EP1807443A1 - Acylierte nonadepsipeptide als lysobactinderivate - Google Patents
Acylierte nonadepsipeptide als lysobactinderivateInfo
- Publication number
- EP1807443A1 EP1807443A1 EP05798234A EP05798234A EP1807443A1 EP 1807443 A1 EP1807443 A1 EP 1807443A1 EP 05798234 A EP05798234 A EP 05798234A EP 05798234 A EP05798234 A EP 05798234A EP 1807443 A1 EP1807443 A1 EP 1807443A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hplc
- mmol
- compound
- water
- salts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- KQMKBWMQSNKASI-AVSFGBOWSA-N lysobactin Chemical class O1C(=O)[C@H](CO)NC(=O)[C@H]([C@H](O)C(N)=O)NC(=O)CNC(=O)[C@H]([C@H](C)O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@H](O)C(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CC(C)C)[C@H]1C1=CC=CC=C1 KQMKBWMQSNKASI-AVSFGBOWSA-N 0.000 title abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 143
- 239000003814 drug Substances 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 109
- -1 2,2-dimethylbut-1-yl Chemical group 0.000 claims description 64
- 150000003839 salts Chemical class 0.000 claims description 36
- 239000012453 solvate Substances 0.000 claims description 24
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 23
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
- 238000011282 treatment Methods 0.000 claims description 16
- 241001465754 Metazoa Species 0.000 claims description 12
- 238000011321 prophylaxis Methods 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 208000035143 Bacterial infection Diseases 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 108010011530 lysobactin Proteins 0.000 abstract description 12
- KQMKBWMQSNKASI-UHFFFAOYSA-N lysobactin Natural products O1C(=O)C(CO)NC(=O)C(C(O)C(N)=O)NC(=O)CNC(=O)C(C(C)O)NC(=O)C(C(C)CC)NC(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(C(O)C(C)C)NC(=O)C(NC(=O)C(CC(C)C)NC(=O)C(N)CC(C)C)C1C1=CC=CC=C1 KQMKBWMQSNKASI-UHFFFAOYSA-N 0.000 abstract description 12
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 3
- 239000005445 natural material Substances 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 72
- 238000004128 high performance liquid chromatography Methods 0.000 description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 59
- 239000000243 solution Substances 0.000 description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000003480 eluent Substances 0.000 description 44
- 235000002639 sodium chloride Nutrition 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 32
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- 239000000203 mixture Substances 0.000 description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 19
- 239000000126 substance Substances 0.000 description 18
- 239000012043 crude product Substances 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- 238000000825 ultraviolet detection Methods 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 13
- 238000002953 preparative HPLC Methods 0.000 description 13
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 208000015181 infectious disease Diseases 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 239000007821 HATU Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 230000000844 anti-bacterial effect Effects 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000005227 gel permeation chromatography Methods 0.000 description 9
- 210000003734 kidney Anatomy 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 210000002421 cell wall Anatomy 0.000 description 8
- 235000019253 formic acid Nutrition 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
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- 230000008929 regeneration Effects 0.000 description 8
- 238000011069 regeneration method Methods 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 6
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- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 6
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- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 6
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- QFTZULJNRAHOIY-UHFFFAOYSA-N 1,4-dibromo-2,3,5,6-tetrafluorobenzene Chemical compound FC1=C(F)C(Br)=C(F)C(F)=C1Br QFTZULJNRAHOIY-UHFFFAOYSA-N 0.000 description 5
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- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical compound COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 1
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- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
Definitions
- the invention relates to nonadepsipeptides and processes for their preparation and their use for the production of medicaments for the treatment and / or prophylaxis of diseases, in particular bacterial infectious diseases.
- the bacterial cell wall is synthesized by a number of enzymes (cell wall biosynthesis) and is essential for the survival or multiplication of microorganisms.
- the structure of this macromolecule, as well as the proteins involved in its synthesis, are highly conserved within the bacteria. Due to their essential nature and uniformity, cell wall biosynthesis is an ideal target for new antibiotics (D.W.Green, The bacterial cell wall as a source of antibacterial targets, Expert Opin. Ther. Targets, 2002, 6, 1-19).
- Vancomycin and penicillins are inhibitors of bacterial cell wall biosynthesis and represent successful examples of the antibiotic potency of this active principle. They have been used for several decades in the clinic for the treatment of bacterial infections, especially with Gram-positive pathogens. Due to the increasing incidence of resistant germs, e.g. Methicillin-resistant staphylococci, penicillin-resistant pneumococci, and vancomycin-resistant enterococci (F. Baquero, Gram-positive resistance: challenge for the development of new antibiotics, J.
- the present invention describes a new class of cell wall biosynthesis inhibitors without cross-resistance to known antibiotic classes.
- lysobactin and some derivatives are described as having antibacterial activity in US 4,754,018.
- the isolation and antibacterial activity of lysobactin is also described in EP-A-196 042 and JP 01132600.
- WO04 / 099239 describes derivatives of lysobactin having anti-bacterial activity.
- An object of the present invention is to provide alternative compounds having comparable or improved antibacterial activity, better compatibility, e.g. B. lower nephrotoxicity, and better distribution in the body, ie better pharmacokinetic properties, such. B. increase of the free fraction (f u ) to provide for the treatment of bacterial diseases in humans and animals.
- the invention relates to compounds of the formula
- R 1 is hydrogen
- R 2 is 2,2-dimethylbut-1-yl, 2-ethyl-2-methylbut-1-yl, 2,2-diethyl-but-1-yl, 2,2-dimethylpent-1-yl or trimethylsilylmethyl,
- R 1 is trifluoromethyl
- R 2 2,2-dimethylprop-1-yl, 2,2-dimethylbut-1-yl, 2-ethyl-2-methylbut-1-yl, 2,2-diethyl-but-1-yl, 2,2- Dimethylpent-1-yl or trimethylsilylmethyl,
- Compounds according to the invention are the compounds of the formula (I) and their salts, solvates, solvates of the salts and prodrugs, the compounds of the formulas below and their salts, solvates, solvates of the salts and prodrugs and of the formula (I) I), hereinafter referred to as exemplary compounds and their salts, solvates, solvates of the salts and prodrugs, as far as the compounds encompassed by formula (I) below are not already salts, solvates, solvates of the salts and prodrugs.
- the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
- the invention therefore relates to the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
- the present invention encompasses all tautomeric forms.
- Salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. But also included are salts which are not suitable for pharmaceutical applications themselves but can be used for example for the isolation or purification of the compounds of the invention or mixed salts.
- mixed salt is understood as meaning an addition salt which contains two or more different acids or bases, such as, for example, B. a trifluoroacetate mesylate salt.
- Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
- Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
- Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
- solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvox,
- R 1 is hydrogen
- R 2 is 2,2-dimethylbut-1-yl or trimethylsilylmethyl
- R 1 is trifluoromethyl
- R 2 is 2,2-dimethylprop-1-yl, 2,2-dimethylbut-1-yl or trimethylsilylmethyl,
- R 1 is hydrogen
- R 2 is 2,2-dimethylbut-1-yl, 2-ethyl-2-methylbut-1-yl, 2,2-diethyl-but-1-yl or trimethylsilyl-methyl,
- R 1 is hydrogen
- R 2 is 2,2-dimethylbut-1-yl, 2-ethyl-2-methylbut-1-yl, 2,2-diethyl-but-1-yl, 2,2-dimethylpent-1-yl or trimethylsilylmethyl.
- the invention furthermore relates to a process for the preparation of the compounds of the formulas (I), where the compound of the formula
- R 1 and R 2 have the meaning given above, and
- X 1 is halogen, preferably bromine, chlorine or fluorine, or hydroxy
- the reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from -3O 0 C to 50 0 C at atmospheric pressure.
- Inert solvents are, for example, tetrahydrofuran, methylene chloride, pyridine, dioxane or dimethylformamide, preference is given to methylene chloride or dimethylformamide.
- bases are triethylamine, diisopropylethylamine or N-methylmorpholine, preferably diisopropylethylamine.
- the reaction is generally carried out in inert solvents, in the presence of a dehydrating reagent, if appropriate in the presence of a base, preferably in a temperature range from -3O 0 C to 50 0 C at atmospheric pressure.
- Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, nitromethane, dioxane, dimethylformamide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred is dichloromethane or dimethylformamide.
- Suitable dehydrating here for example, carbodiimides such as N 1 N'-diethyl-, N 1 N, dipropyl, N, N'-diisopropyl-, N, N'-dicyclohexylcarbodiimide, N- (3-di- methylaminoisopropyl) are - N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimida- ,
- EDC N'-ethylcarbodiimide hydrochloride
- PS-carbodiimide N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene
- carbonyl compounds such as carbonyldiimida-
- 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy -l-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchlorofo ⁇ nat, or bis (2-oxo-3-oxazolidinyl) -phosphorylchlorid or Benzotriazolyloxy-tri (dimethylamino) - phosphoniumhexafluorophosphat, or O- (Benzot ⁇ iazol-l -yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-l- (2H) -pyridyl) -1,3,
- Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
- alkali carbonates e.g. Sodium or potassium carbonate
- hydrogen carbonate or organic bases
- organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
- the condensation is carried out with HATU or with EDC in the presence of HOBt.
- the compounds of the formula (HI) optionally carry protective groups, so that in these cases the reaction of the compound of the formula (II) with compounds of the formula (DI) involves cleavage of the protective groups with trifluoroacetic acid by methods known to the person skilled in the art.
- the free base of the salts of the compounds of the formula (I) can be obtained, for example, by addition of a base and subsequent extraction, precipitation or chromatographic separation of the compound by methods known to the person skilled in the art.
- polymer-bound bases such as, for example, polymer-bound bicarbonate.
- the invention further provides a process for the preparation of the compounds of the formula (I) or their solvates according to claim 1, in which salts of the compounds or solvates of the salts of the compounds are converted into the compounds by addition of a base.
- the compound of the formula (H) can be synthesized by double Edmann degradation from lysobactin (Example 1), as described in the experimental section under Example 2A.
- the compounds of the formula (III) are known or can be synthesized by known processes from the corresponding starting materials.
- the compounds of the invention show an unpredictable, valuable pharmacological and pharmacokinetic spectrum of activity. They show an antibacterial effect.
- the compounds according to the invention are distinguished by a lower nephrotoxicity compared to lysobactin.
- the compounds according to the invention are distinguished by a better pharmacokinetics than by lysobactin. They show a better distribution in the body with the same or improved pharmacological effect, which results in a lower therapeutic dose and a broader therapeutic window of treatment.
- the compounds of the invention have a higher free fraction (f u ) in plasma than lyso ⁇ bactin.
- the described nonadepsipeptides act as inhibitors of bacterial cell wall biosynthesis.
- the preparations according to the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly suitable for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine, which are caused by these pathogens.
- the preparations according to the invention can be used against all bacteria and bacterium-like microorganisms which are in the possession of a bacterial cell wall (murein sacculus) or the associated enzyme systems, for example by the following pathogens or by mixtures of the following pathogens:
- Gram-negative cocci Neisseria gonorrhoeae
- Gram-negative rods such as Enterobacteriaceae, e.g. Escherichia coli, Haemophilus influenzae, Pseudomonas, Klebsiella, Citrobacter (C. freundii, C. divernis), Sahnonella and Shigella; also Enterobacter (E. aerogenes, E. agglomerans), Hafhia, Serratia (S. marcescens), Providencia, Yersinia, as well as the genera Acinetobacter, Branhamella and Chlamydia.
- Enterobacteriaceae e.g. Escherichia coli, Haemophilus influenzae, Pseudomonas, Klebsiella, Citrobacter (C. freundii, C. divernis), Sahnonella and Shigella
- Enterobacter E. aerogenes,
- the antibacterial spectrum includes strictly anaerobic bacteria such as e.g. Bacteroides fragilis, members of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; furthermore, mycobacteria, e.g. M. tuberculosus.
- the compounds according to the invention show particularly pronounced activity against gram-positive cocci, e.g. Staphylococci (S. aureus, S. epidermidis, S. haemolyticus, S. carnosus), enterococci (E. faeca-Us, E. faecium) and streptococci (S. agalactiae, S. pneumoniae, S. pyogenes).
- Staphylococci S. aureus, S. epidermidis, S. haemolyticus, S. carnosus
- enterococci E. faeca-Us, E. f
- pathogens are merely exemplary and by no means restrictive.
- diseases which are caused by the named pathogens or mixed infections and which can be prevented, ameliorated or cured by the preparations according to the invention are:
- Human infectious diseases such as uncomplicated and complicated urinary tract infections, uncomplicated skin and surface infections, complicated skin and soft tissue infections, hospital and community-acquired pneumonia, nosocomial pneumonia, acute exacerbations and secondary bacterial infections of chronic bronchitis, acute otitis media, acute sinusitis , streptococcal pharyngitis, bacterial meningitis, uncomplicated gonococcal and non-gonococcal urethritis / cervicitis, acute prostatitis, endocarditis, uncomplicated and complicated intra-abdominal infections, gynecological infections, pelvic inflammatory disease, bacterial vaginosis, acute and chronic osteomyelitis, acute bacterial arthritis, empirical therapy in febrile neutropenic patients, further bacteremia, MRSA infections, acute infectious diarrhea, Helicobacter pylori infections, postoperative infections, odontogenic infections, ophthalmological In infections, postoperative infections (incl. peripro
- bacterial infections can also be treated in other species. Examples include:
- Pig diarrhea, enterotoxemia, sepsis, dysentery, salmonellosis, metritis-mastitis-agalactiae syndrome, mastitis;
- Ruminants (cattle, sheep, goats): diarrhea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, genital infections;
- Horse bronchopneumonia, foal disease, puerperal and postpuerperal infections, salmonella;
- Dog and cat bronchopneumonia, diarrhea, dermatitis, otitis, urinary tract infections, prostatitis;
- Poultry (chicken, turkey, quail, pigeon, ornamental birds and others): E. co / z infections, chronic respiratory diseases, salmonellosis, pasteurellosis, psittacosis.
- bacterial diseases in the rearing and keeping of farmed and ornamental fish can be treated, with the antibacterial spectrum on the aforementioned pathogens out to further pathogens such.
- Pasteurella Brucella, Campylobacter, Listeria, Erysipelothris, Corynebacteria, Borellia, Treponema, Nocardia, Rikettsia, Yersinia.
- a further subject of the present invention is the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, in particular of bacterial infectious diseases.
- Another object of the present invention is the use of Ver ⁇ compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned ge diseases.
- Another object of the present invention is the use of Ver ⁇ compounds of the invention for the preparation of a medicament for the treatment and / or prophylaxis of Erkran- kungen, in particular the aforementioned diseases.
- the compounds according to the invention are preferably used for the preparation of medicaments which are suitable for the prophylaxis and / or treatment of bacterial diseases.
- Another object of the present invention is a method for the treatment and / or Pro ⁇ phylaxis of diseases, in particular the aforementioned diseases, using an antibacterially effective amount of the compounds of the invention.
- compositions containing at least one compound of the invention and at least one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
- Preferred combination active ingredients are antibacterial compounds which have a different spectrum of activity, in particular complementary spectrum of action, and / or are synergistic with the compounds according to the invention.
- the compounds according to the invention can act systemically and / or locally.
- they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
- the compounds according to the invention can be administered in suitable administration forms.
- Tablets uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings containing the
- Soft gelatin capsules Soft gelatin capsules
- dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
- Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
- a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
- absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
- injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
- inhalation medicaments including powder inhalers, nebulizers
- nasal drops solutions, sprays
- lingual, sublingual or buccal tablets to be applied
- films / wafers or capsules films / wafers or capsules, suppositories, ear or eye preparations
- vaginal capsules aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches ), Milk, pastes, ,
- Foams, scattering powders, implants or stents are used as therapeutically active agents.
- the compounds according to the invention can be converted into the stated administration forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries.
- These adjuvants include, among others. Carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin ), Stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) and flavor and / or odoriferous agents.
- Carriers for example microcrystalline cellulose, lactose, mannitol
- solvents for example liquid polyethylene glycols
- emulsifiers and dispersants or wetting agents for example sodium dode
- the present invention further relates to medicaments which comprise at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and to their use for the purposes mentioned above.
- EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide also EDCI
- TOF-HR-MS-ESI + spectra are provided with a Micromass LCT apparatus (capillary voltage: 3.2 KV, cone voltage: 42 V, source temperature: 12O 0 C, desolvation temperature: 280 0 C).
- a syringe pump Hard Apparatus
- the standard is leucine-enkephalin (Tyr-Gly-Gly-Phe-Leu).
- Method 2 (Preparative HPLC): Device: Gilson Abimed HPLC; UV detector 210 nm; binary pump system; Column: Waters Symmetry-Prep TM Ci 8 , 7 ⁇ m, 300 x 19 mm; Eluent A: 0.2% trifluoroacetic acid in water, eluent B: acetonitrile; Flow rate: 25 mL / min; Column temperature RT; 0 min 20% B, ramp 0-10 min 70% B, ramp 10-10.1 min 20% B, 15 min 20% B.
- Method 3 gel chromatography on Sephadex LH-20: Gel chromatography is performed without pressure on Sephadex LH-20 (Pharmacia). It is fractionated after UV activity (UV detector for 254 nm, Knauer) (fraction collector ISCO Foxy 200). Column dimensions: 32 x 7 cm (1000-100 ⁇ mol scale); 30 x 4 cm (100-10 ⁇ mol scale); 25 x 2 cm (10-1 ⁇ mol scale). At scales of 1 mmol to 11 mmol, a column of the dimension 80 ⁇ 30 cm is used. In this case, the fractions are collected manually and without upstream UV detector. The assignment of the fractions is carried out by HPLC (Method 9).
- Method 4 (preparative HPLC, Kromasil, acetic acid): Device: Gilson Abimed HPLC; UV detector 210 nm; binary pump system; Column: Kromasil 100 A Ci 8 , 5 ⁇ m; 250 x 20 mm; Flow: 25 mL / min; Eluent A: water / 0.25-0.5% acetic acid, eluent B: acetonitrile; Gradient: 0-3 min 5% B, 3-30 min 5-100% B, 30-38 min 100% B, then regeneration of the chromatography column.
- Method 5 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 L water + 0.5 mL 50% formic acid, eluent B: 1 L acetonitrile + 0.5 mL 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A -> 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 mL / min, 2.5 min / 3.0 min / 4.5 min 2 mL / min; Oven: 5O 0 C; UV detection: 208-400 nm.
- Method 6 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 L water + 0.5 mL 50% formic acid, eluent B: 1 L acetonitrile + 0.5 mL 50% formic acid; Gradient: 0.0 min 90% A ⁇ * 2.5 min 30% A -> 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 mL / min, 2.5 min / 3.0 min / 4.5 min 2 mL / min; Oven: 5O 0 C; UV detection: 210 nm.
- Method 7 Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 L water + 0.5 mL 50% formic acid, eluent B: 1 L acetonitrile + 0.5 mL 50% formic acid; Gra ⁇ serves: 0.0 min 90% A -> 2.5 min 30% A -> 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 mL / min, 2.5 min / 3.0 min / 4.5 min 2 mL / min; Oven: 5O 0 C; UV detection: 210 nm.
- Method 8 (Analytical HPLC): Device Type HPLC: HP 1050 Series; UV DAD 1100 Series; Column: Kromasil Ci 8 , 60 ⁇ 2 mm, 3.5 ⁇ m; Eluent A: water / 0.5% perchloric acid, eluent B: acetonitrile; Gradient: 0-0.5 min 2% B, 0.5-4.5 min 2-90% B, 4.5-9.0 min 90% B, 9.0-9.2 min 90-2% B, 9.2-10.0 min 2% B; Flow: 0.75 mL / min, oven: 30 ° C., UV detection 210 nm.
- Method 9 (analytical HPLC, Agilent Zorbax C 8 ): Device: Agilent 1100 with DAD (GI 315B), binary pump (G1312A), autosampler (G1313A), solvent degasser (G1379A) and column thermostat (G1316A); Column: Agilent Zorbax Eclipse XDB-C8 4.6 x 150 x 5 mm; Eluent A: 0.05% 70% perchloric acid in water; Eluent B: acetonitrile; Gradient: 0-1 min 10% B, ramp, 4-5 min 90% B, ramp, 5.5 min 10% B; Flow: 2.00 mL / min; Column temperature: 3O 0 C.
- Method 11 (Preparative HPLC Symmetry): Device: Gilson Abimed HPLC; binary pump system; Column: SymmetryPrep TM C 18 , Waters, 7 ⁇ m; 300mm x 19mm; Eluent A: water / 0.2% trifluoroacetic acid, eluent B: acetonitrile; Gradient: 0-10 min 15-65% B, then regeneration of the chromatography column; Flow: 25 mL / min; UV detection 210 nm.
- Method 12 (Preparative HPLC Kromasil): Device: Gilson Abimed HPLC; binary pump system; Column: Kromasil Ci 8 , 5 ⁇ m, 100 A, 250 ⁇ 20 mm; Eluent A: 0.05% trifluoroacetic acid in water, eluent B: 0.05% trifluoroacetic acid in acetonitrile; Gradient: 0-3 min 10% B, ramp, 30-38 min 90% B, 38-45 min 10% B; Flow: 20 mL / min; UV detection 210 nm.
- Method 13 (Preparative HPLC Waters Symmetry): Device: Gilson Abimed HPLC; binary pump system; Column: Waters Symmetry-Prep TM Ci 8 , 7 ⁇ m, 300 x 19 mm; Eluent A: 0.05% trifluoroacetic acid in water, eluent B: 0.05% trifluoroacetic acid in acetonitrile; Gradient: 0-3 min 10% B, ramp, 30-38 min 90% B, 38-45 min 10% B; Flow: 20 mL / min; UV detection 210 nm.
- Method 14 (preparative HPLC): Device: Gilson Abimed HPLC; binary pump system; Column: Waters Symmetry-Prep TM Ci 8 , 7 ⁇ m, 300 x 19 mm; Eluent A: water / 0.2% trifluoroacetic acid, eluent B: acetonitrile; Gradient: 0-10 min 25-65% B, then regeneration of the chromatographic column; Flow: 25 mL / min; UV detection 210 nm.
- Method 15 Chiral HPLC Daicel Chiralpak: Agilent 1100 HPLC; Column: Daicel Chiralpak AD-H 5 ⁇ m; 250 x 20 mm; isocratic: 75% hexane, 25% 2-propanol with 0.2% trifluoroacetic acid and 1% water; Flow: 1.0 mL / min; Oven: 25 ° C; UV detector 212 nm.
- Method 16 (Preparative HPLC): Device: Gilson Abimed HPLC; binary pump system; Column: YMC ODS-AQ 5 ⁇ m, 250 x 30 mm; Eluent A: 0.05% trifluoroacetic acid in water, eluent B: 0.05% trifluoroacetic acid in acetonitrile; Gradient: 0-3 min 10% B, ramp, 30-38 min 90% B, 38- 45 min 10% B; Flow: 50 mL / min; UV detector 210 nm.
- Method 17 Instrument: Micromass GCT, GC6890; Column: Restek RTX-35MS, 30 m ⁇ 250 ⁇ m ⁇ 0.25 ⁇ m; Gradient: 60 0 C (0.30 keep min), 50 ° C / min ⁇ 12O 0 C, 16 ° C / min ⁇ 25O 0 C, C / min ⁇ C (hold 1.7 min) 300 30 ° 0; constant flow with helium: 0.88 mL / min; Oven: 60 ° C; Let: 25O 0 C.
- Method 19 (HPLC): Column: Kromasil RP-18, 60 mm ⁇ 2 mm, 3.5 ⁇ m; Eluent A: 5 mL HCIO 4 / I water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9 min 90% B; Flow: 0.75 mL / min; Oven: 3O 0 C; UV detection: 210 nm.
- Method 20 (HPLC): Column: Kromasil RP-18, 250 mm x 4 mm, 5 ⁇ m; Eluent A: 5 mL HClO 4 /! Water, eluent B: acetonitrile; Gradient: 0 min 5% B, 10 min 95% B; Flow: 1 mL / min; Oven: 40 ° C; UV detection: 210 nm.
- Method 21 (HPLC): Column: Kromasil RP-18, 250 mm x 4 mm, 5 ⁇ m; Eluent A: 2 mL HCIO 4 / l water, eluent B: acetonitrile; Isocratic: 45% B, 55% A; Flow: 1 mL / min; Oven: 4O 0 C; UV detection: 210 nm.
- Method 22 Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Grom-Sil 120 ODS-4 HE 50 ⁇ 2 mm, 3.0 ⁇ m; Eluent A: water / 0.025% formic acid / l, eluent B: acetonitrile / 0.025% formic acid; Gradient: 0-2.9 min 0-70% B, 2.9-3.1 min 70-90% B, 3.1-4.5 min 70-90% B; Oven: 5O 0 C, flow: 0.8 mL / min, UV detection: 210 nm.
- Method 23 Device Type HPLC: HP 1050 Series; UV DAD 1100 Series; Column Symmetry-Prep TM Ci 8 , Waters, 50 x 2.1 mm, 3.5 ⁇ m; Eluent A: water / 0.05% trifluoroacetic acid, eluent B: acetonitrile; Gradient: 0-9 min 0-100% B, 9-11 min 100% B, 11-12 min 100-0% B, subsequent regeneration of the chromatography column; Oven: 4O 0 C, flow: 0.4 mL / min, UV detection: 210 nm.
- Method 24 Quantitative 19 F-NMR Spectroscopy: Approximately 10 mg of sample substance weighed in exactly and approximately 20 mg of 1,4-dibromotetrafluorobenzene weighed in exactly are dissolved in pyridine and measured by 19 F-NMR spectroscopy, ⁇ -74 (cf. TFA) and -132.0 (1,4-dibromotetrafluorobenzene) are integrated and compared. The TFA content is expressed in percent TFA of the mass of the sample substance.
- Method 25 Ion Chromatography: Ion chromatography system with suppressor system and conductivity detector; Guard column: A SUPP 4/5 Guard, separation column: A SUPP 5 4.0 x 250 mm; Eluent: 3.2 mM sodium carbonate and 2.4 mM sodium bicarbonate in water; Flow: 0.7 mL / min.
- the sample is dissolved in methanol (20% of the final sample volume), treated in an ultrasonic bath for 3 minutes and made up with water.
- the sample is filtered through an ion-free cellulose acetate filter (Por 0.45 ⁇ m) and injected. Quantification against external standards (0.5 mg / L - 10 mg / L).
- YM Yeast Malt Agar: D-glucose (4 g / l), yeast extract (4 g / l), malt extract (10 g / l), 1 liter of Lewatit water. Before sterilization (20 minutes at 121 0 C), the pH is adjusted to 7.2.
- HPM mannitol (5.4 g / L), yeast extract (5 g / L), meat peptone (3 g / L).
- the lyophilized strain (ATCC 53042) is grown in 50 mL YM medium.
- Piston Fermentation Inoculate 150 mL of YM medium or 100 mL of HPM medium in a 1 L Erlenmeyer flask with 2 mL of the working fluid and allow to grow for 30-48 hours at 28 0 C on a shaker at 240 rpm.
- 30 L fermentation 300 mL of the piston fermentation (HPM medium) are used to inoculate a sterile 30 L culture medium solution (1 mL antifoam SAG 5693/1). This culture is wm for 21 hours at 28 0 C, 300 rpm and aeration with sterile air of 0.3 grown.
- YM sterile 200 L culture media solution
- the culture broth of the main culture is separated at 17000 rpm in supernatant and sediment.
- the supernatant (183 L) is adjusted to pH 6.5-7 with concentrated trifluoroacetic acid or sodium hydroxide solution and applied to a Lewapol column (OC 1064, 60 L content). The mixture is then eluted with pure water, water / methanol 1: 1 and then with pure methanol (with 0.1% trifluoroacetic acid). This organic phase is concentrated in vacuo to a remaining aqueous residue of 11.5 L.
- aqueous phase is bound to silica gel Cig and separated (MPLC, Biotage Flash 75, 75 ⁇ 30 cm, KP-C18-WP, 15-20 ⁇ m, flow: 30 mL, eluent: acetonitrile / water with 0.1% trifluoroacetic acid, gradient : 10%, 15% and 40% acetonitrile).
- MPLC Biotage Flash 75, 75 ⁇ 30 cm, KP-C18-WP, 15-20 ⁇ m, flow: 30 mL, eluent: acetonitrile / water with 0.1% trifluoroacetic acid, gradient : 10%, 15% and 40% acetonitrile).
- the 40% acetonitrile phase containing the majority of Example IA is concentrated in vacuo and then lyophilized (about 13 g).
- Example IA This process provides 2250 mg of Example IA.
- the solvent is concentrated in vacuo and the residue is freeze-dried.
- the lyophilizate obtained (89.9 g) is taken up in methanol, filtered off, concentrated and separated on silica gel (Method 21).
- Example IA is then purified by gel filtration (Sephadex LH-20, 5 ⁇ 68 cm, water / acetonitrile 9: 1 (with 0.05% trifluoroacetic acid), flow: 2.7 mL / min, fraction size 13.5 mL) to give the pure substance.
- Lysobactin bistrifluoroacetate (60.0 g, 39.88 mmol) is dissolved under argon atmosphere in pyridine (840 WLL). Then phenylisothiocyanate (32.35 g, 239.28 mmol, 6 equivalents) is added ben and the reaction mixture is stirred at 37 ° C for 7 h. Subsequently, the solvent is distilled off on a rotary evaporator at 4O 0 C bath temperature. The residue is treated with methyl tert-butyl ether (1400 ml) and stirred vigorously for 30 min. Then it is filtered off with suction through a glass frit (pore width 3, 13 cm diameter). The intermediate product (Edman OJ degradation product) is isolated in a crude yield of 72 g and further reacted without workup.
- the crude product is dissolved under argon atmosphere in trifluoroacetic acid (1026 mL) and stirred at RT for 30 min. Then the solution is concentrated on a rotary evaporator under vacuum at 2O 0 C bath temperature. The residue is taken up in methyl tert-butyl ether (1400 ml) and stirred vigorously until a powdery amorphous solid is formed. This is filtered off with a vacuum over a frit (pore width 3, 18 cm in diameter). The solid is then stirred with diethyl ether (1400 ml) and filtered off again. The same procedure is repeated with 2 portions of dichloromethane (900 mL each). The crude product is dried in vacuo. This gives 58 g of crude des (lD-leucyl) -lysobactin-bis-trifluoroacetate (Edman , o degradation product).
- the intermediate product ( Edman® 5 -degradation product) is isolated in a crude yield of 65 g and, after drying in an oil pump vacuum, dissolved directly under argon atmosphere in trifluoroacetic acid (1240 mL) and stirred at RT for 30 min. Then, the solution is Lö ⁇ on a rotary evaporator under vacuum at 20 0 C. bath temperature concentrated. The residue is taken up in methyl tert-butyl ether (1400 ml) and stirred vigorously until a pulverulent amorphous solid is formed. This is filtered off with a vacuum over a frit (pore width 3, 18 cm in diameter).
- X 1113x (qualitative) 220 nm (s), 255-270 (w).
- 6-Trifluoromethylpyridine-3-carbaldehyde (4.85 g, 27.70 mmol) and methyl ⁇ [(benzyloxy) carbonyl] amino] (dimethoxyphosphoryl) acetate (9.17 g, 27.70 mmol, 1.0 equiv.) Are dissolved in THF (70 mL ) and cooled to -70 0 C.
- N, N, N-tetramethylguanidine (6:38 g, 55.39 mmol, 6.95 mL, 2.0 equivalents) was added dropwise slowly and then stirred for 4 h then at -70 0 C for 12 h at RT.
- Example 3A The compound of Example 3A (10.15 g, 26.69 mmol) is dissolved in methanol (10 mL). With a cannula, argon is passed through for about 5 minutes, then (+) - l, 2-bis - [(2> S r , 5 ) S) diethylphospholano] benzene (cyclooctadiene) rhodium (I) triflate (289 mg , 400 ⁇ mol 0.015 equivalent). It is hydrogenated for 12 h at 4 bar hydrogen pressure and RT. It is then filtered through Kie selgur (methanol) and the eluate is concentrated. The crude product is chromatographed (Kie selgel, eluent: toluene / ethyl acetate 5: 1). There are obtained 9.9 g (97% of theory) of the title compound.
- Example 4A The compound from Example 4A (9.90 g, 25.89 mmol) is dissolved in methanol (100 mL). With a cannula, argon is passed for about 5 minutes, then Pd on charcoal (10%, 990 mg) is added. It is hydrogenated for 12 h at 4 bar hydrogen pressure and RT. It is then filtered through kieselguhr, concentrated and dried in an oil pump vacuum. Yield: 5.8 g (90% of theory) of the title compound.
- IR v max (NaCl, cm -1 ): 2959, 1742, 1655, 1520, 1336, 1160, 1136, 1087, 1050, 1027.
- Example 2A To a solution of the compound from Example 2A (7.00 g, 1.0 equivalents, 5.48 mmol) and Example 7A (3.03 g, 1.2 equivalents, 6.57 mmol) in dry DMF (119 mL) at -3O 0 C slowly N-methylmorpholine (2.77 g, 3.01 mL, 5 eq, 27.38 mmol) and HATU (4.37 g, 2.1 eq, 11.50 mmol). The reaction mixture warmed slowly to RT (about 1 h), with complete conversion being observed by means of HPLC / UV-Vis (Method 9). The reaction is quenched with potassium dihydrogen phosphate (7.45 g, 10.0 equivalents, 54.76 mmol).
- reaction mixture is purified by gel chromatography (method 10, eluent methanol / acetone 4: 1) to give 12.63 g (quant.) Product.
- HPLC / UV-Vis (Method 8): R 4 4.78 min.
- Example I IA The compound from Example I IA (11.8 g, 42.09 mmol) is dissolved in trifluoroacetic acid in dichloromethane (160 mL, 30% solution) and 30 min. stirred at RT. Then you narrow in a vacuum. The residue is taken up in a little water and lyophilized. The lyophilizate is then treated with toluene and concentrated in vacuo. Finally, it is dried to constant weight in an oil pump vacuum. Yield: 17.15 g (quant).
- Example 9A The compound from Example 9A (10.31 g, 39.4 mmol) and the compound from Example 12A (16.10 g, 39.4 mmol, 1 equivalent) are dissolved at 0 ° C. in DMF (186 ml). Then N-methylmorpholine (17.34 mL, 16.00 g, 4 equiv) and HATU (22.49 g, 59.16 mmol, 1.5 equiv) are added. The batch is stirred for two hours at RT. It is mixed with tert-butyl methyl ether and washed with saturated sodium carbonate solution.
- aqueous phase is back-extracted once with tert-butyl methyl ether, then the combined organic phases are washed with 1 M aqueous citric acid and again with saturated sodium carbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. It is filtered through silica gel (cyclohexane / ethyl acetate 2: 1). Yield: 14.1 g (84% of theory).
- Example 13A The compound from Example 13A (7.4 g, 17:56 mmol) in THF / water (6: 4) was added, cooled to 0 0 C, and (g 1:47, 35.13 mmol, 2 equivalents) of lithium hydroxide monohydrate is ver ⁇ . The mixture is stirred at 0 ° C. After one hour, another equivalent (0.74 g) of lithium hydroxide monohydrate is added and the mixture is stirred for a further hour. The majority of the THF is distilled off in vacuo, washed with two portions of methyl tert-butyl ether and then the aqueous phase is adjusted to pH 4 by addition of citric acid. A solid precipitates out.
- Example 2A The compound from Example 2A (3.00 g, 2.35 mmol) and the compound from Example 14A (1.44 g, 3.52 mmol, 1.5 equivalents) are dissolved in DMF (50 mL) and cooled to 0 ° C. Then, firstly 4.7 mL (4.7 mmol, 2 equivalents) of a 1 M solution of 4-methylmorpholine in DMF are added. Subsequently, HATU (1.52 g, 3.99 mmol, 1.7 equivalents) is added immediately and stirred at 0 ° C. for 15 min. Then another 4.7 mL (4.7 mmol, 2 equivalents) of the 1 M solution of 4-methylmorpholine in DMF are added dropwise. The batch is then stirred for 2 h at RT. The crude product is gel-chromatographed (Method 3). The product is further reacted without fine cleaning. Yield: 3.6 g (82% of theory).
- 2,2-Dimethyl-1-butanol (4.0 g, 39 mmol) is dissolved in dichloromethane (136 mL) and washed with alumina (7.98 g, 78 mmol, 2 equivalents) and with pyridinium chlorochromate (16.88 g, 78 mmol, 2 Equivalents). The batch is stirred at RT for 1 h and then filtered through a layer of silica gel. The filtrate is carefully concentrated and the residue is distilled at normal pressure (boiling point: 102 0 C (990 mbar)). Yield: 2.97 g (75% of theory).
- Example 19A The compound from Example 19A (430 mg, 1.47 mmol) and the compound from Example 12A (809 mg, 1.47 mmol, 1 equivalent) are dissolved at 0 ° C. in DMF (5 mL), then 4- Methylmorpholine (644 .mu.l, 5.86 mmol, 4 equivalents) and HATU (836 mg, 2.20 mmol, 1.5 equivalents) was added. The batch is stirred for three hours at RT. It is mixed with ethyl acetate and washed with saturated sodium bicarbonate solution.
- aqueous phase is extracted once with ethyl acetate, then the combined organic phases are washed with 1 M aqueous citric acid and again with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed (method 16). Yield: 496 mg (74% of theory).
- Example 2A The compound from Example 2A (0.28 g, 0.22 mmol) and the compound from Example 21A (148 mg, 0.33 mmol, 1.5 equivalents) are dissolved in DMF (4 mL) and cooled to 0 ° C. Then first 0.47 mL (0.44 mmol, 2 equivalents) of a 1 M solution of N-methylmorpholine in DMF is added. Then immediately HATU (141 mg, 0.37 mmol, 1.7 equivalents) was added and stirred at 0 0 C for 15 min. Then another 0.44 mL (0.47 mmol, 2 equivalents) of the 1 M solution of 4-methylmorpholine in DMF are added dropwise. The mixture is then stirred overnight at RT.
- Example 15A The compound from Example 15A (9.12 g, 4.93 mmol, crude product) is taken up in trifluoroacetic acid in dichloromethane (65 mL, 30% solution). The batch is stirred at RT for 20 min. The solvent is distilled off. The residue is dried in an oil pump vacuum and then purified by chromatography (Method 14). Yield: 5.54 g (67% of theory).
- the structure is confirmed by a single-crystal X-ray structure analysis.
- Example 2 3- (trimethylsilyl) -D-alanyl-3- (pyridin-3-yl) -L-alanyl-des (ID-leucyl-2-L-leucyl) -lysobactin tris-trifluoroacetate (Example 2) dissolved in 90 mL of water and the solution was abandoned and slowly eluted. The column is refilled with approx. 20 mL of water. flushes. Product-containing eluates are combined, finely filtered (pore size 0.20 ⁇ m) and lyophilized. The column is conditioned again and reused. This gives 1.79 g (1.10 mmol, 92% of theory) of Example 3 from 2000 mg (1.19 mmol) of Example 2.
- Example 22A The compound from Example 22A (149 mg, 0.09 mmol) is dissolved in methanol / containing 0.05% trifluoroacetic acid (10 mL). Palladium on activated carbon (10%, 20 mg) is added, then a total of 2.5 h is hydrogenated at RT and atmospheric pressure with hydrogen. The crude product is filtered off from the catalyst and the filtrate is concentrated. The residue is purified by chromatography (Method 13). Yield: 68 mg (46% of theory).
- Example 2 2.00 g (1.19 mmol) of 3- (trimethylsilyl) -D-alanyl-3- (pyridin-3-yl) -L-alanyl-des (ID-leucyl-2-L-leucyl) -lysobactin tris-trifluoroacetate (Example 2) dissolved in 90 mL of water and the solution was abandoned and slowly eluted. The column is rinsed with approx. 20 mL of water. Product-containing eluates are combined, finely filtered (pore size 0.20 ⁇ m) and lyophilized. The column is conditioned again and reused. This gives 1.54 g (1.06 mmol, 89% of theory) of Example 6 from 2000 mg (1.19 mmol) of Example 2.
- Example 7 is obtained from 2000 mg (1.19 mmol) of Example 2.
- Example 2 100 mg (59 ⁇ mol) of Example 2 are then dissolved in 10 mL of water and applied to the column. Then it is washed in several portions of about 10 mL of water. The educt dissolves only moderately and remains partly on the column. Product-containing eluate fractions are combined and lyophilized. 57 mg (31 ⁇ mol, 52% of theory) of the product are obtained.
- the integration of the 1 H-NMR spectrum indicates a stoichiometry 1: 3 for (trimethylsilyl) -D-alanyl-3- (pyridin-3-yl) -L-alanyl-des (ID-leucyl-2-L-leucyl) -lysobactin: D-tartaric acid.
- Example 3 By recrystallization of Example 3 from TFA-doped water at RT, the title compound can be obtained as a crystalline substance (slow evaporation of the solution).
- the MIC is determined in the liquid dilution test according to the NCCLS guidelines. Overnight cultures of Staphylococcus aureus 133, Entercococcus faecalis 27159, E. faecium 4147 and Streptococcus pneumoniae G9a are incubated with the described test substances in a 1: 2 dilution series. The MIC determination is carried out with a cell count of 10 5 germs per 1 ml in Iso-sensitest medium (Difco Co., Irvine / USA), with the exception of S. pneumoniae, which is in BHI broth (Difco, Irvine / USA) is tested with 10% bovine serum at a cell count of 10 6 germs per mL. The cultures are incubated at 37 ° C for 18-24 hours, S. pneumoniae in the presence of 10% CO 2 .
- the lowest substance concentration at which no visible bacterial growth occurs is defined as MIC.
- the MIC values are given in ⁇ g / mL.
- S. aureus 133 cells are grown overnight in BHI broth (Oxoid, New York / USA). The overnight culture is diluted 1: 100 in fresh BHI broth and incubated for 3 hours. The cells, which are then in the logarithmic growth phase, are centrifuged off and washed twice with buffered physiological saline. Thereafter, a cell suspension in saline solution with an extinction of 50 units is adjusted by photometry. After a dilution step (1:15), this suspension is mixed 1: 1 with a 10% mucin solution. 0.25 ml / 20 g of mouse are administered intraperitoneally from this infectious solution (corresponding to 1 ⁇ 10 6 germs / mouse). Therapy is intraperitoneal or intravenous 30 minutes after infection. For the infection experiment, female CFW1 mice are used. The survival of the animals is recorded over 6 days.
- Nephrotoxic side effects of nonadepsipeptides are analyzed by histopathological investigations of the kidneys in mice after repeated administration of a specific dose. 5-6 animals are treated daily either intravenously (iv) or intraperitoneally (ip) with substances which are dissolved in aqueous solution or with the addition of solutol. Kidney toxic effects are determined by light microscopic analysis of hematoxylin and eosin (H & E) stained paraffin sections of the kidneys. A Periodic Acid Schiff (PAS) reaction is optionally carried out to better display glycoproteins.
- PAS Periodic Acid Schiff
- Nephrotoxic side effects of the nonadepsipeptides are analyzed by histopathological investigations of the kidneys in rats after repeated administration of a specific dose. For this purpose, 5 animals are treated intravenously (i.v.) daily with substances which are dissolved in saline or Ringer's lactate solution. Kidney toxic effects are determined by light microscopic evaluation of hematoxylin and eosin (H & E) stained paraffin sections of the kidneys. A periodic acid Schiff (PAS) reaction is optionally carried out for the better presentation of glycoproteins.
- PAS periodic acid Schiff
- the average severity of tubular degeneration / regeneration and the incidence (number of affected animals) are calculated per animal group or derivative. Beyond kidney changes such as tubular dilatation and necrosis and accumulation of necrotic material are also listed.
- the plasma is usually diluted with isotonic phosphate-buffer (pH 7.4) and then suspended with Transil ®.
- the determination of f u '(free fraction in diluted plasma) in this diluted protein solution is carried out analogously to the determination of f u .
- the free fraction in undiluted plasma is calculated from f u 'and the dilution factor. Comparison to this method also: Schuhmacher, Joachim; Kohlsdorfer, Christian; Buehner, Klaus; Brandenburger, Tim; Kruk, Renate, "High-throughput determination of the free fraction of drugs bound to plasma proteins.” Journal of Pharmaceutical Sciences 2004, 93, 816-830.
- the mixtures are incubated for 30 min at room temperature, for example on a mini shaker at an angle of about 45 ° at about 400 rpm.
- at least one aliquot of, for example, 100 .mu.l is taken, the remaining batch is centrifuged for about 10 min at about 1800 g. From each sample, at least 2 aliquots (eg, 100 ⁇ l) of the supernatant are taken for concentration determination.
- Transil ® volume The total incubation and the added Transil ® volume will depend on the expected free fraction. In general, the total volume of 0.5 mL -1 is that Transil ® volume 10- 100 ul. In the case of very low free fractions of the plasma to be tested is Spe ⁇ zies with isotonic buffer solution, pH 7.4, for example, 10 -400fach diluted and then added with Tran ⁇ sil ®. The further procedure is as described above for the determination of the MAb Uffer values.
- the plasma of the species to be examined is filtered through a semipermeable membrane.
- the concentration of the substance in the filtrate is measured and from this the free fraction fu is calculated.
- the Centrifree micropartition system from Millipore / Amicon is used.
- the ultrafiltration membranes have an exclusion size of 30,000 Da.
- the substance is added to 1 mL plasma at a concentration of approx. 1 ⁇ g / mL.
- the solvent content should be ⁇ 2%.
- the plasma is pipetted into the ultrafiltration system and centrifuged for 10 minutes at 1800 g.
- the compounds according to the invention can be converted into pharmaceutical preparations as follows:
- Example 1 100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
- the mixture of active ingredient, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
- the granules are mixed after drying with the magnesium stearate for 5 min.
- This mixture is compressed with a conventional tablet press (for the tablet format see above).
- a pressing force of 15 kN is used as a guideline for the compression.
- a single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.
- the rhodigel is suspended in ethanol, the active ingredient is added to the suspension. While stirring, the addition of water. Until the swelling of the Rhodigels is complete, it is stirred for about 6 hours.
- Intravenously administrable solution
- Example 1 The compound of Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring.
- the solution is sterile-filtered (pore diameter 0.22 ⁇ m) and filled under aseptic conditions into heat-sterilized infusion bottles. These are closed with infusion stoppers and crimp caps.
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE102004053407A DE102004053407A1 (de) | 2004-11-05 | 2004-11-05 | Acylierte Nonadepsipeptide II |
PCT/EP2005/011363 WO2006048139A1 (de) | 2004-11-05 | 2005-10-22 | Acylierte nonadepsipeptide als lysobactinderivate |
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EP05798234A Withdrawn EP1807443A1 (de) | 2004-11-05 | 2005-10-22 | Acylierte nonadepsipeptide als lysobactinderivate |
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US (1) | US7531507B2 (ja) |
EP (1) | EP1807443A1 (ja) |
JP (1) | JP4843614B2 (ja) |
KR (1) | KR20070083984A (ja) |
CN (1) | CN101056887A (ja) |
AR (1) | AR053775A1 (ja) |
AU (1) | AU2005300815B2 (ja) |
BR (1) | BRPI0516677A (ja) |
CA (1) | CA2586704A1 (ja) |
CR (1) | CR9079A (ja) |
DE (1) | DE102004053407A1 (ja) |
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IL (1) | IL182739A (ja) |
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DE102004051024A1 (de) * | 2004-10-20 | 2006-04-27 | Bayer Healthcare Ag | Heterocyclyl-substituierte Nonadepsipeptide |
DE102004051023A1 (de) * | 2004-10-20 | 2006-05-04 | Bayer Healthcare Ag | Desoxo-Nonadepsipeptide |
DE102004051025A1 (de) * | 2004-10-20 | 2006-04-27 | Bayer Healthcare Ag | Substituierte Nonadepsipeptide |
DE102004053410A1 (de) * | 2004-11-05 | 2006-05-11 | Bayer Healthcare Ag | Cyclische Nonadepsipeptidamide |
DE102006003443A1 (de) * | 2006-01-25 | 2007-07-26 | Aicuris Gmbh & Co. Kg | Asparagin-10-substituierte Nonadepsipeptide |
DE102006018250A1 (de) * | 2006-04-13 | 2007-10-18 | Aicuris Gmbh & Co. Kg | Verfahren zum Herstellen von cyclischen Depsipeptiden |
DE102006018080A1 (de) * | 2006-04-13 | 2007-10-18 | Aicuris Gmbh & Co. Kg | Lysobactinamide |
TW201717991A (zh) | 2015-08-17 | 2017-06-01 | 拜耳動物保健有限公司 | 用於治療牛乳房炎之溶桿菌素 |
EP3363452A1 (en) * | 2017-02-17 | 2018-08-22 | Bayer Animal Health GmbH | Combinations of lysobactin and aminogylcosides against diseases caused by gram-positive and gram-negative bacteria in non-human animals |
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CA1266247C (en) | 1985-03-25 | 1990-02-27 | ANTIBIOTIC PREPARED BY LYSOBACTER SP. SC14.067 | |
JPH01132600A (ja) | 1987-11-17 | 1989-05-25 | Shionogi & Co Ltd | カタノシンaおよびbならびにその製造法 |
DE10320781A1 (de) * | 2003-05-09 | 2004-11-25 | Bayer Healthcare Ag | Acylierte Nonadepsipeptide |
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NO20072854L (no) | 2007-08-01 |
CR9079A (es) | 2007-08-28 |
BRPI0516677A (pt) | 2008-09-16 |
MA29218B1 (fr) | 2008-02-01 |
RU2007120686A (ru) | 2008-12-10 |
KR20070083984A (ko) | 2007-08-24 |
AU2005300815A1 (en) | 2006-05-11 |
PE20060942A1 (es) | 2006-10-20 |
GT200500308A (es) | 2006-06-02 |
HN2005030779A (es) | 2010-08-19 |
DE102004053407A1 (de) | 2006-05-11 |
CN101056887A (zh) | 2007-10-17 |
IL182739A0 (en) | 2007-07-24 |
JP2008518982A (ja) | 2008-06-05 |
RU2414477C2 (ru) | 2011-03-20 |
ZA200703674B (en) | 2008-09-25 |
WO2006048139A1 (de) | 2006-05-11 |
JP4843614B2 (ja) | 2011-12-21 |
UA89800C2 (en) | 2010-03-10 |
MY145448A (en) | 2012-02-15 |
TW200621799A (en) | 2006-07-01 |
US20060264358A1 (en) | 2006-11-23 |
AU2005300815B2 (en) | 2011-05-19 |
MX2007005382A (es) | 2007-08-14 |
AR053775A1 (es) | 2007-05-23 |
US7531507B2 (en) | 2009-05-12 |
UY29189A1 (es) | 2006-06-30 |
NZ554813A (en) | 2009-11-27 |
CA2586704A1 (en) | 2006-05-11 |
SV2006002290A (es) | 2006-10-13 |
IL182739A (en) | 2013-03-24 |
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