S,3aS,6S,6aR)-6-amino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilin is obtained. I-OG) 14-0-(rf3S.3aS.6S.6aR)-6-Amino-hexahvdro-furor3,2-b1furan-3-vlsulfanvn-acetvlV mutilin in the fonn of a hvdrochloride 180 mg of 14-0-{[(3S,3aS,6S,6aR)-6-amino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilin are distributed between diethylether and 0.1 N HCI. The aqueous layer obtained is lyophilized. 14-0-{[(3S,3aS,6S,6aR)-6-Amino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilin in the form of a hydrochloride is obtained. Characterisation data see in TABLE 4, Example 36a above. Example l-P 14-0-{[(3S,3aS,6S,6aR)-6-({R)-Amlno-3-methyl-butyrylamino)-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilin In the form of a hydrochloride A solution of 400 mg of 14-0-{[(3S,3aS,6S,6aR)-6-amino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilin in 20 mi of CH2CI2 is treated with 128 mg of N-Boc-(R)-valine, 147 mg of EDC, 104 mg of HOST and the mixture obtained is stirred overnight at RT. The mixture obtained is diluted with CH2CI2, extracted with H2O, dried and solvent is evaporated. The evaporation residue obtained is subjected to chromatography on silica gel, relevant chromatographic fractions obtained are treated again with TFA in GH2CI2, solvent is evaporated, the evaporation residue obtained is distributed between Et20 and 0.1 N HCI and the aqueous layer obtained is lyophilized. 14-0-{[(3S,3aS,6S,6aR)-6-((R)-2-amino-3-methyl-butyrylamino)-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutiIin in the form of a hydrochloride is obtained. Characterisation data see in TABLE 5, Example 38a. Example l-Q 14-0-[((3-(R/S)-Amlno-cyclohexan-1-{R/S)-yl)-sulfanyl acetyl)]-mutilin in the form of a hydrochloride 10.6g of pleuromutilin-22-O-tosylate dissolved in 10 ml of THF are slowly added to a solution of 5.2 g of N-BOC-3-(RyS)-mercapto-cycloheyylamin and 2.74 g of potassium-tert.butyiate in 250 ml of THF. The mixture obtained is stirred for 2 hours, distributed between brine and EtAc, and extracted with 0.1 N HCI. The organic phase obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected o chromatography. l4-0-[((N-BOC-3(R/S)-amino-cyclohexan-1-(R/S)-yl)-sulfanyl acetyl)]-mutilin is obtained and is converted into14-0-[((3-(R/S)-Amino-cyclohexan-1-(R/S)-yl)-sulfanyl acetyl)]-mutilin in the form of a hydrochioride by treatment with etheric HCI. 'H-NMR(d6-DMS0): 8.0 (b.SH.NHs*), 6.15, 5.1 (2xm,Hi9,H2o,H2i), 5.52(d,1H,J=5,2Hz,Hi4), 3.4(m,1H,Hii,), 3.3 (m,2H,H22), 2.9 (m,1H,NCH), 2.7(m,1H,CHS), 1.18,1.45 (2xs,(CH3)i5, (CH3)i8), 0.75,0.88 (2xd,(CH3)i6,(CH3)i7,J=5.4Hz) II. Preparation of intermediates (starting materials) for the preparation of a (novel) pleuromutilln of the present invention Example ll-A 14-Mercapto-acetyl-mutilln ll-AA) 14-0-r(Carbamimidovlsulfanvl)acetvnmutilin-tosvlate A solution of 15.2 g of thiourea and 106.4 g of pleuromutilin-22-O-tosyiate in 250 ml of acetone is heated under reflux for 1.5 hours, solvent is removed and 100 ml of hexane are added. A precipitate forms, is filtrated off and dried. 14-0-[(carbamimidoylsulfanyl)acetyl]mutilin-tosylate is obtained. II-AB) 14-Mercapto-acetvl-mutilin A solution of 4.7 g of Na2S205 in 25 ml of H2O is added to a solution of 12.2 g of 14-0- [(carbamimidoylsulfanyl)acetyl]mutiiin-tosylate in a mixture of 20 ml of EtOH and 35 ml of H2O (warmed to ca. 90°). 100 ml of CCI4 are added to the reaction mixture obtained and the mixture obtained is heated under reflux for ca. 2 hours. The two-phase system obtained is separated, the organic phase is dried and solvent is evaporated. 14-mercapto-acetyl-mutilin is obtained. Example ll-B N-BOC-3(R)-methylsulfonyloxy-piperldine ll-BA)N-BOC-3fR)-Hvdroxv-piDeridine A suspension of 3.48 g of 3-(R)-hydroxypiperidine, 8.72 g of di-tert.butyl-dicarbonat and 4 g of N-metyl-morpholine in 70 ml of dioxane is stirred for 18 hours at RT. From the mixture obtained solvent is evaporated and the evaporation residue obtained is dissolved in CH2CI2 and extracted with IN HCI. The organic phase obtained is dried and solvent is evaporated. N-BOC-3(R)-hydroxy-piperidine is obtained. H-BB)N-BOC-3fRVmethvlsuifonvloxv-piperidine A solution of 5.08 g of N-BOC-3(R)-hydroxy-piperidine and 8.7 g of methanesulfonic acid anhydride in 100 ml pyridine is stirred at RT for 22 hours, pyridine is distilled off, the distillation residue is dissolved in CH2CI2, the mixture obtained is extracted with 1N HCI, the organic phase obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to chromatography. N-BOC-3(R)-methylsulfonyloxy-piperidine is obtained. ^H-NMR(CDCl3): 4.7(m,1H,CHOS02CH3), 3.2-3.6(m,4H,CHN), 3.0(s,3H,CH3SO2),1.4(m, 9H,tert.butyl). Example ll-C N-BOC-Piperldlne-3(S)-thiol ll-CA)N-BOC-3-fS)-Thioacetoxv-piperidine A solution of 2.2 g of N-BOC-3-(R)-hydroxy-piperidine in 10 ml of THF is added under argon and 1 ml of thiolacetic acid to a solution of 3.4 g of triphenylphosphine and 2.65 ml of azadicarbonic acid-isopropylate in 10 ml of THF. The mixture obtained is kept for 18 hours at 70°, solvent is evaporated and the evaporation residue obtained is subjected to chromatography. N-BOC-3-(S)-thioacetoxy-piperidine is obtained. ^H-NMR (CDCI3): 3.78 (dd.lH.NCHjCHS, J=3.1Hz, J=13.3Hz), 3.5-3.6 (m,2H, CHSC=0, NCH2CH2), 2.32(s,3H,SC=OCH3),1.46(s,9H, tert.butyl) ll-CB)N-BOC-Piperidine-3(S)-thiol To a solution of 259 mg of N-BOC-3-{S)-thioacetoxy-piperidine inIO ml of MeOH a solution of 262 mg of NaSCH3 in 5 ml of MeOH is added and the mixture obtained is stirred for 2 hours, solvent is evaporated and the evaporation residue obtained is distributed between EtAc and aqueous HCI. Solvent from the organic phase obtained is evaporated. N-BOC-piperidine-3(S)-thiol is obtained. 'H-NMR(d6-DMS0):2.6 (d.lH.SH, J=7.2Hz),, 2.9- 2.7 (m.3H, NCH2,CHS), 1.35 (b,9H,tert.butyl). MS(ESI) 457 (2M+Na). Example ll-D 3-(N-B0C-(R)-Valyl-amino)-cyclohexane-(R/S)-thiol ll-DA)3-fR/S)-(2.4.6-Trimethvl-benzvl-sulfanvn-cvclohexanone A solution of 3.32 g of 2,4,6-trimethyl-benzylmercaptane and 3.84 g of cyclohexen-3-one in 30 ml of pyridine is heated at 40° for 3 hours. The mixture obtained is poured into 200 ml of 1M HCI and the mixture obtained is extracted with CH2CI2. The organic phase obtained is dried, solvent is evaporated and the evaporation residue is subjected to chromatography on silica gel. 3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexanone is obtained. 'H-NMR{d6-DMS0): 6.8 (s,2H,arom.H), 3.8 (s,2H,C6H5CH2S-), 3.3 (m,1H,CHS), 3.18 (dd.lH, CHC=NOH, J= 4Hz, 13.9Hz), 2.65-2.8, 2.44-2.49(2xm,4H,CH2C=OCH2),2.15.2.3( 9H,3xCH3). II-DB) 3-fR/S)-(2.4.6-Trimethvl-ben2vl-sulfanvl)- cvclohexanone-oxime (syn and anti-forms) A solution of 5.24 g of 3-(R/S)-(2,4,6-trimetlnyl-benzyl-sulfanyl)-cyclolnexanone, 1.38 g of liydroxylamine in the form of a Inydrochloride and 2 g of triethylamine in 50 ml of MeOH is stin-ed at 25° for 12 hours, the mixture obtained is poured into 200 ml of brine and the mixture obtained is extracted with CH2CI2. The organic phase obtained is dried and solvent is evaporated. A mixture of the syn- and anti fomns of 3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexanone-oxime is obtained which is subjected to chromatography. Pure syn- and pure anti-3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexanone-oxime is obtained. ^H-NIVlR(d6-DIVlS0) of the syn-form: 10.3 (s,1H,0H), 6.8 (s,2H,arom.H), 3.75 (s,2H, C6H5CH2S-), 2.88 (m.lH.CHS), 3.18 (dd,1H,CHC=N0H, J= 4Hz,13.9Hz), 2.13 (dd,1H, CHC=NOH, J= 5.2Hz, 13.9Hz), 2.15,2.3{ 9H, 3XCH3). 'H-NMR(d6-DMS0) of the anti-form: 10.3 (s,1H,0H), 6.8 (s,2H,arom.H), 3.75 (s,2H, C6H5CH2S-), 2.92(m,1H,CHS), 2.58 (dd,1H,CHC=N0H, J= 4Hz,13.9Hz), 2.15 (dd.lH, CHC=NOH, J= 4.2Hz, 13.6Hz), 2.15,2.3( 9H, SxCHg). ll-DC)3-(R/SH2.4.6-trimethvl-benzvl-sulfanvn-cvclohexvl-(RyS)-amine 2.7 g of 3-(R/S)-(2,4,6-Trimethyl-benzyl-su!fanyi)-cyclohexanone-oxime are added to a mixture of 20 ml of a IM-solution of LiAIHa and 15 ml of dioxane, the mixture obtained is heated for 1 hour at 80° and the mixture obtained is poured into 200 ml of a 20% aqueous NH4CI-solution. The mixture obtained is extracted with EtAc, the organic phase obtained is dried and solvent is evaporated. 3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexyl-(R/S)-amine is obtained. ll-DC)3-(N-BOC-fRVValvl-amino)-cvclohexan-1-(R/S)-vl-sulfanvlmethvl-(2.4.6-trimethvl-benzoU A mixture of 1.05 g of 3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexyl-(R/S)-amine, 870 mg of BOC-R-valine, 760 mg of EDC and 404 mg of triethylamine in 20ml THF is stirred at RT for 2 hours. The mixture obtained is distributed between brine and EtAc, the organic phase obtained is dried, solvent is evaporated and the evaporation residue is subjected to chromatography. 3-(N-BOC-{R)-valyl-amino)-cyclohexan-1-(R/S)-yl-sulfanylmethyl-(2,4,6-trimethyl-benzol) is obtained. M-NMR(d6-DMS0): Rotamers, 7.78, 7.3, 6.52 (3xd,2H,NH), J=7.9Hz), 6.8, 6.82 (2xs,2H, arom.H), 6.55 (m,1H,NHC=0).3.7 (m,1H,a-H-valyl), 3.6 (m,1H,NHCH), 2.75, 3.0 (2xm,1H, CHS), 1.39(s,9H,tert.butyl) ll-DD)3-(N-BOC-(RVValvl-amino>-cvclohexane-(R/S)-thiol 10 ml ammonia are condensed at -70° within a solution of 600 mg of 3-(N-B0C-(R)-valyl-amino)-cyclohexan-1-(R/S)-yl- sulfanylmethyl-2,4,6-trimethyl-benzol in 15 ml of THF and sodium is added in portions until the solution remains deep blue. Solid NH4CI is added to the mixture obtained and the mixture obtained is allowed to warm up to RT, is flushed with nitrogen, the solid residue obtained is filtered off, the filtrate obtained is concentrated and subjected to chromatography on silica gel. 3-(N-BOC-(R)-Valyl-amino)-cyclohexane-(R/S)-thioi is obtained. 'H-NMR(d6-DMS0): Rotamer, 7.75 (m,1H,NHCHC=0), 6.55 (m,1H,NHC=0),2.75 (m,1H,CHS), 2.58(d,1H,SH,J=6.6Hz), 1.39(s,9H,tert.butyl) Analogously to the method as set out in Example ll-D but using appropriate starting materials the following compounds are obtained: Example ll-D-1 N-BOC-3-(R/S)-mercapto-cyclohexylamin Example ll-D-2 4-(R/S)-Mercapto-azepan-2-one from 4-(R/SH2,4,6-trimethyl-benzyl-sulfanyl)-azepan-2-one. ^H-NMR(d6-DMS0): 6.15, 5.1 (2xm,Hi9.H2o,H2i), 5.52(d,1H,J=5,2Hz,Hi4), 3.4(m,1H,Hii,), 3.3 (m,2H,H22), 2.99-3.12(b,2H,CH2N), 3.18(m,1H,SCH), 2.7 (m,1H,C=0CH), 2.67(d,1H,SH,J=5.5Hz), 2.58(d,1H,C=OCH,J=13.5Hz), 1.18,1.45 (2xs,(CH3)i5,(CH3)i8), 0.75,0.88 (2xd,(CH3)i6.(CH3)i7,J=5.4Hz). Example ll-E N-BOC-3-(R/S)-{2,4,6-trlmethyl-benzyl-sulfanyl)- cyclohexyl-{R/S)-amine A solution of 11 g of 3-(RyS)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexylamine, 9.15 g of BOC-anhydride and 4.2 g of triehylamine in 100 ml of THF is stinted at 25° for 12 hours, solvent is evaporated and the concentrated residue is distributed between CH2CI2 and 1M HCI. From the organic phase obtained solvent is evaporated and the evaporation residue is subjected to chromatography. N-BOC-3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)- cyclohexyl-{R/S)-amine is obtained. ^H-NMR(d6-DMS0): 6.81,(s,1H,NHCO), 6.8 (s,2H, arom.H), 3.75 (s,2H,C6H5CH2S-),3.2 (m,1H,CHN), 2.70 (m,1H,CHS), 2.13 2.15,2.3( 9H, 3xCH3),1.4(s.9H,tert.butyl) Example ll-F Toluene-4-sulfonlc acid (3S, 3aS, 6R, 6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester and Toluene-4-sulfonlc acid {3R, 3aS, 6S, 6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester A solution of 8.76 g of (3S, 3aS, 6R, 6aR)-hexahydro-furo[3,2-b]furan-3,6-diol in 80 ml of pyridine is stirred for 16 hours with 13.7 g of toluenesulfonylchloride, solvent is distilled off and the distillation residue is dissolved in EtAc and extracted with IN HCI, saturated aqueous NaHCOa-solution and H2O. The organic layer obtained is dried, solvent Is evaporated and the evaporation residue is subjected to chromatography, Toluene-4-sulfonic acid (3S, 3aS, 6R, 6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester (a) and toluene-4-sulfonic acid (3R, 3aS, 6S, 6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester (b) are obtained. ^HNMR(DMS0-d6) of forni (a): 7.8 (d,2H,Ar-H,J=8.2Hz), 7.5 (d,2H,Ar-H,J=8.6Hz), 4.95 {d,1H,6-0H), 4.8 (m, 1H, H-3), 4.42 (dd,1H,H-6a,J=4.6 and4.8Hz), 4.38 (d,1H,H-3a,J=4.6), 4.08 (m,1H,H-6), 3.8 (m,2H,2xH-2), 3.7, 3.25 (2xdd. 2H, 2xH-5), 2.4 (s, 3H, Ar-CH3). ^HNMR(DMS0-d6) of form (b): 7.8 (d,2H,Ar-H,J=8.6H2), 7.5 (d,2H,Ar-H,J=8.6H2), 5.15 (d, 6-OH, J=3.5), 4.9 (m,1H,H-3), 4.45 (dd,1H,H-3a,J=4.3 and 4.8Hz), 4.2 (d,1H,H-Ba,J=4.3), 4.0 (m,1H,H-6), 3.7 (m,3H,H-2 and 2xH-5), 3.5 (dd,1H,H-2,J=9.5 and 6.3Hz), 2.4 (s, 3H, Ar-CHa). Example ll-G N-BOC-4-Hydroxy-piperidin-3-thiol, N-BOC-3-Hydroxy-piperidln-4-thlol \ solution of 1 g of N-BOC-3,4-epoxy-piperidin, 1.9 g of triphenylsilylmercaptane and 0.7 ml Df triethylamine in 12.5 ml of THF is stirred for 24 hours at 70°, and 1.7g of TBAF and 0.9 ml acetic acid are added. The mixture obtained is stirred for 1 hour and distributed between 3rine and EtAc. The organic phase is dried, solvent is evaporated and the evaporation esidue obtained is subjected to chromatography on silica gel. (a): N-BOC-4-Hydroxy-}iperidin-3-thiol, and (b): N-BOC-3-hydroxy-piperidin-4-thiol are obtained. H-NMR (CDCI3) of (a): 4.45, 4.12, 2.8 (3xm,3H,CH2NCH), 3.31 (dt, 1H, CHO, l=4.3Hz,J=10Hz), 2.65,2.6(2xm,2H,CHN,CHS), 1.5(s,9H,tert.butyl). H-NMR (CDCI3) of (b): 4.25, 3.45 2.7, (3xm,3H,CH2NCH), 3.2 (m,1H,CH0), 2.55(m,2H, ^CH,CHS), 1.5(s,9H,tert.butyl). rest Examples Example A )etennination of Mycobacterium tuberculosis strain resistance Activity of the known compounds Isoniacid, Rifampicin and Streptomycin against /^.tuberculosis strains 1 to 14 as set out in TABLE A is detemnined in the Agar Dilution Test iccording to the method as described in the General Procedure. The MIC is determined ifter 3, 4 and 5 weeks. The strains 1 to 7 tested were found to be either sensible (S) or esistant (R) against Isoniacid, Rifampicin and/or Streptomycin. Results are as set out in 'ABLE A below: Example B Activity of TEST COMPOUNDS (TCs) against M.tuberculosis strains 1 to 5 and 7 as set out in TABLE A is determined in the Agar Dilution Test under conditions as in Example A in different agar concentrations of the TEST COMPOUNDS. The MIC is determined after 3, 4 and 5 weeks. Activity of the following TEST COMPOUNDS (TC) is tested: A compound of formula l-Tiamulin: TC-1 A compound of formula l-Valnemulin: TC-2 A compound of fomnula I-PREF1: TC-3 A compound of fomnula I-PREF2: TC-4 Example C Is carried out according to the method of Example B. Test results obtained are as set out in TABLE C and in TABLE D and in TABLE E: COMPOUND as defined above, e.g. TC-1 indicates a compound of formula l-Tiamulin; and 7week" indicates tine MIC-determination point (in weeks from inoculation) in the testing of such TEST COMPOUND. "TC-1/3" for example indicates that the MIC of a compound of formula l-Tiamulin was determined after 3 weeks from inoculation. MIC is the minimum inhibition concentration as defined above. The strain numbers 1 to 4 and 6 to 7 indicated in TABLE B, the strain numbers 1 to 9 indicated in TABLE C and the strain numbers 10 to 15 indicated in TABLE D, and the strain numbers 1, 12 and 15 indicated in TABEL E refer to the corresponding Mycobacterium tuberculosis strains of Example A. Furthermore compounds of formula lexand compounds of fomnula I'EX wherein REX is as defined in TABLE 6 below have also proved to show activity against strains 1,12 and 15 (all compounds tested in the form of hydrochlorides): WE CLAIM : 1. A compound selected from the group consisting of compounds of formulae as set out in wherein - the dotted Hne is a bond (double bond between positions a=b), RIA is hydrogen and R2A is not present, or - the dotted line is no bond (single bond between positions a-b) and RIA and R2A independently of each other are hydrogen, halogen or deuterium, R3Ais(C,.6)alkyl, R4Ais hydrogen, (Ci.6)alkyl, a group -C(=NH)-NH2, or the residue of an amino acid, RsA is hydrogen, or R4A and RsA together are a group =CH-NH2, R^A is hydrogen or deuterium, and mA 0,1,2,3,4, or5. 3. 14-0-(oximino-(C3.8)cycloalkyl-sulfanylmethylcarbonyl)-pleuromutilin and a 14-0-(hydrazono-(C3..8)cycloalkyl-sulfanylmethylcarbonyl)-pleuromutilin. 4. A compound of formula wherein RIB has the meaning of RJA as claimed in claim 7, R2B has the meaning of as claimed in claim 7, Rioehas the meaning of R^A as claimed in claim 7, the dotted line has the meaning as claimed in claim 7, me has the meaning of m^ as claimed above, R3B is hydrogen or (Ci.6)alkyl, XB -O-R4B or -NR5BR6B, RtB is hydrogen or (Ci.6)alkyl, optionally substituted by a group -NR7BR8B, RsB and R^B independently of each other are (Ci.4)alkyl, R7B and RgB independently of each other are (CM)alkyl, or R7B and RgB together with the nitrogen atom to which they are attached form aliphatic heterocyclyl, having 5 to 8 ring members, and R9B is hydrogen or (CM)alkyl. 5. A compound of formula wherein Richas the meaning of RIA as claimed in claim 7, R2chas the meaning of RiAas claimed in claim 7, the dotted line has the meaning as claimed in claim 7, Ric has the meaning of R^A as claimed in claim 7, and Racis amino, (CM)alkylamino, di(CM)alkylamino, the residue of an amino acid, hydroxy, or (CM)alkoxy. 6. A compound of formula wherein RID has the meaning of RIA as claimed in claim 7, R2ohas the meaning of R2A, as claimed in claim 7, R4Dhas the meaning of R6A as claimed in claim 7, the dotted line has the meaning as claimed in claim 7, and R3D is aliphatic heterocyclyl of 4 to 8 ring members, and comprising one nitrogen atom as the heteroatom, or (C4.8)cycloalkyl, which heterocyclyl or cycloalkyl is substituted by hydroxy or 0x0. 7. The compound as claimed in any one of claims 1 to 6 in the form of a salt. 8. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 7 in association with at least one pharmaceutical excipient.

Documents:

2130-chenp-2004 abstract.pdf

2130-chenp-2004 assignment.pdf

2130-chenp-2004 claims.pdf

2130-chenp-2004 correspondence-others.pdf

2130-chenp-2004 correspondence-po.pdf

2130-chenp-2004 description (complete).pdf

2130-chenp-2004 form-1.pdf

2130-chenp-2004 form-18.pdf

2130-chenp-2004 form-26.pdf

2130-chenp-2004 form-3.pdf

2130-chenp-2004 form-5.pdf

2130-chenp-2004 form-6.pdf

2130-chenp-2004 others.pdf

2130-chenp-2004 pct.pdf

2130-chenp-2004 petition.pdf