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  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
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  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
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  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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  • A61P31/06—Antibacterial agents for tuberculosis
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  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/61—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
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  • C07C2601/00—Systems containing only non-condensed rings
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  • C07C2601/14—The ring being saturated
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  • C07C2603/95—Spiro compounds containing "not free" spiro atoms
  • C07C2603/98—Spiro compounds containing "not free" spiro atoms containing at least one ring with more than six ring members
  • C07C2603/99—Spiro compounds containing "not free" spiro atoms containing at least one ring with more than six ring members containing eight-membered rings

Definitions

• the present invention relates to organic compounds, namely pleuromutilins.
• Pleuromutilin a compound of formula A
• pleuromutilin derivatives e.g. 14-O-[(Aminocyclohexan-2-yl (and -3-yl)-sulfanyl)-acetyl]-mutilins; from WO 07/014409 A1 e.g. 14-O-[((Mono- or dialkylamino)-cycloalkylsulfanyl)-acetyl]-mutilins and from WO 07/000004 A1 e.g. [((Acyl-hydroxy-amino)cycloalkylsulfanyl)-acetyl]-mutilins, are known.
• pleuromutilin derivatives according to the invention are compounds of formula (I)
• n 0 to 4; R is ethyl or vinyl; R 1 is hydrogen or (C 1-6 )alkyl, R 2 is hydrogen or
• n, R 1 and R 2 are as defined above.
• 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 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 present invention provides a compound of the present invention in the form of a salt and/or solvate.
• the salts include preferably pharmaceutically acceptable salts, although pharmaceutically unacceptable salts are included, e.g. for preparation/isolation/purification purposes.
• a salt of a compound of the present invention includes a base salt or an acid addition salt.
• Pharmaceutically acceptable base salts include ammonium salts such as trimethylammonium salt, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine, preferably sodium salts.
• Acid addition salts include salts of a compound of the present invention with an acid, e.g.
• 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/or 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 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 enatiomers or diastereoisomers and mixtures thereof, e.g. racemates or diastereomeric mixtures. Any asymmetric carbon atom may be present in the R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration.
• the carbon atom of the cycloalkyl ring which is attached to the sulphur atom, the carbon atom of the cycloalkyl ring which is attached to the hydroxy group, and the carbon atom of the cycloalkyl ring to which the (CH 2 ) n N(R 1 R 2 ) group is attached all are asymmetric carbon atoms.
• Substituents attached to such asymmetric carbon atom may thus exist in (R) and (S) configuration, including mixtures thereof.
• R 2 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 substituent 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.
• the compounds of the present invention exhibit pharmacological activity and are therefore useful as pharmaceuticals.
• the compounds of the present invention show antimicrobial, e.g. antibacterial, activity against gram positive bacteria, such as coagulase positive Staphylococci, e.g. Staphylococcus aureus , coagulase negative Staphylococci, e.g. Staphylococcus epidermidis, Staphylococcus haemolyticus , and Streptococci, e.g. Streptococcus pyogenes, Streptococcus pneumoniae , Enterococci, e.g. Enterococcus faecium and Listeria monocytogenes and against gram negative bacteria such as Moraxella, e.g.
• Moraxella catarrhalis and Haemophilus, e.g. Haemophilus influenzae , and Legionella, e.g. Legionella pneumophila , Neisseriaceae, e.g. Neisseria gonorrhoeae , as well as against Mycoplasms, Chlamydia and obligatory anaerobes, e.g Bacteroides fragilis, Clostridium difficile, Fusobacterium spp., and Propionibacterium spp.
• the in vitro activity against aerobic bacteria was determined by Agar Dilution Test or Microdilution Test according to the Clinical and Laboratory Standards Institute (CLSI, former NCCLS) Document M7-A7 Vol. 26, No. 2: “Methods for dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Approved Standard; Seventh Edition (2006)”; and the test against anaerobic bacteria was performed according to the Clinical and Laboratory Standards Institute (CLSI, former NCCLS), Document, M11-A ⁇ , Vol. 24, No.
• 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 may also be treated include e.g. diseases mediated by Helicobacter, such as Helicobacter pylori , and diseases mediated by Mycobacterium tuberculosis .
• Diseases which may also be treated include in general inflammatory diseases, where microbes are mediating said inflammation, e.g. including acne.
• 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.
• an antimicrobial such as an antibiotic, e.g. and an anti-anaerobic.
• the present invention provides a compound of the present invention for use in acne treatment.
• 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
• bacteria e.g. selected from Staphylococci, Streptococci, Enterococci;
• bacteria e.g. selected from Moraxella, Haemophilus, Legionella, Neisseriaceae;
• 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.
• 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.
• an indicated daily dosage is in the range from about 0.5 mg 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, subcutaneous 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 creams, gels, pastes, inhaler powder, foams, tinctures, lip sticks, drops, sprays, or in the form of suppositories, e.g. in analogous manner to macrolides, such as erythromycins, e.g. clarithromycin or azithromycin.
• 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 a base addition salt, e.g. a metal salt, or in free form, optionally in the form of a solvate.
• a pharmaceutically acceptable salt e.g. an acid addition salt or a base addition salt, e.g. a metal salt
• a compound of the present invention in the form of a salt exhibits 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.
• 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.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of the present invention in free form or in the form of a pharmaceutically acceptable salt 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.
• excipient e.g. carrier or diluent
• 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 0.5 mg to about 2000 mg, such as 10 mg to about 500 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.
• 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.
• the present invention provides a compound of the present invention for use as a veterinary agent.
• the present invention provides a compound of the present invention for the preparation of a veterinary composition which is useful as a veterinary agent.
• the present invention provides a veterinary method for the prophylaxis and 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.
• microbial e.g. bacterial diseases
• the metabolic stability for compounds of the present invention was determined by using cryopreserved primary human hepatocytes. 1 ⁇ 10 6 cells/mL were incubated in the absence and the presence of 5 and 25 ⁇ g/mL of the test compounds at 37° C., 5% CO 2 for 4 hours, To evaluate the in vitro degradation under assay conditions, a sample of each test compound was incubated also in the absence of hepatocytes. The incubation was stopped by freezing the reaction mixture. After ultrafiltration and washing of the filter with acetonitrile, the sample solution was analyzed for parent compound disappearance or metabolite appearance using LC/MS (ion trap). The metabolic stability value corresponds to the detected parent compound in % after incubation.
• the introduction of a hydroxy group in ortho position to the sulphur substituent in the cyclohexyl ring reveals unexpected improvements in metabolic stability of the microbiologically active components.
• Parent compound or active metabolite were more stable after incubation with primary human hepatocytes in comparison to derivatives without a hydroxy group in the cyclohexyl moiety of the pleuromutilin side chain.
• mutilin refers to the IUPAC systematic name (1S, 2R, 3S, 4S, 6R, 7R, 8R, 14R)-3,6-dihydroxy-2,4,7,14-tetramethyl-4-vinyl-tricyclo[5.4.3.0 1,8 ]tetradecan-9-one.
• pleuromutilin derivatives are numbered in analogy to the mutilin numbering system described by H. Berner (Berner, H.; Schulz, G.; Schneider H. Tetrahedron 1980, 36, 1807-1811.):
• Pleuromutilin thiol and pleuromutilin tosylate are compounds of formulae:
• Step A 14-O- ⁇ [(1R, 2R, 4R)-4-tert-Butoxycarbonylamino-2-hydroxy-cyclohexylsuffanyl]-acetyl ⁇ -mutilin+(1S, 2S, 4S) diastereomer and 14-O- ⁇ [(1R, 2R, 5S)-5-tert-Butoxycarbonylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 5R) diastereomer and
• Step B 14-O- ⁇ [(1R, 2R, 4R)4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 4S) diastereomer
• Step C 14-O- ⁇ [(1R, 2R, 4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin hydrochloride+(1S, 2S, 4S) diastereomer hydrochloride
• Step A 14-O- ⁇ [(1R, 2R, 5S)-5-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 5R) diastereomer and
• Example 1 Step A A mixture of 14-O- ⁇ [(1R, 2R, 5S)-5-tert-butoxycarbonylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 5R) diastereomer and 14-O- ⁇ [(1R, 2R, 4S)4-tert-butoxycarbonylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 4R) diastereomer (1.12 g, 1.84 mmol) from Example 1 Step A was treated according to the method of Example 1 Step B.
• Step B 14-O- ⁇ [(1R, 2R, 5S)-5-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin hydrochloride+(1S, 2S, 5R) diastereomer hydrochloride
• Example 2 Step A 14-O- ⁇ [(1R, 2R, 4S)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 4R) diastereomer (152 mg, 0.30 mmol) from Example 2 Step A was treated according to the method of Example 1 Step C to obtain 14-O- ⁇ [(1R, 2R, 4S)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin hydrochloride+(1S, 2S, 4R) diastereomer hydrochloride (148 mg, 91% yield) as colorless amorphous solid.
• Step A tert-Butyl-dimethyl-(cis-3,4-epoxycyclohexyloxy)-silane
• the resulting reaction mixture was treated with tert-butyldimethylsilyl chloride (16.9 g, 112 mmol), imidazole (9.02 g, 132 mmol) and 4-dimethylaminopyridine (2.49 g, 20 mmol) at 4° C. and stirred for 5 hours at room temperature.
• the reaction mixture was diluted with dichloromethane and subsequently extracted with 10% NaHSO 3 solution, saturated NaHCO 3 solution and brine. The organic layer was dried over sodium sulfate and filtered.
• Step B 14-O- ⁇ [(1R, 2R, 5S)-5-(tert-Butyl-dimethyl-silyloxy)-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 5R) diastereomer
• Step C 14-O- ⁇ [(1R, 2R, 5S)-2,5-Dihydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 5R) diastereomer
• Step D 14-O- ⁇ [(1R, 2R, 5S)-2-Hydroxy-5-methanesulfonyloxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 5R) diastereomer
• Step E 14-O- ⁇ [(1R, 2R, 5R)-5-Azido-2-hydroxy-5-methanesulfonyloxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 5S) diastereomer
• Step F 14-O- ⁇ [(1R, 2R, 5R)-5-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 5S) diastereomer
• Triphenylphosphine (1.18 g, 4.50 mmol) was added to a solution of 14-O- ⁇ [(1R, 2R,5R)-5-azido-2-hydroxy-5-methanesulfonyloxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 5S) diastereomer (2.4 g, 4.50 mmol) in 30 ml of THF and stirred overnight at room temperature. Subsequently water (approx. 3 ml) was added and the reaction mixture was heated for 1 hour at reflux. After evaporation of the solvent the residue was diluted with water and brine and extracted three times with ethyl acetate.
• Step A 14-O- ⁇ [(1R, 2R, 3R)-3-tert-Butoxycarbonylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 3S) diastereomer
• Step B 14-O- ⁇ [(1R, 2R, 3R)-3-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 3S) diastereomer
• the resulting reaction mixture was treated with sodium triacetoxyborohydride (750 mg, 3.54 mmol) and stirred overnight at room temperature, diluted with dichloromethane and subsequently extracted with NaHCO 3 solution and brine. The organic layer was dried over sodium sulfate and filtered.
• sodium triacetoxyborohydride 750 mg, 3.54 mmol
• Step A N-Ethyl-N-(cyclohex-3-enyl)-carbamic acid tert-butyl ester
• Step B N-ethyl-N-(cis-3,4-epoxycyclohexyl)-carbamic acid tert-butyl ester
• Step C 14-O- ⁇ [(1R, 2R, 5S)-5-(tert-Butoxycarbonyl-ethyl-amino)-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 5R) diastereomer
• N-Ethyl-N-(cis-3,4-epoxycyclohexyl)-carbamic acid tert-butyl ester (1.5 g, 6.2 mmol) was treated with pleuromutilin thiol according to the method of Example 1 Step A1.
• Step E 14-O- ⁇ [(1R, 2R, 5S)-5-Ethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin hydrochloride+(1S, 2S, 5R) diastereomer hydrochloride
• Step A 14-O- ⁇ [(1R, 2R, 5S)-5-Diethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilia+(1S, 2S, 5R) diastereomer
• Step B 14O- ⁇ [(1R, 2R, 5S)-5-Diethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin hydrochloride+(1S, 2S, 5R) diastereomer hydrochloride
• Example 2 Step A 14-O- ⁇ [(1R, 2R, 4S)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 4R) diastereomer (680 mg, 1.34 mmol) from Example 2 Step A was treated according to the method of Example 6.
• Example 4 Step F 14-O- ⁇ [(1R, 2R, 5R)-5-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 5S) diastereomer (420 mg, 0.827 mmol) from Example 4 Step F was treated according to the method of Example 6.
• Step A [(1R, 2R, 3R)-2-Hydroxy-3-(2,4,6-trimethyl-benzylsulfanyl)-cyclobexyl]-carbamic acid tert-butyl ester+(1S, 2S, 3S) diastereomer
• Step B [(1R, 2R, 3R)-2-(tert-Butyl-dimethyl-silanyloxy)-3-(2,4,6-trimethyl-benzylsulfanyl)-cyclohexyl]-carbamic acid tert-butyl ester+(1S, 2S, 38) diastereomer
• Step C [(1R, 2R, 3R)2-(tert-Butyl-dimethyl-silanyloxy)-3-(2,4,6trimethyl-benzylsulfanyl)-cyclohexyl]-ethyl-carbamic acid tert-butyl ester+(1S, 2S, 3S) diastereomer
• Step F 14-O- ⁇ [(1R, 2R, 3R)-3-Etlhylamino-2-(tert-butyl-dimethyl-silanyloxy)-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 3S) diastereomer and 14-O-([(1R, 2R, 3R)-3-Ethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 3S) diastereomer
• Step A 14-O- ⁇ [(1R, 2R, 3R)-3-Diethylamino)-2-(tert-butyl-dimethyl-silanyloxy)-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 35) diastereomer
• Example 11 14-O- ⁇ [(1R, 2R, 3R)-3-Ethylamino-2-(tert-butyl-dimethyl-silanyloxy)-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 3S) diastereomer (144 mg, 0.222 mmol) from Example 11 Step F was treated with acetaldehyde (25 ⁇ l, 0.444 mmol) according to the method of Example 6.
• Step B 14-O- ⁇ [(1R, 2R, 3R)-3-Diethylamino-2-hydroxy-cyclohexylsulfanyll-acetyl ⁇ -mutilin+(1S, 2S, 3S) diastereomer
• Step A 14-O- ⁇ [(7R, 8R)-7-Hydroxy-1,4-dioxa-spiro[4.51dec-8-ylsulfanyl]-acetyl ⁇ -mutilin+(7S, 8S) diastereomer
• Step B 14-O- ⁇ [(7R, 8R)-7-(tert-Butyl-diphenyl-silanyloxy)-1,4-dioxa-spiro[4.5]dec-8-ylsulfanyl]-acetyl ⁇ -mutilin+(7S, 8S) diastereomer
• Step C 14O- ⁇ [(1R, 2R)-2-(tert-Butyl-diphenyl-silanyloxy)-4-oxo-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S) diastereomer
• Step D 14-O- ⁇ [(1R, 2R)-2-(tert-Butyl-diphenyl-silanyloxy)-4-hydroxyimino-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S) diastereomer
• Step E 14-O- ⁇ [(1R, 2R, 4S)-2-(tert-Butyl-diphenyl-silanyloxy)-4-hydroxyamino-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 4R) diastereomer and 14-O- ⁇ [(1R, 2R, 4R)-2-(tert-Butyl-diphenyl-silanyloxy)-4-hydroxyamino-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 4S) diastereomer
• Step F 14-O- ⁇ [(1R, 2R, 4S)-2-(tert-Butyl-diphenyl-silanyloxy)-4-(formyl-hydroxy-amino-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 4R) diastereomer
• Step G 14-O- ⁇ [(1R, 2R, 4S)-4-(Formyl-hydroxy-amino)-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 4R) diastereomer
• Step B Acetic acid (7R, 8R)-7-(2,4,6-trimethylbenzylsufanyl)-1,4-dioxa-spiro[4.5]dec-8-yl ester+(7S, 8S) diastereomer
• Step D 14-O- ⁇ [(7R, 8R)-8-Hydroxy-1,4-dioxa-spiro[4.5]dec-7-ylsulfanyl]-acetyl ⁇ -mutilin+ ⁇ 7S, 8S) diastereomer
• Step F 14-O- ⁇ [(1R, 2R)-2-(tert-Butyl-diphenyl-silanyloxy)-5-oxo-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S) diastereomer
• Step G 14-O- ⁇ [(1R, 2R)-2-(tert-Butyl-diphenyl-silanyloxy)-5-hydroxyimino-cyclobexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S) diastereomer
• Step H 14-O- ⁇ [(1R, 2R, 5S)-2-(tert-Butyl-diphenyl-silanyloxy)-5-hydroxyamino-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 5R) diastertomer and 14-O- ⁇ [(1R, 2R, 5R)-2-(Iert-Butyl-diphenyl-silanyloxy)-5-hydroxyamino-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 5S) diastereomer
• Step I 14-O- ⁇ [(1R, 2R, 5S)-2-(tert-Butyl-diphenyl-silanyloxy)-5-(formyl-hydroxy-amino-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 5R) diastereomer
• Step A 14-O- ⁇ [(6R, 7R)-6-Hydroxy-1,4-dioxa-spiro[4.5]dec-7-ylsulfanyl]-acetyl ⁇ -mutilin +(6S, 7S) diastereomer
• Step B 14-O- ⁇ [(1R, 2R)-2-Hydroxy-3-oxo-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 25) diastereomer
• Step C 14-O-([(1R, 2R)-2-Hydroxy-3-hydroxyimino-cyclohexylsulfanyl]-acetyl ⁇ -mutilin +(1S, 2S) diastereomer
• Step D 14-O- ⁇ [(1R, 2R, 3R/S)-2-Hydroxy-3-Hydroxyamino-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 3R/S) diastereomer
• Step E 14-O- ⁇ [(1R, 2R, 3R/S)-3-(Formyl-hydroxy-amino)-2-hydroxy-cyclohexylsulfanyl]-acetyl ⁇ -mutilin+(1S, 2S, 3R/S) diastereomer

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