JP2008518982A - アシル化ノナデプシペプチドii - Google Patents
アシル化ノナデプシペプチドii Download PDFInfo
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- JP2008518982A JP2008518982A JP2007539492A JP2007539492A JP2008518982A JP 2008518982 A JP2008518982 A JP 2008518982A JP 2007539492 A JP2007539492 A JP 2007539492A JP 2007539492 A JP2007539492 A JP 2007539492A JP 2008518982 A JP2008518982 A JP 2008518982A
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- leucyl
- acid
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- 238000000034 method Methods 0.000 claims abstract description 144
- -1 3- (3-pyridyl) -alanyl group Chemical group 0.000 claims abstract description 57
- 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 claims abstract description 26
- 108010011530 lysobactin Proteins 0.000 claims abstract description 24
- 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 claims abstract description 24
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- 150000001875 compounds Chemical class 0.000 claims description 109
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- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 22
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 17
- 241001465754 Metazoa Species 0.000 claims description 13
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
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- 239000002904 solvent Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
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- 238000012360 testing method Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
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- 239000007821 HATU Substances 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000011148 porous material Substances 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
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 235000015165 citric acid Nutrition 0.000 description 7
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- 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
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 6
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- 208000037942 Methicillin-resistant Staphylococcus aureus infection Diseases 0.000 description 1
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- 239000001888 Peptone Substances 0.000 description 1
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- 241000191992 Peptostreptococcus Species 0.000 description 1
- 206010034839 Pharyngitis streptococcal Diseases 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
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- 241000606701 Rickettsia Species 0.000 description 1
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- 241000607720 Serratia Species 0.000 description 1
- 241000607715 Serratia marcescens Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000589886 Treponema Species 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000006374 Uterine Cervicitis Diseases 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000025255 bacterial arthritis Diseases 0.000 description 1
- 201000009904 bacterial meningitis Diseases 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 206010008323 cervicitis Diseases 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000019258 ear infection Diseases 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000009112 empiric therapy Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 208000029182 enterotoxemia Diseases 0.000 description 1
- 208000020612 escherichia coli infection Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 208000020426 gonococcal urethritis Diseases 0.000 description 1
- 244000000059 gram-positive pathogen Species 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- CJNBYAVZURUTKZ-UHFFFAOYSA-N hafnium(IV) oxide Inorganic materials O=[Hf]=O CJNBYAVZURUTKZ-UHFFFAOYSA-N 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000022760 infectious otitis media Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000001023 inorganic pigment Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical class C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 108010039179 katanosin A Proteins 0.000 description 1
- 229940116871 l-lactate Drugs 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- RXODQKWWQKRIDH-CQSZACIVSA-N methyl (2r)-4,4-dimethyl-2-(phenylmethoxycarbonylamino)hexanoate Chemical compound CCC(C)(C)C[C@H](C(=O)OC)NC(=O)OCC1=CC=CC=C1 RXODQKWWQKRIDH-CQSZACIVSA-N 0.000 description 1
- BPLHXQWGULLXMO-LSDHHAIUSA-N methyl (2s)-2-[[(2r)-4,4-dimethyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoyl]amino]-3-[6-(trifluoromethyl)pyridin-3-yl]propanoate Chemical compound CC(C)(C)OC(=O)N[C@H](CC(C)(C)C)C(=O)N[C@H](C(=O)OC)CC1=CC=C(C(F)(F)F)N=C1 BPLHXQWGULLXMO-LSDHHAIUSA-N 0.000 description 1
- HIKBKVKOBSMUOR-ZROIWOOFSA-N methyl (z)-2-(phenylmethoxycarbonylamino)-3-[6-(trifluoromethyl)pyridin-3-yl]prop-2-enoate Chemical compound C=1C=C(C(F)(F)F)N=CC=1/C=C(C(=O)OC)\NC(=O)OCC1=CC=CC=C1 HIKBKVKOBSMUOR-ZROIWOOFSA-N 0.000 description 1
- WTGLUWUWVAUYIQ-KAMYIIQDSA-N methyl (z)-4,4-dimethyl-2-(phenylmethoxycarbonylamino)hex-2-enoate Chemical compound CCC(C)(C)\C=C(C(=O)OC)/NC(=O)OCC1=CC=CC=C1 WTGLUWUWVAUYIQ-KAMYIIQDSA-N 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 235000019645 odor Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 238000005375 photometry Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- KKVTYAVXTDIPAP-UHFFFAOYSA-M sodium;methanesulfonate Chemical compound [Na+].CS([O-])(=O)=O KKVTYAVXTDIPAP-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229940037649 staphylococcus haemolyticus Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
R1は水素を表し、
R2は、2,2−ジメチルブタ−1−イル、2−エチル−2−メチルブタ−1−イル、2,2−ジエチルブタ−1−イル、2,2−ジメチルペンタ−1−イルまたはトリメチルシリルメチルを表すか、または
R1はトリフルオロメチルを表し、
R2は、2,2−ジメチルプロパ−1−イル、2,2−ジメチルブタ−1−イル、2−エチル−2−メチルブタ−1−イル、2,2−ジエチルブタ−1−イル、2,2−ジメチルペンタ−1−イルまたはトリメチルシリルメチルを表す]
で示される化合物およびそれらの塩、それらの溶媒和物またはそれらの塩の溶媒和物に関するものである。
R1が水素を表し、
R2が、2,2−ジメチルブタ−1−イルまたはトリメチルシリルメチルを表すか、または
R1がトリフルオロメチルを表し、
R2が、2,2−ジメチルプロパ−1−イル、2,2−ジメチルブタ−1−イルまたはトリメチルシリルメチルを表す
場合の化合物およびそれらの塩、それらの溶媒和物およびそれらの塩の溶媒和物である。
R1が水素を表し、
R2が、2,2−ジメチルブタ−1−イル、2−エチル−2−メチルブタ−1−イル、2,2−ジエチルブタ−1−イルまたはトリメチルシリルメチルを表す
場合の化合物およびそれらの塩、それらの溶媒和物またはそれらの塩の溶媒和物である。
R1が水素を表し、
R2が、2,2−ジメチルブタ−1−イル、2−エチル−2−メチルブタ−1−イル、2,2−ジエチルブタ−1−イル、2,2−ジメチルペンタ−1−イルまたはトリメチルシリルメチルを表す
場合の化合物である。
R1およびR2は前記の意味を有し、X1は、ハロゲン、好ましくは臭素、塩素またはフッ素、またはヒドロキシを表す]
で示される化合物と反応させる、式(I)の化合物の製造方法に関するものである。
ブタ:下痢、腸性毒血症、敗血症、赤痢、サルモネラ症、乳腺炎−子宮炎−アガラクシア症候群、乳腺炎;
反芻動物(ウシ、ヒツジ、ヤギ):下痢、敗血症、気管支肺炎、サルモネラ症、パスツレラ症、生殖器感染症;
ウマ:気管支肺炎、子ウマの関節炎、産褥および産褥後感染症、サルモネラ症;
イヌおよびネコ:気管支肺炎、下痢、皮膚炎、耳炎、尿路感染症、前立腺炎;
家禽(ニワトリ、七面鳥、ウズラ、ハト、観賞用鳥類など):エシェリキア・コリ(E.coli)感染症、慢性気道疾患、サルモネラ症、パスツレラ症、オウム病。
ペプチドおよびシクロペプチドの命名法については、下記参照:
1.A Guide to IUPAC Nomenclature of Organic Compounds(Recommendations 1993)、1993、ブラックウェル・サイエンティフィック・パブリケーションズ。
2.Nomenclature and symbolism for amino acids and peptides.Recommendations 1983.IUPAC-IUB Joint Commission on Biochemical Nomenclature、イギリス国、Biochemical Journal、1984、219、345−373、および引用文献。
方法1(TOF−HR−MS):Micromass LCT器具(キャピラリー電圧:3.2KV、コーン電圧:42V、ソース温度:120℃、デソルベーション(脱溶媒和)温度:280℃)を用いて、TOF−HR−MS−ESI+スペクトルを記録する。この目的のため、シリンジポンプ(Harvard Apparatus)を試料導入に用いる。ロイシンエンセファリン(Tyr−Gly−Gly−Phe−Leu)を標準として用いる。
実施例1A
D−ロイシル−N1−{(3S,6S,12S,15S,18R,21S,24S,27S,28R)−6−[(1S)−2−アミノ−1−ヒドロキシ−2−オキソエチル]−18−(3−{[アミノ(イミノ)メチル]アミノ}プロピル)−12−[(1S)−1−ヒドロキシエチル]−3−(ヒドロキシメチル)−24−[(1R)−1−ヒドロキシ−2−メチルプロピル]−21−イソブチル−15−[(1S)−1−メチルプロピル]−2,5,8,11,14,17,20,23,26−ノナオキソ−28−フェニル−1−オキサ−4,7,10,13,16,19,22,25−オクタアザシクロオクタコサン−27−イル}−L−ロイシンアミドビストリフルオロアセテート(リソバクチン)
培養培地:
YM:酵母−麦芽寒天:D−グルコース(4g/l)、酵母抽出物(4g/l)、麦芽抽出物(10g/l)、1リットルの Lewatit 水。滅菌(121℃で20分)前、pHを7.2に調節する。
HPM:マンニトール(5.4g/l)、酵母抽出物(5g/l)、肉ペプトン(3g/l)。
実験用保存材料:凍結乾燥株(ATCC53042)を、50mlのYM培地中で生育する。
上清(183リットル)を、濃トリフルオロ酢酸または水酸化ナトリウム溶液を用いてpH6.5〜7に調節し、Lewapol カラム(OC 1064、60リットル含有量)にローディングする。それに続いて、純水、水/メタノール1:1、次いで純メタノール(0.1%トリフルオロ酢酸含有)で溶離を実施する。この有機相を真空下、残留する水性残さが11.5リットルとなるまで濃縮する。
この工程により、447mgの実施例1A生成物を得る。
HPLC(方法18):Rt=6.19分(min)
MS (ESIpos): m/z = 1277 (M+H)+
1H NMR (500.13 MHz, d6−DMSO): δ = 0.75 (d, 3H), 0.78 (d, 6H), 0.80 (t, 3H), 0.82 (d, 3H), 0.90 (d, 3H), 0.91 (d, 3H), 0.92 (d, 3H), 0.95 (d, 3H), 0.96 (d, 3H), 1.05 (m, 1H), 1.19 (d, 3H), 1.25 (m, 2H), 1.50 (m, 4H), 1.51 (m, 2H), 1.55 (m, 1H), 1.61 (m, 1H), 1.65 (m, 1H), 1.84 (m, 1H), 1.85 (m, 1H), 1.86 (m, 1H) , 1.89 (m, 1H), 1.95 (m, 1H), 2.75 (m, 2H), 3.40 (m, 1H), 3.52 (m, 2H), 3.53 (dd, 1H), 3.64 (m, 2H), 3.66 (m, 1H), 3.68 (dd, 1H), 3.73 (m, 2H), 4.00 (dd, 1H), 4.02 (br., 1H), 4.13 (br., 1H), 4.32 (dd, 1H), 4.39 (t, 1H), 4.55 (m, 1H), 4.75 (dd, 1H), 5.19 (t, 1H), 5.29 (d, 1H), 5.30 (br., 1H), 5.58 (m, 2H), 6.68 (m, 3H), 6.89 (d, 1H), 6.93 (m, 3H), 6.94 (br., 1H), 6.98 (d, 1H), 7.12 (br., 1H), 7.20 (br., 2H), 7.23 (m, 2H), 7.42 (m, 2H), 7.54 (d, 1H), 7.58 (d, 1H), 8.32 (br., 1H), 9.18 (br., 1H), 9.20 (m, 2H), 9.50 (br., 1H)。
13C−NMR (125.77 MHz, d6−DMSO): δ = 10.3, 15.3, 19.0, 19.2, 19.6, 20.0, 20.9, 22.0, 22.4, 23.0, 23.2, 24.3, 24.4, 25.0, 25.4, 26.0, 27.8, 30.9, 35.4, 39.5, 40.8, 40.9, 41.6, 44.1, 51.5, 52.7, 55.9, 56.2, 56.4, 57.9, 58.8, 60.2, 61.1, 62.6, 70.1, 71.6, 71.7, 75.5, 128.1, 128.6, 136.7, 156.8, 168.2, 170.1, 170.4, 171.2, 171.5, 171.9, 172.2, 172.4, 173.7。
HPLC/UV-Vis(方法23):Rt= 4.71分、
λmax (定性的)= 220nm (s), 255-270(w)。
LC−MS(方法22): Rt=1.65分;
MS(ESIpos.): m/z(%)=526(100)[M+2H]2+, 1051(15)[M+H]+。
メチル・(2Z)−2−{[(ベンジルオキシ)カルボニル]アミノ}−3−(6−トリフルオロメチルピリジン−3−イル)アクリレート
HPLC/UV-Vis(方法8): Rt= 4.60分、
HPLC/UV-Vis(方法9): Rt= 4.54分。
1H-NMR (400 MHz, d6−DMSO): δ = 3.74 (s, 3H, OMe), 5.10 (s, 2H, CH2), 7.27 (s, 1H, PyrH), 7.33-7.38 (m, 5H, ArH), 7.94 (d,J=8.5 Hz, 1H, PyrH), 8.27 (d,J= 8.5 Hz, 1H, PyrH), 8.93 (s, 1H, β−CH), 9.51 (s, 1H, NH)。
LC−MS (方法7):Rt=2.44分; MS(ESIpos.): m/z(%)=381 (100) [M+H]+;MS(ESIneg.):m/z(%)= 379 (100)[M−H]-。
HR−TOF−MS (方法1): C18H16N2O4F3 [M+H]+ 計算値 381.1062, 実測値 381.1065。
N−[(ベンジルオキシ)カルボニル]−3−(6−トリフルオロメチルピリジン−3−イル)−L−アラニンメチルエステル
[α]20 Na=-24°(c=0.093、メタノール中).
HPLC/UV-Vis(方法8): Rt= 4.50分。
HPLC/UV-Vis(方法9): Rt= 4.49分.
1H-NMR (400MHz, d6-DMSO): δ = 2.99 (dd,J=3.5, 11.0Hz, 1H, β-CH), 3.22 (dd,J=3.5, 11.0Hz, 1H, β-CH), 3.66 (s, 3H, OMe), 4.40 (m, 1H, α-CH), 4.97 (s, 2H, CH2), 7.23 (m, 2H), 7.29-7.33 (m, 3H), 7.83 (d,J=6.5Hz, 1H), 7.93-7.98 (m, 2H), 8.65 (s, 1H, NH).
LC-MS (方法7): Rt=2.40分; MS (ESIpos.): m/z (%)=383 (100) [M+H]+; MS (ESIneg.): m/z (%)= 273 (100), 381 (50) [M−H]-.
HR−TOF−MS (方法1): C18H18N2O4F3 [M+H]+ 計算値 383.1219, 実測値 383.1223。
3−(6−トリフルオロメチルピリジン−3−イル)−L−アラニンメチルエステル
[α]19.9 Na=+3°(c=0.186 メタノール中)。
HPLC/UV−Vis(方法8): Rt=3.34分.
HPLC/UV−Vis(方法9): Rt=3.22分.
IR vmax (NaCl, cm-1): 3415, 1734, 1339, 1136, 1087.
1H-NMR (500MHz, d6-DMSO): δ = 2.85 (dd,J=5.5, 13.5Hz, 1H, β-CH), 3.01 (dd,J=5.5, 13.5Hz, 1H, β-CH), 3.61 (s, 3H, OMe), 3.63-3.69 (m, 1H, α-CH), 7.82 (d,J=7.5 Hz, 1H), 7.93 (d,J=7.5Hz, 1H), 8.61 (s, 1H)。
LC-MS (方法7): Rt=1.74分; MS (ESIpos.): m/z (%)=249 (100) [M+H]+。
HR-TOF-MS (方法1): C12H15N3O2F3 [M+ CH3CN+H]+ 計算値 290.1116, 実測値 290.1122。
N−(tert−ブトキシカルボニル)−3−(tert−ブチル)−D−アラニル−3−(6−トリフルオロメチルピリジン−3−イル)−L−アラニンメチルエステル
[α]19.9 Na=+7.0°(c=0.044 メタノール中).
HPLC/UV-Vis(方法8): Rt=4.89 分。
HPLC/UV-Vis(方法9): Rt=4.75 分。
IR vmax (NaCl, cm-1): 2959, 1742, 1655, 1520, 1336, 1160, 1136, 1087, 1050, 1027.
1H-NMR (500 MHz, d6-DMSO): δ = 0.74 (s, 9H, tBu), 0.97-1.00 (m, 1H, β−CH2), 1.20-1.25 (m, 1H, β−CH2), 1.35 (s, 9H, OtBu), 2.99-3.05 (m, 1H, β−CH2), 3.23-3.26 (m, 1H, β−CH2), 3.66 (s, 3H, OMe), 3.94 (m, 1H, α−CH), 4.60 (m, 1H, α−CH), 6.82 (d,J=8.5Hz, 1H, NH), 7.78 (d,J=8.0Hz, 1H, PyrH), 7.94 (d,J=8.0Hz, 1H, PyrH), 8.34 (d,J=8.5Hz, 1H, NH), 8.64 (s, 1H, PyrH)。
LC−MS (方法7): Rt=2.67分; MS (ESIpos.): m/z (%)=476 (100), [M+H]+; MS (ESIneg.): m/z (%)=400 (80), 474 (40) [M−H]-.
HR-TOF-MS (方法1): C22H33N3O5F3 [M+H]+ 計算値 476.2372、実測値 476.2364。
N−tert−ブトキシカルボニル−3−tert−ブチル−D−アラニル−3−(6−トリフルオロメチルピリジン−3−イル)−L−アラニン
[α]20 Na=+51.3°(c=0.402 メタノール中)。
HPLC/UV-Vis(方法8): Rt=4.63 分。
HPLC/UV-Vis(方法9): Rt=4.55 分。
IR vmax (NaCl, cm-1): 3305, 2959, 1663, 1519, 1336, 1173, 1134, 1086.
1H-NMR (500MHz, d6-DMSO): δ=0.77 (s, 9H, tBu), 1.06-1.13 (m, 1H, β−CH2), 1.23-1.26 (m, 1H, β−CH2), 1.34 (s, 9H, OtBu), 3.01 (tapp,J= 11.0Hz, 1H, β−CH2), 3.23 (br d、J=11.0Hz, 1H,β−CH2), 3.94 (t,J= 8.0Hz, 1H, α−CH), 4.42 (br s, 1H, α−CH), 6.90 (d,J=8.5Hz, 1H, NH), 7.74 (d,J=7.5Hz, 1H, PyrH), 7.86 (d,J=7.5Hz, 1H, PyrH), 8.00 (br s, 1H, NH), 8.56 (s, 1H, PyrH)。
LC−MS (方法7): Rt=2.42分; MS (ESIpos.):m/z(%)=406 (100), 462 (85) [M+H]+; MS (ESIneg.):m/z(%)= 460 (100) [M−H]-。
HR−TOF−MS(方法1): C21H31N3O5F3 [M+H]+ 計算値 462.2216, 実測値 462.2203。
N−tert−ブトキシカルボニル−3−tert−ブチル−D−アラニル−3−(6−トリフルオロメチルピリジン−3−イル)−L−アラニル−デ(1−D−ロイシル−2−L−ロイシル)リソバクチントリフルオロアセテート
HPLC/UV-Vis(方法8): Rt= 4.78分.
HPLC/UV-Vis(方法9): Rt= 4.35分.
LC-MS (方法7): Rt=2.28分; MS (ESIpos.):m/z(%)=697 (100) [M+2H]2+, 1493 (15) [M+H]+; MS (ESIneg.):m/z(%)=745 (100) [M - 2H]2-, 1491 (5) [M - H]-.
HR-TOF-MS (方法1): C67H104N16O19F3 [M+H]+ 計算値 1493.7616, 実測値 1493.7594。
(2S)−N−(tert−ブトキシカルボニル)−3−(トリメチルシリル)アラニンおよび(2R)−N−(tert−ブトキシカルボニル)−3−(トリメチルシリル)アラニン
M.Merget、K.Gunther、M.Bernd、E.Gunther、R.Tacke、J.Organomet.Chem.2001、628、183〜194に従って合成を行う。キラル相での分取HPLC:Gilson Abimed HPLC;カラム:Daicel Chiralpak AD−H 5μm;250×20mm;溶離液A:イソへキサン、溶離液B:0.2%酢酸/1%水/2−プロパノール;無勾配;流速:15ml/分;UV検出器212nmにより、鏡像体の分離を行う。N−(tert−ブトキシカルボニル)−L−3−トリメチルシリルアラニン(2R化合物、Mercachem、AMR39.260)の本物のサンプルとのHPLC比較により異性体を割当てる。
N−(tert−ブトキシカルボニル−D−3−トリメチルシリルアラニン(2S化合物)
[α]D 20= +1.1 (c= 0.83 メタノール中)。
N−(tert−ブトキシカルボニル)−L−3−トリメチルシリルアラニン(2R化合物)
[α]D 20= −1.6 (c=0.66 メタノール中)。
N−(tert−ブトキシカルボニル)−3−(ピリジン−3−イル)−L−アラニンメチルエステル
HPLC/UV-Vis(方法9): Rt=3.28 分。
LC−MS (方法7): Rt = 1.21分, MS (ESIpos.): m/z (%)= 281 (100) [M+H]+。
1H−NMR (400MHz, d6-DMSO): δ = 1.30 (s, 9H), 2.86 (m, 1H), 3.04 (m, 1H), 3.63 (s, 3H), 4.22 (m, 1H), 7.28 - 7.39 (m, 2H), 7.69 (d, 1H), 8.43 (m, 2H)。
3−(ピリジン−3−イル)−L−アラニンメチルエステルビストリフルオロアセテート
HPLC/UV-Vis(方法9): Rt=0.88 分。
LC−MS (方法7): Rt = 0.46分, MS(ESIpos.): m/z(%)=181 (100) [M+H]+。
1H−NMR (400MHz, d6-DMSO): δ =2.79 (dd, 1H), 2.92 (dd, 1H), 3.60 (s, 3H), 3.63 (m, 1H), 7.30 (m, 1H), 7.62 (d, 1H), 8.41 (m, 2H)。
N−(tert−ブトキシカルボニル)−3−(トリメチルシリル)−D−アラニル−3−(ピリジン−3−イル)−L−アラニンメチルエステル
HPLC/UV-Vis(方法9): Rt=3.91 分。
LC−MS (方法7): Rt = 1.90分, MS (ESIpos.): m/z (%)=424 (100) [M+H]+。
1H−NMR (400MHz, d6-DMSO): δ = -0.09 (s, 9H), 0.56 - 0.75 (m, 2H), 1.47 (s, 9H), 2.90 (dd, 1H), 3.09 (dd, 1H), 3.62 (s, 3H), 3.98 (m, 1H), 4.49 (m, 1H), 6.68 (d, 1H), 7.26 (dd, 1H), 7.61 (m, 1H), 8.20 (d, 1H), 8.40 (m, 2H)。
N−(tert−ブトキシカルボニル)−3−(トリメチルシリル)−D−アラニル−3−(ピリジン−3−イル)−L−アラニン
HPLC/UV-Vis(方法9): Rt=3.73分。
LC−MS (方法7): Rt = 1.68 分, MS (ESIpos.): m/z(%)=410 (40) [M+H]+。
1H−NMR(300MHz, d6−DMSO):δ= -0.090 (s, 9H), 0.56 - 0.75 (m, 2H), 1.35 (s, 9H), 2.90 (dd, 1H), 3.09 (dd, 1H), 3.98 (m, 1H), 4.41 (m, 1H), 6.70 (d, 1H), 7.26 (dd, 1H), 7.60 (m, 1H), 8.00 (d, 1H), 8.37 (m, 2H)。
N−(tert−ブトキシカルボニル)−3−(トリメチルシリル)−D−アラニル−3−(ピリジン−3−イル)−L−アラニル−デ(1−D−ロイシル−2−L−ロイシル)リソバクチントリフルオロアセテート
HPLC(方法9): Rt=3.90 分。
LC−MS(方法7): Rt=2.00 分, MS (ESIpos.): m/z (%)=721.8 (100) [M+2 H]2+; 1442.1 (5)[M+H]+。
2,2−ジメチル−1−ブタナール
GC-MS (方法17): Rt = 2.21 分, MS (ESIpos.): m/z (%)= 99.9 (5) [M]+;
1H−NMR (400MHz, CDCl3) δ 0.83 (t, 3H), 1.03 (s, 6H), 1.51 (q, 2H), 9.42 (s, 1H)。
(2Z)−2−{[(ベンジルオキシ)カルボニル]アミノ}−4,4−ジメチルヘキサ−2−エン酸メチル
HPLC (方法9): Rt=3.71 分。
MS (DCI): m/z (%) = 323.3 (100)[M+NH4]。
1H−NMR (400MHz, CDCl3): δ=0.83 (m, 3H), 1.13 (s, 6H), 1.49 (q, 2H), 3.75 (br s, 3H), 5.72 (br s, 1H), 6.58 (br s, 1H), 5.12 (s, 2H), 7.36 (m, 5H)。
N−[(ベンジルオキシ)カルボニル]−4,4−ジメチル−D−ノルロイシンメチルエステル
HPLC(方法9): Rt = 4.96 分。
LC−MS(方法7): Rt = 2.76 分; MS (ESIpos.): m/z (%) = 308 (25)[M+H]+。
1H−NMR (400MHz, CDCl3): δ = 0.80 (t, 3H), 0.86 (s, 6H), 1.29 (q, 2H), 1.41 (dd, 1H), 1.73 (dd, 1H), 3.72 (s, 3H), 4.40 (m, 1H), 5.02 (d, 1H), 5.11 (m, 2H), 7.35 (m, 5H)。
N−[(ベンジルオキシ)カルボニル]−4,4−ジメチル−D−ノルロイシン
HPLC(方法9): Rt=4.54 分。
LC−MS(方法7): Rt =2.44 分, MS (ESIpos.): m/z(%) = 294 (20)[M+H]+。
1H−NMR (400MHz, d6-DMSO): δ = 0.80 (t, 3H), 0.83 (s, 6H), 1.21 (q, 2H), 1.53 (dd, 1H), 1.60 (dd, 1H), 3.99 (m, 1H), 5.02 (s, 2H), 7.35 (m, 5H), 7.58 (d, 2H), 12.52 (br s, 1H)。
N−[(ベンジルオキシ)カルボニル]−4,4−ジメチル−D−ノルロイシル−3−(ピリジン−3−イル)−L−アラニンメチルエステル
HPLC(方法9): Rt= 3.94 分。
LC−MS(方法7): Rt=1.85 分; MS(ESIpos.): m/z(%)= 456 (100)[M+H]+。
1H−NMR (300MHz, d6-DMSO): δ =0.80 (m, 9H), 1.10 (m, 3H), 1.30 (dd, 1H), 2.91 (dd, 1H), 3.12 (dd, 1H), 3.30 (s, 3H), 4.02 (m, 1H), 4.51 (m, 1H), 5.01 (d, 1H), 5.06 (d, 1H), 7.22 (dd, 1H), 7.30 (m, 5H), 7.63 (m, 1H), 8.40 (m, 2H)。
N−[(ベンジルオキシ)カルボニル]−4,4−ジメチル−D−ノルロイシル−3−(ピリジン−3−イル)−L−アラニン
HPLC(方法9):Rt=3.76 分。
LC−MS(方法7):Rt=1.88 分;MS(ESIpos.):m/z(%)=442 (100)[M+H]+。
1H−NMR (400MHz, d6-DMSO): δ = 0.70 (m, 9H), 1.14 (m, 3H), 1.30 (dd, 1H), 2.64 (d, 1H), 2.75 (d, 1H), 2.89 (dd, 1H), 3.11 (dd, 1H), 4.03 (m, 1H), 4.45 (m, 1H), 4.98 (d, 1H), 5.05 (d, 1H), 7.22 (dd, 1H), 7.30 (m, 5H), 7.61 (m, 1H), 8.40 (m, 2H)。
N−[(ベンジルオキシ)カルボニル]−4,4−ジメチル−D−ノルロイシル−3−(ピリジン−3−イル)−L−アラニル−デ(1−D−ロイシル−2−L−ロイシル)−リソバクチントリフルオロアセテート
HPLC(方法9):Rt=3.93 分。
LC−MS(方法7):Rt=2.13 分、MS(ESIpos.):m/z(%)=737.4 (100)[M+2H]2+, 1473 (2)[M+H]+。
実施例1
3−tert−ブチル−D−アラニル−3−(6−トリフルオロメチルピリジン−3−イル)−L−アラニル−デ(1−D−ロイシル−2−L−ロイシル)−リソバクチンビストリフルオロアセテート
HPLC/UV−Vis(方法8):Rt=4.03分。
HPLC/UV−Vis(方法9):Rt=3.64分。
LC−MS(方法7):Rt=1.69分;MS(ESIpos.): m/z(%)=697(100)[M+2H]2+, 1393 (5)[M+H]+;MS(ESIneg.): m/z(%)=695(100)[M−2H]2-, 1391 (20)[M−H]−。
19F−NMR (400MHz, d5-ピリジン):δ=-67 (Ar-CF3), -74 (CF3COOH), -132 (レファレンスとして1,4−ジブロモテトラフルオロベンゼン)。TFA含有率:14.3重量%。
HR−MS(方法1):C62H96N16O17F3 [M+H]+ 計算値 1393.7091,実測値 1393.7119。
3−(トリメチルシリル)−D−アラニル−3−(ピリジン−3−イル)−L−アラニル−デ(1−D−ロイシル−2−L−ロイシル)−リソバクチントリストリフルオロアセテート
HPLC(方法9):Rt=3.32 分。
LC−MS(方法7):Rt=1.41 分、MS (ESIpos.): m/z(%)= 671.7 (100)[M+2H]2+。
HR−TOF−MS(方法1):C60H97N16O17Si [M+H]+ 計算値 1341.6987、実測値 1341.7019。
1H−NMR(500MHz,d5-ピリジン): δ = -0.172 (s, 9H), 0.611 (d, J = 6.9 Hz, 3H), 0.881 (d, J = 7.9Hz, 3H), 0.948 (d, J = 6.3 Hz, 3H), 0.954 - 0.997 (m, 6H), 1.135 (d, J = 6.0 Hz, 3H), 1.208 (m, 2H), 1.361 (d, J = 5.4 Hz, 3H), 1.439 (m, 1H), 1.497 (m, 1H), 1.953 (m, 2H), 2.04 (m, 1H), 2.154 (m, 3H), 2.372 (m, 3H), 3.111 (m, 1H), 3.266 (m, 1H), 3.563 (d, J= 14.95 Hz, 1H), 3.726 (dd, J = 12.2, 14.95 Hz, 1H), 3.840 (d, J = 9.6 Hz, 1H), 3.960 (m, 1H), 4.152 (m, 1H), 4.198 (m, 1H), 4.278 (m, 1H), 4.382 (m, 1H), 4.488 (m, 1H), 4.565 (dd, J = 9.5, 9.6 Hz, 1H), 4.628 (m, 1H), 4.630 (m, 1H), 4.779 (d, J= 12.2 Hz, 1H), 5.069 (m, 1H), 5.159 (dd, J = 9.3 Hz, 1H), 5.264 (m, 1H), 5.362 (s, 1H), 5.98 (d, J = 9.9 Hz, 1H),6.351 (dd, J = 8.5 Hz, J = 8.7 Hz, 1H), 7.169 (m, 1H), 7.246 (m, 1H), 7.382 (d, J = 9.9 Hz, 1H), 7.512 (m, 2H), 7.583 - 7.614 (m, 2H), 7.728 (m, 2H), 7.90 (d, J = 8.7 Hz, 1H), 8.126 (m, 3H), 8.341 (m, 1H), 8.576 (d, J = 3.6 Hz, 1H), 8.695 (m, 2H), 8.793 (m, 1H), 9.139 (br s, 1H), 9.715 (m, 1H), 10.957 (br s, 1H), 11.268 (br s, 1H)。
13C−NMR (126MHz、d5-ピリジン): δ = -1.8, 11.08, 15.84, 18.8, 18.8, 19.79, 20.89, 20.93, 21.65, 23.38, 24.78, 26.57, 26.88, 28.80, 31.04, 34.06, 36.84, 40.95, 41.25, 44.38, 50.94, 52.82, 55.99, 56.10, 56.74, 58.40, 59.10, 60.34, 60.72, 62.33, 62.55, 70.72, 72.06, 75.58, 75.65, 123.66, 128.25, 128.95, 129.80, 132.39, 136.77, 137.18, 149.17, 158.11, 162.15, 162.41, 162.70, 162.96, 169.01, 169.69, 170.21, 172.57, 173.27, 173.44, 173.66, 174.07, 174.36, 175.34, 175.56。
19F−NMR(400MHz,d5−ピリジン): δ=−74 (CF3COOH), -132(レファレンスとして1,4−ジブロモテトラフルオロベンゼン)。TFA含有率:19.3重量%。構造を単結晶X線構造解析により確認する。
3−(トリメチルシリル)−D−アラニル−3−(ピリジン−3−イル)−L−アラニル−デ(1−D−ロイシル−2−L−ロイシル)−リソバクチントリスメタンスルホネート
LC−MS(方法7):Rt=1.49 分、MS(ESIpos.):m/z(%)= 671.8 (100)[M+2H]2+ , 1342.1 (5) [M+H]+。
1H−NMR (500MHz、d5-ピリジン): δ = -0.170 (s, 9H), 0.702 (d, J = 6.3 Hz, 3H), 0.867 (d, J = 6.1 Hz, 3H), 0.972 (d, J = 6.2 Hz, 3H), 0.966 - 1.069 (m, 9H), 1.186 (d, J = 6.5 Hz, 3H), 1.315 (m, 2H), 1.448 - 1.501 (m, 6H), 2.010 (m, 1H) , 2.084 (m, 3H), 2.180 - 2.365 (m, 4H), 2.540 (m, 1H), 3.082 (s, 9H), 3.166 (m, 1H), 3.325 (m, 1H), 3.623 (d, J= 14.05 Hz, 1H), 3.865 (dd, J = 13.7, 14.05 Hz, 1H), 3.967 - 3.986 (m, 2H), 4.257 (m, 1H), 4.339 (m, 2H), 4.410 (m, 1H), 4.566 (m, 1H), 4.591 - 4.686 (m, 2H), 4.75 (d, 1 H, J = 12.1 Hz, 1H), 4.859 (m, 1H), 5.086 (m, 1H), 5.229 (m, 1H), 5.348 (m, 1H), 5.375 (s, 1H) 6.02 (d, J = 10.0 Hz, 1H), 6.403 (m, 1H), 7.068 (d, J = 9.8 Hz, 1H), 7.222 (m, 3H), 7.544 (m, 3H), 7.625 (m, 1H), 7.681 (m, 1H), 7.830 (d, J = 7.6 Hz, 1H), 7.921 (d, J = 9.35 Hz, 1H), 8.071 (m, 2H), 8.188 (br s, 1H), 8.285 (br s, 1H), 8.420 (d, J = 8.4 Hz, 1H), 8.614 (d, J = 4.0 Hz, 1H), 8.701 (m, 1H), 8.874 (br s, 1H), 10.175 (m, 1H), 10.279 (m, 1H), 10.941 (br s, 1H)。
19F−NMR (ピリジン、 400 MHz, 方法24): δ -74.0 (s, TFA, 0.20), -132.0 (s, 1,4-ジブロモテトラフルオロベンゼン、 1000.0),TFA=0.02重量%。
4,4−ジメチル−D−ノルロイシル−3−(ピリジン−3−イル)−L−アラニル−デ(1−D−ロイシル−2−L−ロイシル)リソバクチントリストリフルオロアセテート
HPLC(方法9):Rt=3.29 分。
LC−MS(方法7):Rt=1.49 分、MS(ESIpos.):m/z(%)=671.0 (100)[M+2H]2+, 1340 (5) [M+H]+。
HR−TOF−MS(方法1):C62H98N16O17[M+H]+ 計算値 1339.7369、実測値 1339.7368。
(トリメチルシリル)−D−アラニル−3−(ピリジン−3−イル)−L−アラニル−デ(1−D−ロイシル−2−L−ロイシル)リソバクチントリス−塩酸塩
LC−MS(方法7):Rt =1.47分、MS(ESIpos.):m/z(%)=671.5 (100) [M+2H]2+, 1341.4 (20), [M+H]+。
イオンクロマトグラフィー(方法25):Cl− (計算値) = 7.43%, Cl− 実測値 = 7.1%; TFA(実測値)< 0.1%。
1H−NMR (500 MHz, d5-ピリジン) δ = -0.170 (s, 9H), 0.580 (d, J = 6.3 Hz, 3H), 0.772 (d, J = 5.7 Hz, 3H), 0.920 (d, J = 5.8 Hz, 3H), 0.974 - 0.985 (m, 6H), 1.147 (d, J = 6.4 Hz, 3H), 1.250 - 1.358 (m, 2H), 1.411 (d, J = 5.7 Hz, 3H), 1.468 (m, 1H), 1.604 (m, 1H), 1.959 - 2.049 (m, 3H), 2.154 - 2.228 (m, 3H), 2.380 (m, 3H), 2.935 (m, 1H), 3.120 (m, 1H), 3.300 (m, 1H), 3.607 (d, J= 14.9 Hz, 1H), 3.762 (dd, J= 14.7 Hz, 1H), 3.882 (d, J = 9.1 Hz, 1H), 3.938 (m, 1H), 4.204 (m, 1H), 4.253 (m, 1H), 4.389 (m, 1H), 4.465 (m, 1H), 4.589 - 4.661 (m, 4H), 4.806 (d, J= 12.1 Hz, 1H), 5.027 (m, 1H), 5.202 (dd, J= 9.4 Hz, 1H), 5.289 (m, 1H), 5.390 (s, 1H), 6.000 (d, J = 9.5 Hz, 1H)、6.394 (dd, J= 9.0 Hz, 1H), 7.173 (m, 2H), 7.428 (m, 1H), 7.54 (d, J = 7.0 Hz, 1H), 7.664 - 7.973 (m, 3H), 7.767 (d, J = 8.6, 1H), 7.918 - 7.973 (m, 3H), 8.038 (br s, 2H), 8.098 (br s, 1H), 8.185 (br s, 1H), 8.253 (d, J = 8.6 Hz, 1H), 8.582 (m, 1H), 8.684 (d, J = 9.8 Hz, 1H), 8.741 (br s, 1H), 8.782 (m, 1H), 9.928 (br s, 1H), 10.272 (d, J = 8.3 Hz, 1H), 10.886 (br s, 1H), 11.135 (br s, 1H)。
19F−NMR(ピリジン、400MHz、方法24):TFA<検出限界。
(トリメチルシリル)−D−アラニル−3−(ピリジン−3−イル)−L−アラニル−デ(1−D−ロイシル−2−L−ロイシル)リソバクチントリス−L−ラクテート
LC−MS (方法7): Rt= 1.38 分、MS (ESIpos.): m/z(%)= 671.7 (100) [M+2H]2+, 1341.8 (20),[M+H]+。
1H−NMR (500 MHz,d5−ピリジン): δ= -0.170 (s, 9H), 0.754 (d, J=6.3 Hz, 3H), 0.836 (d, J = 6.1 Hz, 3H), 0.922 (d, J = 6.2 Hz, 3H), 0.922 - 0.957 (m, 6H), 1.054 (d, J = 6.4 Hz, 3H), 1.190 (m, 2H), 1.416 (d, J = 5.8 Hz, 3H), 1.439 - 1.662 (m, 4H), 1.529 (d, J = 7.0 Hz, 3H), 1.598 (d, J = 6.5 Hz, 3H), 1.669 (d, J = 6.9 Hz, 3H), 1.923 - 2.280 (m, 9H), 3.057 (m, 1H), 3.266 (m, 1H), 3.564 (d, J= 14.5 Hz, 1H), 3.761 (dd, J= 13.7 Hz, 1H), 3.840 (m, 1H), 4.049 (m, 1H), 4.109 (m, 1H), 4.164 (m, 1H), 4.202 (m, 1H), 4.410 (m, 1H), 4.484 (m, 1H), 4.616 (dd, J = 6.7, 13.6 Hz, 1H), 4.656 (m, 1H), 4.669 (dd, J = 7.0, 13.9 Hz, 1H), 4.780 (d, J= 13.0 Hz, 1H), 4.921 (m, 1H), 5.144 (dd, J= 9.6 Hz, 1H), 5.281 (m, 1H), 5.363 - 5.426 (m, 3H) 5.362 (s, 1H), 5.989 (d, J = 9.8 Hz, 1H), 6.323 (m, 1H), 7.122 (m, 1H), 7.180 (m, 1H), 7.381 (m, 1H), 7.596 (m, 1H), 7.671 - 7.925 (m, 6H), 8.036 (br s, 1H), 8.208 (m, 3H), 8.412 (m, 1H), 8.551 (d, J = 3.6 Hz, 1H), 8.714 (m, 2H), 8.794 (m, 1H), 10.298 (br s, 1H), 10.938 (br s, 1H).
19F−NMR(ピリジン、400MHz、方法24):TFA<検出限界。
(トリメチルシリル)−D−アラニル−3−(ピリジン−3−イル)−L−アラニル−デ(1−D−ロイシル−2−L−ロイシル)リソバクチントリス−D−タートレート
LC−MS(方法 7):Rt = 1.37 分、MS (ESIpos.):m/z(%)=671.7 (100) [M+2H]2+, 1341.9 (20),[M+H]+。
1H−NMR (500 MHz, d5-ピリジン): δ = -0.172 (s, 9H), 0.597 (d, J = 6.3 Hz, 3H), 0.776 (d, J = 5.7 Hz, 3H), 0.924 (d, J = 5.8 Hz, 3H), 0.954 - 0.997 (m, 6H), 1.173 (d, J = 5.7 Hz, 3H), 1.303 (m, 2H), 1.434 (d, J = 5.7 Hz, 3H), 1.468 (m, 1H), 1.632 (m, 1H), 1.972 (m, 2H), 2.051 (1H, m), 2.174 (m, 3H), 2.402 (m, 3H), 3.129 (m, 1H), 3.305 (m, 1H), 3.602 (d, J= 15.2 Hz, 1H), 3.799 (dd, J= 14.6 Hz, 1H), 3.893 (d, J = 12.3 Hz, 1H), 3.967 (m, 1H), 4.228 (m, 1H), 4.276 (m, 1H), 4.409 (m, 1H), 4.468 (m, 1H), 4.578 - 4.669 (m, 4H), 4.791 (d, Jα,β = 11.5 Hz, 1H), 5.044 (m, 1H), 5.226 (dd, J= 9.4 Hz, 1H), 5.190 (m, 1H), 5.362 (s, 1H), 5.417 (s, 6H), 5.997 (d, J = 9.7 Hz, 1H), 6.403 (dd, J= 8.9 Hz, 1H), 7.182 (m, 1H), 7.551 - 8.210 (m, 13H), 8.589 (d, J = 3.6 Hz, 1H), 8.711 (d, J = 10.0 Hz, 1H), 8.782 (m, 2H), 9.902 (br s, 1H), 10.358 (m, 1H), 10.882 (br s, 1H), 11.093 (br s, 1H)。
(トリメチルシリル)−D−アラニル−3−(ピリジン−3−イル)−L−アラニル−デ(1−D−ロイシル−2−L−ロイシル)リソバクチン
HPLC (方法 9): Rt = 3.30 分。
LC−MS (方法 7):Rt = 1.49 分。MS (ESIpos.): m/z(%)= 671.8 (100) [M+2H]2+, 1341.9 (10), [M+H]+, MS (ESIneg): m/z(%)= 669.9 (100) [M−2H]2-, 1340.0 (100) M−H]-。
19F−NMR(ピリジン、400MHz、方法24):TFA2.9%。
(トリメチルシリル)−D−アラニル−3−(ピリジン−3−イル)−L−アラニル−デ(1−D−ロイシル−2−L−ロイシル)リソバクチンメシレートトリフルオロアセテート
LC−MS(方法6):Rt =1.41 分。MS(ESIpos.):m/z(%)= 671.9 (100)[M+2H]2+, 1342.1 (10), [M+H]+, MS(ESIneg):m/z(%)=669.9 (100)[M−2H]2-, 1340.1 (80)M−H]-。
HR−TOF−MS(方法1):C60H97N16O17Si[M+H]+ 計算値 1341.6982, 実測値 1341.7006。
単結晶X線構造解析により構造および塩形態を確認する。
本発明化合物のインビボ活性は、以下の検定法で立証され得る:
最小阻害濃度(MIC)の測定:
NCCLSガイドラインに従って液体希釈試験でMICを測定する。スタフィロコッカス・アウレウス(Staphylococcus aureus)133、エンテロコッカス・フェカリス(Enterococcus faecalis)27159、エンテロコッカス・フェシウム(E.faecium)4147およびストレプトコッカス・ニューモニエ(Streptococcus pneumoniae)G9aの一晩培養物を、1:2希釈系列で記載された試験物質とインキュベーションする。Isosensitest 培地(Difco、アーヴィン/米国)中1ml当たり105微生物の細胞数によりMIC測定を実施するが、ただし、ストレプトコッカス・ニューモニエ(Streptococcus pneumoniae)については、1ml当たり106微生物の細胞数で10%牛血清含有BHIブロス(Difco、アーヴィン/米国)において試験する。培養物を37℃で18〜24時間、ストレプトコッカス・ニューモニエ(Streptococcus pneumoniae)については10%CO2の存在下でインキュベーションする。
スタフィロコッカス・アウレウス(Staphylococcus aureus)133の細胞を、BHIブロス(Oxoid、ニューヨーク/米国)において一晩生育する。一晩培養物を、新鮮なBHIブロス中で1:100に希釈し、3時間インキュベーションする。次いで、対数成長期にある細胞を遠心分離にかけ、緩衝生理食塩水で2回洗浄する。次いで、食塩水中の細胞懸濁液を、測光法により50単位の吸光度に調節する。希釈(1:15)段階後、懸濁液を1:1で10%ムチン溶液と混合する。この感染液0.25ml/20gマウスを、腹腔内投与する(1×106微生物/マウスに相当)。感染の30分後、腹腔内または静脈内経路により治療を実施する。雌CFW1マウスを感染実験に使用する。動物の生存を、6日間にわたって記録する。
腎毒性作用測定用マウスモデル
ノナデプシペプチドの腎毒性副作用を、特定用量の多剤投与後のマウスにおいて腎臓の組織病理学的試験により分析する。このため、5〜6動物を、水溶液に溶かしたかまたはソルトールを加えた物質により静脈内(i.v.)または腹腔内(i.p.)経路で毎日処置する。腎臓のヘマトキシリンおよびエオシン(H & E)染色パラフィン切片の光学顕微鏡評価により、腎毒性作用を測定する。糖タンパク質の視覚化をより明確にするため、所望により「過ヨウ素酸シッフ」(PAS)反応を実施してもよい。腎細管好塩基球増加症および変性/再生発生の重症度として(重症度:0=作用無し、1=極微の作用、1=軽微な作用、3=中等度の作用、4=重症病変)腎毒性作用を各動物について半定量的に定義する。腎細管変性/再生の平均重症度および発病率(罹患動物の数)を、各動物群または誘導体について計算する。これを凌ぐ腎臓変化、例えば腎細管拡張および壊死並びに壊死物質の蓄積も同様に列挙する。
ノナデプシペプチドの腎毒性副作用を、特定用量の多剤投与後のラットにおいて腎臓の組織病理学的試験により分析する。このため、5動物を、食塩水またはリンガー乳酸溶液に溶かした物質により静脈内(i.v.)経路で毎日処置する。腎臓のヘマトキシリンおよびエオシン(H & E)染色パラフィン切片の光学顕微鏡評価により、腎毒性作用を測定する。糖タンパク質の視覚化をより明確にするため、所望により「過ヨウ素酸シッフ」(PAS)反応を実施してもよい。腎細管好塩基球増加症および変性/再生発生の重症度として(重症度:0=作用無し、1=極微の作用、1=軽微な作用、3=中等度の作用、4=重症病変)腎毒性作用を各動物について半定量的に定義する。腎細管変性/再生の平均重症度および発病率(罹患動物の数)を、各動物群または誘導体について計算する。これを凌ぐ腎臓変化、例えば腎細管拡張および壊死並びに壊死物質の蓄積も同様に列挙する。
試験物質の非結合型分率(fu)測定についての本明細書記載の方法は、2部分に分けられる:
a)Transil(登録商標)緩衝液(pH7.4)分散液中で試験物質をインキュベーションし、それに続いて分散液および緩衝液上清における濃度を測定することによる、Transil(登録商標)/緩衝液分配比(MAbuffer)の測定。
b)Transil(登録商標)血漿分散液中で試験物質をインキュベーションし、それに続いて分散液および血漿中における濃度を測定することによる、Transil(登録商標)/血漿分配比(MAplasma)の測定。
2つの分配比の商によりfuが与えられる。
インキュベーションは全て、適切なガラス容器、例えばガラス瓶、底部連結試験管中で実施される。総体積は、通常0.5〜5mlであり、Transil(登録商標)の体積は10〜100μlである。膜親和力が高いと予測される場合、Transil(登録商標)分散液は、pH7.4のリン酸緩衝液、例えばダルベッコのPBSで20倍以下に希釈され得る。pH7.4のリン酸緩衝液をインキュベーション容器に入れ、十分に混合した後、Transil(登録商標)をピペットで移す。試験物質を例えば200ng/mlの濃度、n=6でピペットにより移し入れる。有機溶媒の比率は2%以下とするべきである。混合物を室温で、30分間、約400rpm、角度約45°で小型振とう器においてインキュベーションする。例えば100μlの少なくとも1アリコートを取ることにより、100%値を決定し、残りの混合物を約1800gで約10分間遠心分離にかける。少なくとも2アリコート(例、100μl)の上清を、濃度測定用に各試料から採取する。
総インキュベーション体積およびTransil(登録商標)の追加体積は、予測される非結合型分率により変化する。総体積は通常0.5〜1mlであり、Transil(登録商標)体積は10〜100μlである。非結合型分率が非常に低い場合、研究する種の血漿を、pH7.4の等張緩衝液で例えば10〜400倍に希釈し、次いで Transil(登録商標)を加える。後続手順は、MAbuffer値測定についての上記要領と同じである。
研究する種の血漿を、半透膜により濾過する。濾液中の物質の濃度を測定し、非結合型分率fuをそこから算出する。Millipore/Amicon からの Centrifree マイクロパーティションシステムを使用する。限外濾過膜は、30000Daの排除サイズを有する。1mlの血漿を、約1μg/mlの濃度の物質で処理する。溶媒の比率は2%未満とするべきである。室温で30分間インキュベーション後、血漿をピペットで限外濾過システムへ移し入れ、1800gで10分間の遠心分離にかける。限外濾液における物質濃度(Cu;未結合物質濃度)および遠心分離前の血漿における同濃度(C;総物質濃度)を測定する。非結合型分率を、式:fu(%)=Cu/C*100により算出する。
本発明化合物は、以下の方法で医薬製剤に変換され得る:
錠剤:
組成:
実施例1の化合物100mg、乳糖(一水和物)50mg、コーンスターチ(天然)50mg、ポリビニルピロリドン(PVP25)(BASF、ドイツ国ルドヴィヒシャーフェン)10mgおよびステアリン酸マグネシウム2mg。
錠剤重量212mg。直径8mm、曲率半径12mm。
有効成分、乳糖および澱粉の混合物を、水中PVPの5%溶液(m/m)により造粒する。顆粒を乾燥し、次いでステアリン酸マグネシウムと5分間混合する。この混合物を慣用的錠剤機により圧縮する(錠剤の形式については上記参照)。圧縮に使用される圧縮力に関するガイドラインは15kNである。
組成:
実施例1の化合物1000mg、エタノール(96%)1000mg、ロージゲル(Rhodigel)(米国ペンシルベニア、FMCによるキサンタンガム)400mgおよび水99g。
ロージゲルをエタノールに懸濁し、活性化合物を懸濁液に加える。攪拌しながら水を加える。ロージゲルの膨張が完了するまで、混合物を約6時間攪拌する。
組成:
実施例1の化合物100〜200mg、15gのポリエチレングリコール400および注射用水250g。
実施例1の化合物をポリエチレングリコール400と一緒に攪拌しながら水に溶かす。溶液を濾過(孔直径0.22μm)により滅菌し、無菌条件下で加熱滅菌注入瓶へ分配する。同瓶を注入栓およびクリンプキャップで密閉する。
Claims (11)
- R1が水素を表し、R2が2,2−ジメチルブタ−1−イルまたはトリメチルシリルメチルを表すか、またはR1がトリフルオロメチルを表し、R2が、2,2−ジメチルプロパ−1−イル、2,2−ジメチルブタ−1−イルまたはトリメチルシリルメチルを表すことを特徴とする、請求項1記載の化合物。
- R1が水素を表し、R2が、2,2−ジメチルブタ−1−イル、2−エチル−2−メチルブタ−1−イル、2,2−ジエチルブタ−1−イルまたはトリメチルシリルメチルを表すことを特徴とする、請求項1記載の化合物。
- 病気の処置および/または予防を目的とする、請求項1〜4のいずれか1項記載の化合物。
- 病気の処置および/または予防用の医薬の製造を目的とする、請求項1〜4のいずれか1項記載の化合物の使用。
- 細菌感染症の処置および/または予防用の医薬の製造を目的とする、請求項1〜4のいずれか1項記載の化合物の使用。
- 不活性で非毒性の医薬上許容される賦形剤と組み合わせて請求項1〜4のいずれか1項記載の化合物を含む医薬。
- 細菌感染症の処置および/または予防を目的とする、請求項9記載の医薬。
- 請求項1〜4のいずれか1項記載の少なくとも1種の化合物、請求項9記載の医薬または請求項7または8に従って得られる医薬の抗菌有効量を投与することによる、ヒトおよび動物における細菌感染症の制御方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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DE102004053407A DE102004053407A1 (de) | 2004-11-05 | 2004-11-05 | Acylierte Nonadepsipeptide II |
DE102004053407.1 | 2004-11-05 | ||
PCT/EP2005/011363 WO2006048139A1 (de) | 2004-11-05 | 2005-10-22 | Acylierte nonadepsipeptide als lysobactinderivate |
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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) |
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DE (1) | DE102004053407A1 (ja) |
GT (1) | GT200500308A (ja) |
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DE102004051025A1 (de) * | 2004-10-20 | 2006-04-27 | Bayer Healthcare Ag | Substituierte Nonadepsipeptide |
DE102004051023A1 (de) * | 2004-10-20 | 2006-05-04 | Bayer Healthcare Ag | Desoxo-Nonadepsipeptide |
DE102004051024A1 (de) * | 2004-10-20 | 2006-04-27 | Bayer Healthcare Ag | Heterocyclyl-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 |
DE102006018080A1 (de) * | 2006-04-13 | 2007-10-18 | Aicuris Gmbh & Co. Kg | Lysobactinamide |
DE102006018250A1 (de) * | 2006-04-13 | 2007-10-18 | Aicuris Gmbh & Co. Kg | Verfahren zum Herstellen von cyclischen Depsipeptiden |
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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WO2004099239A1 (de) * | 2003-05-09 | 2004-11-18 | Bayer Healthcare Ag | Acylierte nonadepsipeptide vom lysobactin-typ |
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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 |
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KR20070083984A (ko) | 2007-08-24 |
RU2414477C2 (ru) | 2011-03-20 |
US7531507B2 (en) | 2009-05-12 |
WO2006048139A1 (de) | 2006-05-11 |
NO20072854L (no) | 2007-08-01 |
MA29218B1 (fr) | 2008-02-01 |
TW200621799A (en) | 2006-07-01 |
UY29189A1 (es) | 2006-06-30 |
MY145448A (en) | 2012-02-15 |
CR9079A (es) | 2007-08-28 |
EP1807443A1 (de) | 2007-07-18 |
JP4843614B2 (ja) | 2011-12-21 |
MX2007005382A (es) | 2007-08-14 |
PE20060942A1 (es) | 2006-10-20 |
IL182739A (en) | 2013-03-24 |
CN101056887A (zh) | 2007-10-17 |
AU2005300815A1 (en) | 2006-05-11 |
GT200500308A (es) | 2006-06-02 |
BRPI0516677A (pt) | 2008-09-16 |
UA89800C2 (en) | 2010-03-10 |
NZ554813A (en) | 2009-11-27 |
SV2006002290A (es) | 2006-10-13 |
RU2007120686A (ru) | 2008-12-10 |
AU2005300815B2 (en) | 2011-05-19 |
ZA200703674B (en) | 2008-09-25 |
US20060264358A1 (en) | 2006-11-23 |
AR053775A1 (es) | 2007-05-23 |
IL182739A0 (en) | 2007-07-24 |
HN2005030779A (es) | 2010-08-19 |
DE102004053407A1 (de) | 2006-05-11 |
CA2586704A1 (en) | 2006-05-11 |
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