TW201602064A - Hydroxamic acid derivative - Google Patents
Hydroxamic acid derivative Download PDFInfo
- Publication number
- TW201602064A TW201602064A TW103136097A TW103136097A TW201602064A TW 201602064 A TW201602064 A TW 201602064A TW 103136097 A TW103136097 A TW 103136097A TW 103136097 A TW103136097 A TW 103136097A TW 201602064 A TW201602064 A TW 201602064A
- Authority
- TW
- Taiwan
- Prior art keywords
- acid
- compound
- patent document
- gram
- present
- Prior art date
Links
- 239000002253 acid Substances 0.000 title description 7
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 11
- 239000003242 anti bacterial agent Substances 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 2
- 241000894006 Bacteria Species 0.000 abstract description 27
- 241000589517 Pseudomonas aeruginosa Species 0.000 abstract description 19
- 239000003814 drug Substances 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 10
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 6
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 229940127557 pharmaceutical product Drugs 0.000 abstract description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 235000002639 sodium chloride Nutrition 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000007788 liquid Substances 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 9
- 238000000132 electrospray ionisation Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- -1 carbapenems Chemical class 0.000 description 8
- 239000002054 inoculum Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000004949 mass spectrometry Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 229920001817 Agar Polymers 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 239000008272 agar Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 5
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 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 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 241000192125 Firmicutes Species 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241000588747 Klebsiella pneumoniae Species 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- LLCSWKVOHICRDD-UHFFFAOYSA-N buta-1,3-diyne Chemical group C#CC#C LLCSWKVOHICRDD-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229920006008 lipopolysaccharide Polymers 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical group NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 241000588697 Enterobacter cloacae Species 0.000 description 2
- 241000194033 Enterococcus Species 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000606790 Haemophilus Species 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000589248 Legionella Species 0.000 description 2
- 208000007764 Legionnaires' Disease Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- 241000607720 Serratia Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 150000001793 charged compounds Chemical class 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229920001971 elastomer Polymers 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- VNDHXHMRJVTMTK-WZVRVNPQSA-H hexasodium 4-[[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecahydroxy-10-(hydroxymethyl)-15,20,25,30,35-pentakis(4-sulfonatobutoxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan-5-yl]methoxy]butane-1-sulfonate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]1[C@H](O)[C@H]2O VNDHXHMRJVTMTK-WZVRVNPQSA-H 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 238000000752 ionisation method Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229950006780 n-acetylglucosamine Drugs 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- GGHDAUPFEBTORZ-UHFFFAOYSA-N propane-1,1-diamine Chemical compound CCC(N)N GGHDAUPFEBTORZ-UHFFFAOYSA-N 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 239000005060 rubber Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- PVPBHKCSQBLDEW-ZQOBQRRWSA-N (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecol 4-hydroxybutane-1-sulfonic acid Chemical compound OCCCCS(O)(=O)=O.OC[C@H]1O[C@@H]2O[C@@H]3[C@@H](CO)O[C@H](O[C@@H]4[C@@H](CO)O[C@H](O[C@@H]5[C@@H](CO)O[C@H](O[C@@H]6[C@@H](CO)O[C@H](O[C@@H]7[C@@H](CO)O[C@H](O[C@@H]8[C@@H](CO)O[C@H](O[C@H]1[C@H](O)[C@H]2O)[C@H](O)[C@H]8O)[C@H](O)[C@H]7O)[C@H](O)[C@H]6O)[C@H](O)[C@H]5O)[C@H](O)[C@H]4O)[C@H](O)[C@H]3O PVPBHKCSQBLDEW-ZQOBQRRWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical class OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RHUYHJGZWVXEHW-UHFFFAOYSA-N 1,1-Dimethyhydrazine Chemical compound CN(C)N RHUYHJGZWVXEHW-UHFFFAOYSA-N 0.000 description 1
- VPLXJIGDEIRJLV-UHFFFAOYSA-N 12,12-dimethyltridec-1-yne Chemical group CC(CCCCCCCCCC#C)(C)C VPLXJIGDEIRJLV-UHFFFAOYSA-N 0.000 description 1
- IANXAXNUNBAWBA-UHFFFAOYSA-N 2,2,3-trimethylundecane Chemical compound CCCCCCCCC(C)C(C)(C)C IANXAXNUNBAWBA-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- GINJNNGWMNSBIG-UHFFFAOYSA-N 2-n-methylpropane-1,2-diamine Chemical compound CNC(C)CN GINJNNGWMNSBIG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical class NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical class C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- 241000588626 Acinetobacter baumannii Species 0.000 description 1
- 241000588624 Acinetobacter calcoaceticus Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 241000606125 Bacteroides Species 0.000 description 1
- 241000606124 Bacteroides fragilis Species 0.000 description 1
- 239000005711 Benzoic acid Chemical class 0.000 description 1
- 241000589875 Campylobacter jejuni Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 241001647378 Chlamydia psittaci Species 0.000 description 1
- 241000606153 Chlamydia trachomatis Species 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 241000588923 Citrobacter Species 0.000 description 1
- 241000588919 Citrobacter freundii Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010011409 Cross infection Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Chemical class OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000194031 Enterococcus faecium Species 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Chemical class OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000589989 Helicobacter Species 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 241000588915 Klebsiella aerogenes Species 0.000 description 1
- 241000588749 Klebsiella oxytoca Species 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical class SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical class CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical class OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical class OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000589242 Legionella pneumophila Species 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 229940123346 LpxC inhibitor Drugs 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000588621 Moraxella Species 0.000 description 1
- 241000588655 Moraxella catarrhalis Species 0.000 description 1
- 241000588771 Morganella <proteobacterium> Species 0.000 description 1
- 241000588772 Morganella morganii Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- 201000005702 Pertussis Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000588767 Proteus vulgaris Species 0.000 description 1
- 241000588768 Providencia Species 0.000 description 1
- 241000588778 Providencia stuartii Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000287531 Psittacidae Species 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- 241000607715 Serratia marcescens Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000122971 Stenotrophomonas Species 0.000 description 1
- 241000122973 Stenotrophomonas maltophilia Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 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
- 239000007983 Tris buffer Substances 0.000 description 1
- 241000607598 Vibrio Species 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000001361 adipic acid Chemical class 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Chemical class OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Chemical class OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940038705 chlamydia trachomatis Drugs 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 125000001559 cyclopropyl group Chemical class [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Chemical class SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 230000009034 developmental inhibition Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940092559 enterobacter aerogenes Drugs 0.000 description 1
- 208000028104 epidemic louse-borne typhus Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical class CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000000174 gluconic acid Chemical class 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 239000004220 glutamic acid Chemical class 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940115932 legionella pneumophila Drugs 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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 Chemical class 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940076266 morganella morganii Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Chemical class 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007918 pathogenicity Effects 0.000 description 1
- CRWVOXFUXPYTRK-UHFFFAOYSA-N pent-4-yn-1-ol Chemical compound OCCCC#C CRWVOXFUXPYTRK-UHFFFAOYSA-N 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical class [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- WJKYOQDIQYJXSD-UHFFFAOYSA-N propan-1-imine Chemical compound CCC=N WJKYOQDIQYJXSD-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940007042 proteus vulgaris Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012264 purified product Substances 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
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- ITJHLZVYLDBFOJ-UHFFFAOYSA-N tris[3,5-bis(trifluoromethyl)phenyl]phosphane Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(P(C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)=C1 ITJHLZVYLDBFOJ-UHFFFAOYSA-N 0.000 description 1
- 206010061393 typhus Diseases 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229940118696 vibrio cholerae Drugs 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本發明係關於一種對革蘭氏陰性細菌及其耐藥性菌具有抗菌活性之新穎異羥肟酸衍生物。又,本發明係關於一種含有異羥肟酸衍生物之醫藥組合物或抗菌劑。 The present invention relates to a novel hydroxamic acid derivative having antibacterial activity against Gram-negative bacteria and resistant bacteria thereof. Further, the present invention relates to a pharmaceutical composition or an antibacterial agent containing a hydroxamic acid derivative.
革蘭氏陰性細菌中存在革蘭氏陽性細菌中不存在之包含脂質雙層之外膜。因此,就藥劑透過性之問題而言,與革蘭氏陽性細菌相比,革蘭氏陰性細菌存在具有較強抗藥性之傾向。又,已知革蘭氏陰性細菌具有複數種藥劑排出蛋白。非專利文獻1中揭示藥劑排出蛋白亦與抗藥性有關。進而,作為外膜之主要構成成分之一的脂多糖(LPS)作為內毒素而與毒性有較大關聯。 In the Gram-negative bacteria, there is a membrane comprising a lipid bilayer which is not present in Gram-positive bacteria. Therefore, in terms of the problem of drug permeability, Gram-negative bacteria have a tendency to be more resistant than Gram-positive bacteria. Further, it is known that Gram-negative bacteria have a plurality of drug excretion proteins. Non-Patent Document 1 discloses that drug excretion proteins are also associated with drug resistance. Further, lipopolysaccharide (LPS), which is one of the main constituent components of the outer membrane, is associated with toxicity as an endotoxin.
已知於革蘭氏陰性細菌中,尤其是綠膿桿菌(Pseudomonas aeruginosa)對各種抗菌藥表現出自然抗性之傾向較強。綠膿桿菌廣泛常存於自然環境或生活環境中,但為通常不會對健康者表現出病原性之減毒細菌。但是,對患有嚴重基礎疾病之患者、或因移植等而使用免疫抑制劑之所謂免疫抑制宿主(compromised hosts)之患者、進行有醫療用導管或氣管插管、外科手術等醫療行為之患者而言,綠膿桿菌成為引起敗血症等嚴重急性感染症之病原菌。因此,綠膿桿菌為伺機性感染症或醫院內感染症之重要之起因細菌之一。 It is known that among Gram-negative bacteria, especially Pseudomonas aeruginosa, there is a strong tendency to exhibit natural resistance to various antibacterial agents. Pseudomonas aeruginosa is widely present in the natural environment or living environment, but is an attenuated bacterium that does not usually show pathogenicity to healthy people. However, patients with severe underlying diseases, patients with so-called immunosuppressive hosts who use immunosuppressants for transplantation, etc., and patients with medical procedures such as medical catheters or endotracheal intubation, and surgery are used. In other words, Pseudomonas aeruginosa is a pathogen causing severe acute infections such as sepsis. Therefore, Pseudomonas aeruginosa is one of the important causative bacteria of opportunistic infections or nosocomial infections.
近年來,於醫療現場屢次臨床分離出已對原本期待對綠膿桿菌有效之第三代頭孢烯(cephems)系藥、碳青黴烯(carbapenem)系藥或胺 基醣苷系藥等獲得了抗性的綠膿桿菌(非專利文獻2)。又,亦分離出已對上述3系之藥物均獲得了抗性之多重抗藥性綠膿桿菌(非專利文獻3)。 In recent years, third-generation cephems, carbapenems, or amines that have been expected to be effective against Pseudomonas aeruginosa have been clinically isolated on the medical site. Pseudomonas aeruginosa which is resistant to a glucoside-based drug or the like (Non-Patent Document 2). In addition, the multidrug-resistant Pseudomonas aeruginosa which has been resistant to the above three types of drugs has been isolated (Non-Patent Document 3).
由於若感染多重抗藥性綠膿桿菌則幾乎無有用之藥劑,故而多重抗藥性綠膿桿菌作為難治性感染症疾病之起因菌於世界範圍內成為較大問題。因此,迫切期望開發出具有新穎作用機理之藥劑。 Since there is almost no useful drug when infecting multi-drug resistant Pseudomonas aeruginosa, multidrug-resistant Pseudomonas aeruginosa is a major problem in the world as a cause of refractory infectious diseases. Therefore, it is highly desirable to develop an agent having a novel mechanism of action.
UDP-3-O-醯基-N-乙醯葡糖胺脫乙醯酶(LpxC)係承擔合成作為外膜構成成分之LPS之疏水性錨即脂質A的酶。脂質A生物合成包含10階段之反應。LpxC催化其生物合成反應之第2階段,使UDP-3-O-醯基-N-乙醯葡糖胺之乙醯基脫離(非專利文獻4)。脂質A為外膜形成所必須之成分,結果對革蘭氏陰性細菌之生存而言為必須(非專利文獻5)。 UDP-3-O-mercapto-N-acetylglucosamine deacetylase (LpxC) is an enzyme that synthesizes a hydrophobic anchor, LPS, which is a constituent of the outer membrane. Lipid A biosynthesis involves a 10-stage reaction. LpxC catalyzes the second stage of the biosynthesis reaction, and cleaves the acetyl group of UDP-3-O-mercapto-N-acetylglucosamine (Non-Patent Document 4). Lipid A is a component necessary for the formation of an outer membrane, and as a result, it is necessary for the survival of Gram-negative bacteria (Non-Patent Document 5).
即,LpxC係於脂質A生物合成過程中限制速率之重要酶之一,係脂質A生物合成所必須之酶。因此,由於抑制LpxC之活性的藥劑對包括綠膿桿菌在內之革蘭氏陰性細菌尤其具有不同於先前藥劑之作用機理,故而強烈期待其能夠成為對藥劑抗性綠膿桿菌有效之抗菌劑。 That is, LpxC is one of the important enzymes that limit the rate during lipid A biosynthesis, and is an enzyme necessary for lipid A biosynthesis. Therefore, since the agent which inhibits the activity of LpxC particularly has a mechanism different from that of the prior agent for Gram-negative bacteria including Pseudomonas aeruginosa, it is strongly expected to be an effective antibacterial agent against the drug-resistant Pseudomonas aeruginosa.
作為LpxC抑制劑,於專利文獻1~11及非專利文獻6~13中揭示有具有醯胺結構之抑制劑。 As an LpxC inhibitor, an inhibitor having a guanamine structure is disclosed in Patent Documents 1 to 11 and Non-Patent Documents 6 to 13.
該等之中,作為具有丙二醯胺骨架之化合物,專利文獻5中揭示有具有丙二醯胺骨架及二乙炔基結構之化合物。 Among these, as a compound having a propylene glycol skeleton, Patent Document 5 discloses a compound having a propylene glycol skeleton and a diacetylene structure.
又,專利文獻9中揭示有於二乙炔基末端部分具有羥基乙基之化合物235。 Further, Patent Document 9 discloses a compound 235 having a hydroxyethyl group at a terminal portion of a diacetylenic group.
[專利文獻1]國際公開第2004/062601號 [Patent Document 1] International Publication No. 2004/062601
[專利文獻2]國際公開第2007/069020號 [Patent Document 2] International Publication No. 2007/069020
[專利文獻3]國際公開第2008/154642號 [Patent Document 3] International Publication No. 2008/154642
[專利文獻4]國際公開第2010/031750號 [Patent Document 4] International Publication No. 2010/031750
[專利文獻5]國際公開第2011/132712號 [Patent Document 5] International Publication No. 2011/132712
[專利文獻6]國際公開第2012/154204號 [Patent Document 6] International Publication No. 2012/154204
[專利文獻7]國際公開第2013/039947號 [Patent Document 7] International Publication No. 2013/039947
[專利文獻8]國際公開第2013/170030號 [Patent Document 8] International Publication No. 2013/170030
[專利文獻9]國際公開第2013/170165號 [Patent Document 9] International Publication No. 2013/170165
[專利文獻10]國際公開第2014/142298號 [Patent Document 10] International Publication No. 2014/142298
[專利文獻11]國際公開第2014/165075號 [Patent Document 11] International Publication No. 2014/165075
[非專利文獻1]Antimicrobial Resistance (2002) Mar 1,34,p.634-640. [Non-Patent Document 1] Antimicrobial Resistance (2002) Mar 1, 34, p. 634-640.
[非專利文獻2]J. Antimicrob. Chemother. (2003) Jan 14,51,p.347-352. [Non-Patent Document 2] J. Antimicrob. Chemother. (2003) Jan 14, 51, p. 347-352.
[非專利文獻3]Jpn. J. Antibiotics (2006),59(5),p.355-363. [Non-Patent Document 3] Jpn. J. Antibiotics (2006), 59(5), p. 355-363.
[非專利文獻4]J. Biol. Chem. (1995) Dec 22,270,p.30384-30391. [Non-Patent Document 4] J. Biol. Chem. (1995) Dec 22, 270, p. 30384-30391.
[非專利文獻5]J. Bacteriol. (1987),169,p.5408-5415 [Non-Patent Document 5] J. Bacteriol. (1987), 169, p. 5408-5415
[非專利文獻6]J. Med. Chem. (2002),45,p3112-3129. [Non-Patent Document 6] J. Med. Chem. (2002), 45, p3112-3129.
[非專利文獻7]Proc. Natl. Acad. Sci. USA (2007),104,p18433-18438. [Non-Patent Document 7] Proc. Natl. Acad. Sci. USA (2007), 104, p18433-18438.
[非專利文獻8]Chem. Biol. (2011),18,p38-47. [Non-Patent Document 8] Chem. Biol. (2011), 18, p38-47.
[非專利文獻9]Bioorg. Med. Chem. (2011),19,p852-860. [Non-Patent Document 9] Bioorg. Med. Chem. (2011), 19, p852-860.
[非專利文獻10]Bioorg. Med. Chem. Lett. (2011),21,p1155-1161. [Non-Patent Document 10] Bioorg. Med. Chem. Lett. (2011), 21, p1155-1161.
[非專利文獻11]Current Med. Chem. (2012),19,p2038-2050. [Non-Patent Document 11] Current Med. Chem. (2012), 19, p2038-2050.
[非專利文獻12]Bioorg. Med. Chem. Lett. (2013),23,p2362- 2367. [Non-Patent Document 12] Bioorg. Med. Chem. Lett. (2013), 23, p2362- 2367.
[非專利文獻13]J. Med. Chem. (2013),56,p6954-6966. [Non-Patent Document 13] J. Med. Chem. (2013), 56, p6954-6966.
然而,專利文獻5中所揭示之化合物均於二乙炔基末端部分具有芳香族環或環丙基之環結構。專利文獻5中未揭示於二乙炔基末端部分具有直鏈烷基結構之化合物。又,專利文獻5中亦未揭示於二乙炔基末端部分具有羥基之化合物。 However, the compounds disclosed in Patent Document 5 each have a ring structure of an aromatic ring or a cyclopropyl group at the terminal portion of the diacetylene group. Patent Document 5 does not disclose a compound having a linear alkyl structure at a terminal portion of a diacetylenic group. Further, Patent Document 5 does not disclose a compound having a hydroxyl group at a terminal portion of a diacetylenic group.
本發明之課題在於提供一種對以綠膿桿菌為代表之革蘭氏陰性細菌及其耐藥性菌具有較強之抗菌活性而作為醫藥品有用之新穎化合物。 An object of the present invention is to provide a novel compound which is useful as a pharmaceutical product for having a strong antibacterial activity against Gram-negative bacteria represented by Pseudomonas aeruginosa and its resistant bacteria.
本發明者等人經過努力研究,結果發現於二乙炔基末端部分具有3-羥基丙基之以下述式[1]表示之N-羥基-2-{[4-(7-羥基庚-1,3-二炔-1-基)苯甲醯基](甲基)胺基}-N',2-二甲基丙二醯胺可解決上述課題,從而完成本發明。 The inventors of the present invention have diligently studied and found that N-hydroxy-2-{[4-(7-hydroxyhepta-1) represented by the following formula [1] has a 3-hydroxypropyl group at the terminal portion of the diacetylene group. 3-Diyn-1-yl)benzhydryl](methyl)amino}-N',2-dimethylpropanediamine can solve the above problems, thereby completing the present invention.
本發明如下所述。 The invention is as follows.
一種化合物或其藥學上所容許之鹽,其係式[1]所表示之N-羥基-
2-{[4-(7-羥基庚-1,3-二炔-1-基)苯甲醯基](甲基)胺基}-N',2-二甲基丙二醯胺,
一種化合物或其藥學上所容許之鹽,其係式[2]所表示之(2S)-N-羥基-2-{[4-(7-羥基庚-1,3-二炔-1-基)苯甲醯基](甲基)胺基}-N',2-二甲基丙二醯胺,
一種醫藥組合物,其含有如上述(1)或(2)之化合物或其藥學上所容許之鹽。 A pharmaceutical composition comprising the compound of the above (1) or (2) or a pharmaceutically acceptable salt thereof.
一種抗菌劑,其含有如上述(1)或(2)之化合物或其藥學上所容許之鹽。 An antibacterial agent comprising the compound of the above (1) or (2) or a pharmaceutically acceptable salt thereof.
本發明之新穎異羥肟酸衍生物對以綠膿桿菌為代表之革蘭氏陰性細菌及其耐藥性菌具有較強之抗菌活性。 The novel hydroxamic acid derivative of the present invention has strong antibacterial activity against Gram-negative bacteria represented by Pseudomonas aeruginosa and resistant bacteria thereof.
以下,對用以實施本發明之形態進行詳細說明。再者,本發明並不限定於以下之實施形態,可於其主旨之範圍內進行各種變化而實施。 Hereinafter, the form for carrying out the invention will be described in detail. The present invention is not limited to the embodiments described below, and various modifications can be made without departing from the spirit and scope of the invention.
於本發明中,所謂「藥學上所容許之鹽」,意指於細菌感染症之化學療法及預防中所使用之鹽。 In the present invention, the term "pharmaceutically acceptable salt" means a salt used in chemotherapy and prevention of bacterial infection.
作為「藥學上所容許之鹽」,例如可列舉:與乙酸、丙酸、丁酸、甲酸、三氟乙酸、順丁烯二酸、酒石酸、檸檬酸、硬脂酸、琥珀酸、乙基琥珀酸、丙二酸、乳糖酸、葡萄糖酸、葡庚糖酸、苯甲酸、甲磺酸、乙磺酸、2-羥基乙磺酸、苯磺酸、對甲苯磺酸(tosic acid)、月桂基硫酸、蘋果酸、天冬胺酸、谷胺酸、己二酸、半胱胺酸、N-乙醯半胱胺酸、鹽酸、氫溴酸、磷酸、硫酸、氫碘酸、菸鹼酸、草酸、苦味酸、硫氰酸、十一烷酸、丙烯酸聚合物及羧基乙烯基聚合物(carboxy vinyl polymer)等酸之鹽,與嗎啉及哌啶等有機胺之鹽,以及與胺基酸之鹽等。 Examples of the "pharmaceutically acceptable salt" include acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, and ethyl amber. Acid, malonic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, tosic acid, lauryl Sulfuric acid, malic acid, aspartic acid, glutamic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, Acid salts such as oxalic acid, picric acid, thiocyanic acid, undecanoic acid, acrylic acid polymers, and carboxy vinyl polymers, salts with organic amines such as morpholine and piperidine, and amino acids Salt and so on.
作為「藥學上所容許之鹽」,亦可為與無機鹼之鹽。作為與無機鹼之鹽,例如可列舉:鋰鹽、鈉鹽、鉀鹽、鎂鹽及鈣鹽等。 As a "pharmaceutically acceptable salt", it may be a salt with an inorganic base. Examples of the salt with the inorganic base include a lithium salt, a sodium salt, a potassium salt, a magnesium salt, and a calcium salt.
關於本發明之化合物(以下所謂「本發明之化合物」,係於包含式[1]所表示之化合物、式[2]所表示之化合物或該等之藥學上所容許之鹽之情形的含義下使用),可形成水合物,亦可形成溶劑合物。於本發明之化合物形成水合物或溶劑合物之情形時,該等亦包含於本發明 之範圍內。 The compound of the present invention (hereinafter referred to as "the compound of the present invention" is used in the sense of the case where the compound represented by the formula [1], the compound represented by the formula [2] or the pharmaceutically acceptable salt thereof is contained. When used, a hydrate can be formed, and a solvate can also be formed. In the case where the compound of the present invention forms a hydrate or a solvate, these are also included in the present invention. Within the scope.
於本發明之化合物形成「溶劑合物」之情形時之所謂「溶劑」,只要無特別說明,例如意指極性溶劑(例如甲醇、乙醇、1-丙醇、2-丙醇及丁醇等醇系溶劑以及乙酸乙酯等)、惰性溶劑(例如氯仿及二氯甲烷等鹵化烴系溶劑,二***、異丙醚、四氫呋喃及二烷等醚系溶劑,二甲基甲醯胺及二甲基乙醯胺等醯胺系溶劑,二甲基亞碸及乙腈等非質子性溶劑,甲苯等芳香族烴類以及己烷及環己烷等烴類等)、2-丁酮及丙酮等。 The term "solvent" in the case where the compound of the present invention forms a "solvate" means, for example, a polar solvent (for example, an alcohol such as methanol, ethanol, 1-propanol, 2-propanol or butanol, unless otherwise specified). a solvent, ethyl acetate, etc.), an inert solvent (for example, a halogenated hydrocarbon solvent such as chloroform or dichloromethane, diethyl ether, diisopropyl ether, tetrahydrofuran, and An ether solvent such as an alkane; a guanamine solvent such as dimethylformamide or dimethylacetamide; an aprotic solvent such as dimethyl hydrazine or acetonitrile; an aromatic hydrocarbon such as toluene; and hexane and cyclohexane A hydrocarbon such as an alkane or the like, 2-butanone or acetone.
作為「溶劑」,亦可為此處所例示之溶劑之混合溶劑。 The "solvent" may also be a mixed solvent of the solvent exemplified herein.
於本發明中,所謂「抗菌劑」,意指具有作用於革蘭氏陽性細菌或革蘭氏陰性細菌等細菌而抑制其生長或將其殺滅之能力的物質。亦可為如抑制細菌繁殖或將一部分細菌殺滅而減少其數量者。 In the present invention, the term "antibacterial agent" means a substance having an ability to inhibit growth or kill a bacterium such as a Gram-positive bacterium or a Gram-negative bacterium. It can also be reduced in number, such as inhibiting bacterial growth or killing a portion of the bacteria.
作為革蘭氏陽性細菌,例如可列舉:葡萄球菌屬(金黃色葡萄球菌及表皮葡萄球菌等)、鏈球菌屬(釀膿鏈球菌、B型鏈球菌及肺炎球菌等)、腸球菌屬(糞腸球菌及屎腸球菌等)等。 Examples of the Gram-positive bacteria include Staphylococcus (S. aureus and Staphylococcus epidermidis), Streptococcus (Streptococcus pyogenes, Streptococcus B and Streptococcus pneumoniae), Enterococcus (feces) Enterococcus, Enterococcus faecium, etc.).
作為革蘭氏陰性細菌,例如可列舉:假單胞菌屬(綠膿桿菌等)、大腸桿菌屬(大腸桿菌等)、克留氏菌屬(肺炎桿菌及產酸克留氏菌(Klebsiella oxytoca)等)、嗜血桿菌屬(流行性感冒病毒及副流行性感冒病毒等)、包台拉菌屬(百日咳菌及支氣管敗血症菌等)、沙雷氏菌屬(黏質沙雷氏菌(Serratia marcescens)等)、變形桿菌屬(普通變形桿菌(Proteus vulgaris)及奇異變形桿菌(Proteus mirabilis)等)、腸桿菌屬(產氣腸桿菌(Enterobacter aerogenes)及陰溝腸桿菌(Enterobacter cloacae)等)、曲桿菌屬(空腸曲桿菌等)、檸檬酸桿菌屬(佛氏檸檬酸桿菌(Citrobacter freundii)等)、普羅威登斯菌(Providencia)屬(斯氏普羅威登斯菌(Providencia stuartii)等)、窄食單胞菌(Stenotrophomonas)屬(嗜麥芽窄食單胞菌(Stenotrophomonas maltophilia)等)、弧菌屬(腸炎弧菌 及霍亂菌等)、摩根氏菌屬(摩根氏菌(Morganella morganii)等)、沙門氏桿菌屬(傷寒沙門氏桿菌及副傷寒沙門氏桿菌等)、志賀氏桿菌屬(赤痢菌等)、不動桿菌屬(鮑氏不動桿菌(Acinetobacter baumannii)及乙酸鈣不動桿菌(Acinetobacter calcoaceticus)等)、軍團菌屬(嗜肺性軍團菌(Legionella pneumophilia)等)、擬桿菌屬(脆弱擬桿菌(Bacteroides fragilis)等)、奈瑟菌屬(淋菌及腦膜炎菌等)、莫拉菌屬(卡他莫拉菌(Moraxella catarrhalis)等)、披衣菌屬(沙眼披衣菌(Chlamydia trachomatis)及鸚鵡熱披衣菌(Chlamydia psittaci)等)及螺旋桿菌屬(幽門螺旋桿菌(Helicobacter pylori)等)等。本發明之化合物可較佳地用作針對革蘭氏陰性細菌之抗菌劑。 Examples of the Gram-negative bacteria include Pseudomonas (Pseudomonas aeruginosa, etc.), Escherichia coli (Escherichia coli, etc.), and Klebsiella (Klebsiella pneumoniae and Klebsiella oxytoca). ), etc., Haemophilus (influenza virus and parainfluenza virus, etc.), typhus (pertussis and bronchial septicemia, etc.), Serratia (Serratia serrata ( Serratia marcescens), etc., Proteus (Proteus vulgaris and Proteus mirabilis), Enterobacter (Enterobacter aerogenes) and Enterobacter cloacae (Enterobacter cloacae) , Aspergillus (C. jejuni, etc.), Citrobacter f. (Citrobacter freundii, etc.), Providencia (Providencia stuartii), etc. ), Stenotrophomonas (Stenotrophomonas maltophilia, etc.), Vibrio (Vibrio cholerae) And cholera bacteria, etc., Morganella (Morganella morganii, etc.), Salmonella (S. typhimurium and Salmonella paratyphimurium, etc.), Shigella (erythrobacteria, etc.), not moving Bacillus (Acinetobacter baumannii and Acinetobacter calcoaceticus, etc.), Legionella (Legionella pneumophilia, etc.), Bacteroides (Bacteroides fragilis) Etc.), Neisseria (goniophagous and meningitis), Moraxella (Moraxella catarrhalis, etc.), Chlamydia (Chlamydia trachomatis) and parrot hot cloak Chlamydia psittaci, etc., and Helicobacter (Helicobacter pylori, etc.). The compound of the present invention can be preferably used as an antibacterial agent against Gram-negative bacteria.
本發明之下述式[1]
所表示之N-羥基-2-{[4-(7-羥基庚-1,3-二炔-1-基)苯甲醯基](甲基)胺基}-N',2-二甲基丙二醯胺可存在光學異構物,式[1]所表示之化合物包括該等光學異構物及光學異構物之混合物。醫藥組合物或抗菌劑可含有特定之光學異構物,亦可含有光學異構物之混合物、尤其是外消旋體。 N-hydroxy-2-{[4-(7-hydroxyhept-1,3-1,3-diyn-1-yl)benzylidene](methyl)amino}-N', 2-dimethyl The propylideneamine may have an optical isomer, and the compound represented by the formula [1] includes a mixture of the optical isomers and optical isomers. The pharmaceutical composition or antibacterial agent may contain specific optical isomers, and may also contain mixtures of optical isomers, especially racemates.
本發明包含式[1]所表示之化合物及其藥學上所容許之鹽,亦包含式[1]所表示之化合物及其藥學上所容許之鹽之多晶型。 The present invention includes the compound represented by the formula [1] and a pharmaceutically acceptable salt thereof, and also includes a polymorph of the compound represented by the formula [1] and a pharmaceutically acceptable salt thereof.
本發明之較佳之光學異構物為下述式[2]
所表示之(2S)-N-羥基-2-{[4-(7-羥基庚-1,3-二炔-1-基)苯甲醯基](甲基)胺基}-N',2-二甲基丙二醯胺。 (2S)-N-hydroxy-2-{[4-(7-hydroxyheptyl-1,3-diyn-1-yl)benzylidene](methyl)amino}-N', 2-dimethylpropanediamine.
本發明包含式[2]所表示之化合物及其藥學上所容許之鹽,亦包含式[2]所表示之化合物及其藥學上所容許之鹽之多晶型。 The present invention includes the compound represented by the formula [2] and a pharmaceutically acceptable salt thereof, and also includes a polymorph of the compound represented by the formula [2] and a pharmaceutically acceptable salt thereof.
本發明之化合物可與一種或兩種以上之醫藥上所容許之載體、賦形劑或稀釋劑組合而製成醫藥組合物。 The compound of the present invention can be combined with one or two or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical composition.
作為上述載體、賦形劑及稀釋劑,例如可列舉:水、乳糖、右旋糖、果糖、蔗糖、山梨糖醇、甘露糖醇、聚乙二醇、丙二醇、澱粉、橡膠、明膠、海藻酸鹽、矽酸鈣、磷酸鈣、纖維素、液態糖漿、羥丙基纖維素、羥丙基甲基纖維素、甲基纖維素、聚乙烯吡咯啶酮、烷基對羥基苯并山梨糖醇酯、滑石、硬脂酸鎂、硬脂酸、甘油及各種油(芝麻油、橄欖油及大豆油等)等。 Examples of the carrier, excipient, and diluent include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gelatin, and alginic acid. Salt, calcium citrate, calcium phosphate, cellulose, liquid syrup, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, polyvinylpyrrolidone, alkyl p-hydroxybenzosorbide , talc, magnesium stearate, stearic acid, glycerin and various oils (sesame oil, olive oil and soybean oil, etc.).
關於醫藥組合物,亦可視需要於上述載體、賦形劑或稀釋劑中混合一般使用之增量劑、結合劑、崩解劑、pH值調整劑、溶解劑及調味劑等添加劑。 As the pharmaceutical composition, an additive such as a bulking agent, a binding agent, a disintegrating agent, a pH adjusting agent, a solubilizing agent, and a flavoring agent which are generally used may be mixed with the above-mentioned carrier, excipient or diluent.
關於醫藥組合物,可藉由常用之製劑技術而製備為錠劑、丸劑、膠囊劑、顆粒劑、粉劑、液劑、乳劑、懸浮劑、軟膏劑、注射劑(包括肌肉內注射及靜脈內注射)、靜脈點滴劑及皮膚貼附劑等經口或非經口用醫藥。 The pharmaceutical composition can be prepared into tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, ointments, injections (including intramuscular injections and intravenous injections) by conventional preparation techniques. Oral or non-oral medicine such as intravenous drip and skin patch.
關於本發明之化合物,可對成人患者1天1次或分數次非經口或經口投予30~3000mg、較佳為100~1500mg。較佳之投予形態為靜脈內點滴注射或靜脈內注射,更佳之投予形態為靜脈內點滴注射。關於投予量,可根據成為治療對象之疾病之種類、患者之年齡、體重及症狀等而適當增減。又,本發明之化合物亦可以與其他藥劑之組合之形式使用。 With respect to the compound of the present invention, 30 to 3000 mg, preferably 100 to 1500 mg, may be administered to an adult patient once or several times a day, orally or orally. Preferably, the administration form is intravenous drip injection or intravenous injection, and the preferred administration form is intravenous drip injection. The dose can be appropriately increased or decreased depending on the type of the disease to be treated, the age, weight, and symptoms of the patient. Further, the compound of the present invention can also be used in combination with other agents.
以下,藉由實施例及試驗例更詳細地說明本發明。本發明並不受該等實施例之任何限定。尤其是本發明中之化合物1之合成方法並不限定於以下之方法,亦可採用調換各步驟之順序、經過官能基之保護/去保護等業者周知之方法進行合成。 Hereinafter, the present invention will be described in more detail by way of examples and test examples. The invention is not limited by the examples. In particular, the method for synthesizing the compound 1 in the present invention is not limited to the following methods, and the synthesis may be carried out by a method known in the art of changing the order of each step and protecting/deprotecting the functional group.
MS(質譜)係利用LCMS-IT-TOF(Liquid Chromatography Mass Spectrometry-Ion Trap-Time Of Flight,離子阱-飛行時間液質聯用分析)(Shimadzu)裝置進行測定。作為離子化法,係採用ESI(Electrospray Ionization,電噴灑游離)法、或ESI與APCI(Atmospheric Pressure Chemical Ionization,大氣壓化學離子化)法之雙離子化法。資料係記載實測值(found)。通常觀測到分子離子峰,但於具有羥基(-OH)之化合物之情形時,有時亦觀測到作為碎體峰之H2O脫離之波峰。於鹽之情形時,通常觀測到游離體之分子離子峰或碎體離子峰。 MS (mass spectrometry) was measured by LCMS-IT-TOF (Liquid Chromatography Mass Spectrometry-Ion Trap-Time Of Flight) (Shimadzu) apparatus. As the ionization method, an ESI (Electrospray Ionization) method or a double ionization method using ESI and APCI (Atmospheric Pressure Chemical Ionization) method is employed. The data is recorded as the found value. A molecular ion peak is usually observed, but in the case of a compound having a hydroxyl group (-OH), a peak of H 2 O detachment as a fragment peak is sometimes observed. In the case of salt, a molecular ion peak or a fragment ion peak of the free body is usually observed.
高效液相色譜-質譜分析(LCMS)係採用以下之條件。 High performance liquid chromatography-mass spectrometry (LCMS) was carried out under the following conditions.
測定機械:Agilent公司之Agilent1290及Agilent公司之Agilent6130 Measuring machinery: Agilent 1290 from Agilent and Agilent 6130 from Agilent
管柱:Waters公司之Acquity UPLC® CSHTM C18 1.7μm 2.1×50mm Column: Waters Acquity UPLC ® CSH TM C18 1.7μm 2.1×50mm
離子化法:電子衝擊離子化法(Electron Spray Ionization:ESI) Ionization: Electron Impact Ionization (ESI)
溶劑:A液為含0.1%甲酸之水溶液,B液為含0.1%甲酸之乙腈 Solvent: Liquid A is an aqueous solution containing 0.1% formic acid, and liquid B is acetonitrile containing 0.1% formic acid.
流速:0.8mL/min Flow rate: 0.8mL/min
梯度:0分鐘(A液/B液=80/20)、1.2分鐘(A液/B液=80/20)、1.4分鐘(A液/B液=1/99) Gradient: 0 minutes (A solution / B solution = 80 / 20), 1.2 minutes (A liquid / B liquid = 80 / 20), 1.4 minutes (A liquid / B liquid = 1 / 99)
流速:0.8mL/min(0分鐘~1.2分鐘)、1.0mL/min(1.2分鐘~1.38分鐘) Flow rate: 0.8mL/min (0 minutes to 1.2 minutes), 1.0mL/min (1.2 minutes to 1.38 minutes)
梯度:0分鐘(A液/B液=95/5)、1.2分鐘(A液/B液=50/50)、1.38分鐘(A液/B液=3/97) Gradient: 0 minutes (A liquid / B liquid = 95/5), 1.2 minutes (A liquid / B liquid = 50 / 50), 1.38 minutes (A liquid / B liquid = 3 / 97)
NMR(nuclear magnetic resonance,核磁共振)光譜表示質子NMR,使用四甲基矽烷作為內部基準,將δ值以ppm表示。 The NMR (nuclear magnetic resonance) spectrum indicates proton NMR, using tetramethyl decane as an internal reference, and the δ value is expressed in ppm.
OH型矽膠層析法及NH型矽膠層析法中之載體係使用Grace Japan股份有限公司製造之REVELERISTM等填充管柱。相分離器(Phase Separator)係使用Biotage股份有限公司製造者。 OH NH type silica gel chromatography and chromatography on silica gel type carrier systems used in the manufacture of Grace Japan Co. REVELERIS TM packed column and the like. The phase separator (Phase Separator) is manufactured by Biotage Co., Ltd.
將實施例中之簡稱示於以下。 The abbreviations in the examples are shown below.
AcOEt:乙酸乙酯 AcOEt: ethyl acetate
CuI:碘化銅 CuI: copper iodide
IPE:二異丙醚 IPE: diisopropyl ether
MeOH:甲醇 MeOH: methanol
NBS:N-溴琥珀醯亞胺 NBS: N-bromosuccinimide
PdCl2(PPh3)2:二氯化雙(三苯基膦)鈀(II) PdCl 2 (PPh 3 ) 2 : bis(triphenylphosphine)palladium(II) dichloride
超穩定鈀(Supers-table Pd):三{三[3,5-雙(三氟甲基)苯基]膦}鈀p-TsOH.H2O:對甲苯磺酸一水合物 Supers-table Pd: tris[tris[3,5-bis(trifluoromethyl)phenyl]phosphine}palladium p-TsOH. H 2 O: p-toluenesulfonic acid monohydrate
TEA:三乙基胺 TEA: Triethylamine
THF:四氫呋喃 THF: tetrahydrofuran
s:單峰 s: single peak
br.s.:寬單峰(寬幅單峰) Br.s.: wide single peak (wide single peak)
m:多重峰 m: multiple peak
(2S)-N-羥基-2-{[4-(7-羥基庚-1,3-二炔-1-基)苯甲醯基](甲基)胺基}-N',2-二甲基丙二醯胺(化合物1)
(1)於氮氣環境下於利用專利文獻5(國際公開第2011/132712號)中記載之方法所獲得之(2S)-2-[(4-碘苯甲醯基)(甲基)胺基]-N,2-二甲基-N'-(四氫-2H-吡喃-2-基氧基)丙二醯胺(19.2g)之THF(200mL)懸浮液中於室溫下添加CuI(0.299g)、PdCl2(PPh3)2(0.551g)及TEA(10.9mL)。其後,以5分鐘添加三甲基矽烷基乙炔(5.01g),於室溫下攪拌2小時。利用NH型矽膠(氯仿/MeOH=95/5)對反應混合物進行過濾並濃縮,對所獲得之殘渣利用OH型矽膠管柱層析法(己烷/AcOEt=100/0→0/100)進行精製,將所獲得之淡橙色固體利用IPE進行清洗並使之乾燥而獲得(2S)-N,2-二甲基-2-(甲基{4-[(三甲基矽烷基)乙炔基]苯甲醯基}胺基)-N'-(四氫-2H-吡喃-2-基氧基)丙二醯胺(17.6g,無色固體,97%)。 (1) (2S)-2-[(4-iodobenzylidene)(methyl)amino group obtained by the method described in Patent Document 5 (International Publication No. 2011/132712) under a nitrogen atmosphere. Add a CuI at room temperature in a suspension of -N,2-dimethyl-N'-(tetrahydro-2H-pyran-2-yloxy)propanediamine (19.2 g) in THF (200 mL) (0.299 g), PdCl 2 (PPh 3 ) 2 (0.551 g) and TEA (10.9 mL). Thereafter, trimethyldecyl acetylene (5.01 g) was added over 5 minutes, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated using a EtOAc (EtOAc/MeOH = 95/5), and the obtained residue was subjected to OH type spur column chromatography (hexane/AcOEt=100/0→0/100). Purification, the obtained pale orange solid was washed with IPE and dried to obtain (2S)-N,2-dimethyl-2-(methyl{4-[(trimethyldecyl)ethynyl] Benzomidine}amino)-N'-(tetrahydro-2H-pyran-2-yloxy)propanediamine (17.6 g, colorless solid, 97%).
MS(ESI/APCI dual):m/z=482(M+Na)+,458(M-H)- MS (ESI/APCI dual): m/z = 482 (M+Na) + , 458 (MH) -
1H NMR(600MHz,氯仿-d)δ ppm 0.26(9H,s),1.48-1.90(6H m),[1.80],1.81(3H,s),2.82-2.87(3H,m),[3.13],3.15(3H,s),3.50-3.69 (1H,m),3.82-4.05(1H,m),4.92-5.01(1H,m),7.41-7.48(2H,m),7.48-7.54(2H,m),[6.99],7.62(1H,br.s.),[10.06],10.47(1H,s) 1 H NMR (600MHz, CHLOROFORM -d) δ ppm 0.26 (9H, s), 1.48-1.90 (6H m), [1.80], 1.81 (3H, s), 2.82-2.87 (3H, m), [3.13] , 3.15 (3H, s), 3.50-3.69 (1H, m), 3.82-4.05 (1H, m), 4.92-5.01 (1H, m), 7.41-7.48 (2H, m), 7.48-7.54 (2H, m), [6.99], 7.62 (1H, br.s.), [10.06], 10.47 (1H, s)
(2)於實施例1-(1)中所獲得之化合物(17.1g)之MeOH(250mL)溶液中於冰浴冷卻下添加碳酸鉀(5.14g),於同溫下攪拌50分鐘後,升溫至室溫並攪拌1小時。將反應混合物添加至飽和氯化銨水溶液(1.0L)與氯仿(1.0L)之混合物中並分離有機層,利用氯仿(0.5L)萃取水層。對所收集之有機層進行乾燥(無水硫酸鎂)、過濾、濃縮,對所獲得之粗精製物利用OH型矽膠管柱層析法(己烷/AcOEt=80/20→0/100)進行精製,將所獲得之淡橙色固體利用IPE進行清洗並使之乾燥而獲得(2S)-2-[(4-乙炔基苯甲醯基)(甲基)胺基]-N,2-二甲基-N'-(四氫-2H-吡喃-2-基氧基)丙二醯胺(12.4g,無色固體,86%)。 (2) To a solution of the compound (17.1 g) obtained in Example 1-(1) in MeOH (250 mL). Stir to room temperature and stir for 1 hour. The reaction mixture was added to a mixture of saturated aqueous ammonium chloride (1.0L) and chloroform (1.0L), and the organic layer was separated, and the aqueous layer was extracted with chloroform (0.5 L). The collected organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated, and the obtained crude purified product was purified by OH-type silica gel column chromatography (hexane/AcOEt=80/20→0/100). The obtained pale orange solid was washed with IPE and dried to obtain (2S)-2-[(4-ethynylbenzylidene)(methyl)amino]-N,2-dimethyl -N'-(Tetrahydro-2H-pyran-2-yloxy)propanediamine (12.4 g, colorless solid, 86%).
MS(ESI/APCI dual):m/z=410(M+Na)+,386(M-H)- MS (ESI/APCI dual): m/z = 410 (M+Na) + , 386 (MH) -
1H NMR(600MHz,氯仿-d)δ ppm 1.49-1.91(6H,m),[1.80],1.81(3H,s),2.83-2.87(3H,m),3.12-3.19(1H,m),[3.14],3.16(3H,s),3.53-3.69(1H,m),3.83-4.05(1H,m),4.93-5.01(1H,m),7.44-7.51(2H,m),7.52-7.57(2H,m),[6.98],7.62(1H,br.s.),[10.06],10.47(1H,s) 1 H NMR (600MHz, CHLOROFORM -d) δ ppm 1.49-1.91 (6H, m), [1.80], 1.81 (3H, s), 2.83-2.87 (3H, m), 3.12-3.19 (1H, m), [3.14], 3.16 (3H, s), 3.53-3.69 (1H, m), 3.83-4.05 (1H, m), 4.93-5.01 (1H, m), 7.44-7.51 (2H, m), 7.52-7.57 (2H,m),[6.98],7.62(1H,br.s.),[10.06],10.47(1H,s)
(3)於NBS(6.62g)與三氟乙酸銀(342mg)之丙酮(50mL)混合物中於冰浴冷卻下滴加實施例1-(2)中所獲得之化合物(12.0g)之丙酮(150mL)混合物,於同溫下攪拌1.5小時。將反應混合物添加至飽和碳酸氫鈉水溶液(600mL)中並攪拌0.5小時後,添加氯仿(600mL)並過濾不溶物,分離有機層。利用氯仿(100mL)萃取水層。對所收集之有機層進行乾燥(無水硫酸鎂)、過濾、濃縮。將對所獲得之殘渣添加水(500mL)所獲得之懸浮液攪拌1.5小時後,進行過濾、清洗(水,500mL)。使所獲得之淡橙色固體溶解於氯仿(500mL)。利用水(200mL)清洗所獲得之氯仿溶液,進行乾燥(無水硫酸鎂)、過濾、濃縮。對所獲得之淡橙色固體利用OH型矽膠管柱層析法(氯仿/MeOH=100/0→90/10)進行精製後使之再結晶(AcOEt/IPE)而獲得(2S)-2-{[4-(溴乙炔基)苯甲醯基](甲基)胺基}-N,2-二甲基-N'-(四氫-2H-吡喃-2-基氧基)丙二醯胺(8.02g,56%)。 (3) Acetone (12.0 g) of the compound obtained in Example 1-(2) was added dropwise to a mixture of NBS (6.62 g) and a mixture 150 mL) of the mixture was stirred at the same temperature for 1.5 hours. After the reaction mixture was added to a saturated aqueous solution of sodium hydrogencarbonate (600 mL) and stirred for 0.5 hour, chloroform (600 mL) was added and the insoluble material was filtered, and the organic layer was separated. The aqueous layer was extracted with chloroform (100 mL). The collected organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated. The suspension obtained by adding water (500 mL) to the obtained residue was stirred for 1.5 hours, and then filtered and washed (water, 500 mL). The obtained pale orange solid was dissolved in chloroform (500 mL). The obtained chloroform solution was washed with water (200 mL), dried (anhydrous magnesium sulfate), filtered, and concentrated. The obtained pale orange solid was purified by OH type rubber column chromatography (chloroform / MeOH = 100 / 0 → 90/10) and then recrystallized (AcOEt / IPE) to obtain (2S) - 2 { [4-(Bromoethynyl)benzylidene](methyl)amino}-N,2-dimethyl-N'-(tetrahydro-2H-pyran-2-yloxy)propanedifluoride Amine (8.02 g, 56%).
MS(ESI/APCI dual):m/z=488(M+Na)+,464(M-H)- MS (ESI/APCI dual): m/z = 488 (M+Na) + , 464 (MH) -
1H NMR(600MHz,氯仿-d)δ ppm 1.46-1.90(6H,m),[1.80],1.81(3H,s),2.82-2.87(3H,m),[3.14],3.16(3H,s),3.52-3.68(1H,m),3.82-4.04(1H,m),4.92-5.01(1H,m),7.42-7.53(4H,m),[6.97],7.61(1H,br.s.),[10.05],10.47(1H,s) 1 H NMR (600MHz, CHLOROFORM -d) δ ppm 1.46-1.90 (6H, m), [1.80], 1.81 (3H, s), 2.82-2.87 (3H, m), [3.14], 3.16 (3H, s ), 3.52-3.68 (1H, m), 3.82-4.04 (1H, m), 4.92-5.01 (1H, m), 7.42-7.53 (4H, m), [6.97], 7.61 (1H, br.s. ), [10.05], 10.47 (1H, s)
(4)於超穩定鈀(682mg)及CuI(61mg)之乙腈溶液(40mL)中添加戊-4-炔-1-醇(1.19mL)及TEA(2.70mL)之乙腈(30mL)溶液,滴加實施 例1-(3)中所獲得之化合物(3.0g)之乙腈溶液(40mL),於氮氣環境下於室溫下反應4小時。將反應液於減壓下濃縮,對所獲得之殘留物藉由NH型矽膠層析法(氯仿/MeOH=100/0→90/10)、OH型矽膠層析法(AcOEt/MeOH=100/0)及OH型矽膠層析法(己烷/AcOEt=50/50→0/100)進行精製而獲得(2S)-2-{[4-(7-羥基庚-1,3-二炔-1-基)苯甲醯基](甲基)胺基}-N,2-二甲基-N'-(四氫-2H-吡喃-2-基氧基)丙二醯胺(1.69g,黃色泡狀物,56%)。 (4) Add pent-4-yn-1-ol (1.19 mL) and TEA (2.70 mL) in acetonitrile (30 mL) to a solution of ultra-stable palladium (682 mg) and CuI (61 mg) in acetonitrile (40 mL). Plus implementation An acetonitrile solution (40 mL) of the compound (3.0 g) obtained in Example 1-(3) was reacted at room temperature for 4 hours under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and the obtained residue was purified eluted eluted eluted eluted eluted eluted eluted eluted with 0) and OH type gel chromatography (hexane/AcOEt=50/50→0/100) to obtain (2S)-2-{[4-(7-hydroxyhepta-1,3-diyne- 1-yl)benzylidene](methyl)amino}-N,2-dimethyl-N'-(tetrahydro-2H-pyran-2-yloxy)propanediamine (1.69 g) , yellow bubble, 56%).
LCMS保持時間:0.85分鐘(條件1) LCMS retention time: 0.85 minutes (condition 1)
MS(ESI):m/z=468(M-H)- MS (ESI): m/z = 468 (MH) -
1H NMR(600MHz,氯仿-d)δ ppm 1.75-1.90(2H,m),[1.80],1.81(3H,s),2.46-2.56(2H,m),2.81-2.89(3H,m),[3.14],3.17(3H,s),3.52-3.60(1H,m),3.61-3.69(1H,m),3.75-3.82(2H,m),3.82-3.91(1H,m),3.96-4.05(1H,m),4.91-5.03(1H,m),7.42-7.55(4H,m),[6.97],7.62(1H,br.s.),[10.04],10.46(1H,br.s.) 1 H NMR (600MHz, CHLOROFORM -d) δ ppm 1.75-1.90 (2H, m), [1.80], 1.81 (3H, s), 2.46-2.56 (2H, m), 2.81-2.89 (3H, m), [3.14], 3.17 (3H, s), 3.52-3.60 (1H, m), 3.61-3.69 (1H, m), 3.75-3.82 (2H, m), 3.82-3.91 (1H, m), 3.96-4.05 (1H, m), 4.91-5.03 (1H, m), 7.42-7.55 (4H, m), [6.97], 7.62 (1H, br.s.), [10.04], 10.46 (1H, br.s. )
(5)於實施例1-(4)中所獲得之化合物(1.69g)之MeOH(30mL)溶液中添加p-TsOH.H2O(343mg),於室溫下攪拌1小時。將反應液於冰浴中冷卻後,添加飽和碳酸氫鈉溶液(2mL)及水(40mL),利用氯仿/THF/MeOH=75/15/10進行萃取(40mL×6次)。於水層中添加氯化鈉直至飽和,再次利用氯仿/THF/MeOH=75/15/10進行萃取(40mL×6次),利用相分離器分離有機層並於減壓下將其蒸餾去除。對所獲得 之殘留物藉由OH型矽膠層析法(氯仿/MeOH=99/1→90/10)進行精製而獲得(2S)-N-羥基-2-{[4-(7-羥基庚-1,3-二炔-1-基)苯甲醯基](甲基)胺基}-N',2-二甲基丙二醯胺(化合物1,1.14g,黃色泡狀物,82%)。 (5) p-TsOH was added to a solution of the compound (1.69 g) obtained in Example 1-(4) in MeOH (30 mL). H 2 O (343 mg) was stirred at room temperature for 1 hour. After the reaction mixture was cooled in an ice-bath, brine (2 mL) and EtOAc (EtOAc) Sodium chloride was added to the aqueous layer until saturation, and extracted again with chloroform / THF / MeOH = 75 / 15/10 (40 mL × 6 times), and the organic layer was separated by a phase separator and distilled off under reduced pressure. The residue obtained was purified by OH type gel chromatography (chloroform / MeOH = 99 / 1 → 90/10) to obtain (2S)-N-hydroxy-2-{[4-(7-hydroxyglycol). -1,3-diacetyl-1-yl)benzylidene](methyl)amino}-N',2-dimethylpropanediamine (Compound 1, 1.14 g, yellow foam, 82 %).
LCMS保持時間:1.00分鐘(條件2) LCMS retention time: 1.00 minutes (condition 2)
MS(ESI):m/z=384(M-H)- MS (ESI): m/z =384 (MH) -
1H NMR(600MHz,CD3OD)δ ppm 1.73-1.81(2H,m),1.76(3H,s),2.46-2.51(2H,m),2.78(3H,s),3.13(3H,s),3.63-3.68(2H,m),7.49-7.59(4H,m) 1 H NMR (600 MHz, CD 3 OD) δ ppm 1.73-1.81 (2H, m), 1.76 (3H, s), 2.46-2.51 (2H, m), 2.78 (3H, s), 3.13 (3H, s) , 3.63 - 3.68 (2H, m), 7.49 - 7.59 (4H, m)
藉由以下之試驗確認本發明化合物之作用。 The effects of the compounds of the present invention were confirmed by the following tests.
試驗例1 抗菌活性評估試驗 Test Example 1 Antibacterial activity evaluation test
最小發育阻止濃度(MIC)測定係依據CLSI(美國臨床實驗室標準化協會)標準法,使用下述所示之微量液體稀釋法。 The minimum developmental inhibition concentration (MIC) was determined according to the CLSI (American Clinical Laboratory Standardization Association) standard method using the micro liquid dilution method shown below.
關於嗜肺性軍團菌ATCC33152,刮取於BCYE(Buffered charcoal yeast extract,緩衝活性碳酵母萃取液)瓊脂培養基中培養72小時所獲得之受檢菌體,使之以相當於0.5 McFarland標準之濃度懸浮,將所獲得之懸浮液稀釋至10倍而作為接種菌液。將接種菌液0.005mL接種於包含受檢化合物之BYE(Buffered yeast extract,緩衝酵母萃取液)α培養基中,並於35℃下培養72小時。 For the Legionella pneumophila ATCC33152, the test cells obtained by culturing for 72 hours in BCYE (Buffered charcoal yeast extract) agar medium were suspended at a concentration equivalent to 0.5 McFarland standard. The obtained suspension was diluted to 10 times as an inoculum. 0.005 mL of the inoculum was inoculated into BYE (Buffered yeast extract) α medium containing the test compound, and cultured at 35 ° C for 72 hours.
關於流行性感冒嗜血桿菌(Haemophilus influenza)ATCC43095,刮取於巧克力II瓊脂培養基中培養24小時所獲得之受檢菌體,使之以相當於0.5 McFarland標準之濃度懸浮,將所獲得之懸浮液稀釋至10倍而作為接種菌液。將接種菌液0.005mL接種於包含受檢化合物之HTM(Haemophilus Test Medium,嗜血桿菌檢測培養基)培養基中,並於35℃下培養22小時。 About Haemophilus influenza ATCC43095, the test cells obtained by culturing for 24 hours in chocolate II agar medium were suspended in a concentration equivalent to 0.5 McFarland standard, and the obtained suspension was obtained. Dilute to 10 times as an inoculum. 0.005 mL of the inoculum was inoculated into a HTM (Haemophilus Test Medium) medium containing the test compound, and cultured at 35 ° C for 22 hours.
關於上述菌株以外之菌株,刮取於心臟浸出液(heart infusion)瓊脂培養基中培養1晚所獲得之受檢菌體,使之以相當於0.5 McFarland 標準之濃度懸浮,將所獲得之懸浮液稀釋至10倍而作為接種菌液。將接種菌液0.005mL接種於包含受檢化合物之陽離子調整馬-欣二氏瓊脂(Mueller Hinton Agar)培養基、或者包含受檢化合物之以最終濃度成為5%之方式添加有人類血清白蛋白(HSA)之陽離子調整馬-欣二氏瓊脂培養基中,並於35℃下培養18小時。取無法以肉眼確認到細菌發育之最小藥劑濃度作為MIC。 For strains other than the above strains, the test cells obtained by incubating in a heart infusion agar medium for 1 night were made to correspond to 0.5 McFarland. The standard concentration was suspended, and the obtained suspension was diluted to 10 times as an inoculum. 0.005 mL of the inoculum was inoculated to the cation-adjusted Mueller Hinton Agar medium containing the test compound, or the human serum albumin (HSA) was added in such a manner that the final concentration was 5%. The cations were adjusted in Ma-Xin's agar medium and incubated at 35 ° C for 18 hours. The minimum drug concentration at which bacterial development cannot be visually confirmed is taken as the MIC.
將化合物1之試驗結果示於表1。 The test results of Compound 1 are shown in Table 1.
測定綠膿桿菌30株及肺炎桿菌27株之臨床分離株之最小發育阻止濃度(MIC),算出成功阻止90%菌株發育之MIC,記為MIC90。各臨床分離株之MIC測定係以與試驗例1所示者相同之方式進行。 The minimum developmental inhibitory concentration (MIC) of the clinical isolates of 30 strains of Pseudomonas aeruginosa and 27 strains of Klebsiella pneumoniae was determined, and the MIC which successfully prevented the development of 90% of the strains was calculated and recorded as MIC 90 . The MIC measurement of each clinical isolate was carried out in the same manner as in Test Example 1.
關於化合物1之MIC90,於綠膿桿菌之情形時為2μg/mL,於肺炎桿菌之情形時為4μg/mL。 The MIC 90 of Compound 1 was 2 μg/mL in the case of Pseudomonas aeruginosa and 4 μg/mL in the case of Klebsiella pneumoniae.
使用綠膿桿菌TS88株(臨床分離株)作為細菌。刮取於心臟浸出液瓊脂培養基中培養1晚所獲得之菌體,使之懸浮於生理食鹽液,以成為相當於3.5 McFarland標準之濃度進行製備。利用含有3w/v%黏蛋白之生理食鹽液稀釋所獲得之懸浮液以使之成為約6×105CFU(Colony-Forming Units,菌落形成單位)/mL而作為接種菌液。對小鼠(ICR(Institute of Cancer Research,美國癌症研究所)系,雄性,4.5週齡)於腹腔內接種0.5mL之接種菌液而使之感染,接種1小時後於靜脈內投予化合物1(6.25mg/kg)或介質(11w/v%β-環糊精磺基丁醚鈉鹽(註冊商標:CAPTISOL,Ligand公司))。 Pseudomonas aeruginosa TS88 strain (clinical isolate) was used as a bacterium. The cells obtained by culturing for one night in heart agar extract agar medium were suspended in physiological saline solution to prepare a concentration equivalent to 3.5 McFarland standard. The obtained suspension was diluted with a physiological saline solution containing 3 w/v% of mucin so as to be about 6 × 10 5 CFU (Colony-Forming Units) / mL as an inoculum. Mice (ICR (Institute of Cancer Research), male, 4.5 weeks old) were intraperitoneally inoculated with 0.5 mL of inoculum to infect them, and 1 hour after inoculation, Compound 1 was administered intravenously. (6.25 mg/kg) or medium (11 w/v% β-cyclodextrin sulfobutyl ether sodium salt (registered trademark: CAPTISOL, Ligand)).
化合物1投予群中之接種3天後之生存率為100%(8例中8例生存),介質投予群中之生存率為0%(8例全部死亡)。 The survival rate after 3 days of inoculation in Compound 1 group was 100% (8 of 8 patients survived), and the survival rate in the vehicle administration group was 0% (8 patients all died).
於麻醉下以50分鐘對豚鼠靜脈內持續投予化合物1 0mg/kg(對照)及150mg/kg(5mL/kg/50min),研究對心電圖之影響。關於對照群,以相同之方式投予11%CAPTISOL(註冊商標,Ligand公司)(pH值9)。於人工呼吸及戊巴比妥麻醉下,使用心電計測定四肢標準誘導(第II誘導)心電圖,自試驗物質投予開始15分鐘前起至投予結束30分鐘後為止每隔5分鐘實施解析。使用Bazett式(QTcB=QT/RR)求出修正QTcB,算出自基準線值[試驗物質之投予前3個時間點(-15、-10及-5分 鐘)之平均值]之變化率(△QTcB)。 The guinea pigs were intravenously administered with 10 mg/kg (control) and 150 mg/kg (5 mL/kg/50 min) intravenously under anesthesia for 50 minutes to study the effect on electrocardiogram. For the control group, 11% CAPTISOL (registered trademark, Ligand) (pH 9) was administered in the same manner. Under artificial respiration and pentobarbital anesthesia, the electrocardiogram was used to measure the standard induction (II-induced) electrocardiogram of the extremities, and the analysis was performed every 5 minutes from 15 minutes before the start of the test substance administration to 30 minutes after the end of the administration. . Use Bazett style (QTcB=QT/ RR) The corrected QTcB is obtained, and the rate of change (ΔQTcB) from the reference line value [the average value of the three time points (-15, -10, and -5 minutes before the administration of the test substance)] is calculated.
化合物1之投予結束時之△QTcB為+2.0%,最大為+3.2%(投予開始後40分鐘)(對照群:-2.8~-1.1%),未確認到因投予被試驗物質而對QTcB所產生之明顯影響。可確認化合物1於安全性方面亦優異。 At the end of the administration of Compound 1, ΔQTcB was +2.0%, and the maximum was +3.2% (40 minutes after the start of administration) (control group: -2.8 to -1.1%), and it was not confirmed that the test substance was administered. The obvious impact of QTcB. It was confirmed that Compound 1 is also excellent in safety.
本發明之新穎異羥肟酸衍生物對以綠膿桿菌為代表之革蘭氏陰性細菌及其耐藥性菌具有較強之抗菌活性,而可用作醫藥品。 The novel hydroxamic acid derivative of the present invention has strong antibacterial activity against Gram-negative bacteria represented by Pseudomonas aeruginosa and its resistant bacteria, and can be used as a pharmaceutical.
Claims (4)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2013217011A JP2016210682A (en) | 2013-10-18 | 2013-10-18 | Hydroxamic acid derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
TW201602064A true TW201602064A (en) | 2016-01-16 |
Family
ID=52828237
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW103136097A TW201602064A (en) | 2013-10-18 | 2014-10-17 | Hydroxamic acid derivative |
Country Status (3)
Country | Link |
---|---|
JP (1) | JP2016210682A (en) |
TW (1) | TW201602064A (en) |
WO (1) | WO2015056798A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105073710B (en) | 2013-03-15 | 2018-02-16 | 富山化学工业株式会社 | New hydroxamic acid derivs or its salt |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2170814B1 (en) * | 2007-06-12 | 2016-08-17 | Achaogen, Inc. | Antibacterial agents |
SG184958A1 (en) * | 2010-04-20 | 2012-11-29 | Taisho Pharmaceutical Co Ltd | Novel hydroxamic acid derivative |
JP6006609B2 (en) * | 2011-10-19 | 2016-10-12 | 大正製薬株式会社 | Pharmaceuticals containing novel hydroxamic acid derivatives |
WO2013170165A1 (en) * | 2012-05-10 | 2013-11-14 | Achaogen, Inc. | Antibacterial agents |
WO2014165075A1 (en) * | 2013-03-12 | 2014-10-09 | Achaogen, Inc. | Antibacterial agents |
-
2013
- 2013-10-18 JP JP2013217011A patent/JP2016210682A/en active Pending
-
2014
- 2014-10-17 TW TW103136097A patent/TW201602064A/en unknown
- 2014-10-17 WO PCT/JP2014/077749 patent/WO2015056798A1/en active Application Filing
Also Published As
Publication number | Publication date |
---|---|
JP2016210682A (en) | 2016-12-15 |
WO2015056798A1 (en) | 2015-04-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2010024356A1 (en) | Novel hydroxamic acid derivative having naphthyridine-n-oxide | |
CN105682655B (en) | Antimicrobial compounds | |
KR20130140868A (en) | Isoxazole derivatives useful as antibaterial agents | |
IL203910A (en) | Therapeutic isoxazole compounds | |
JP6130600B2 (en) | Tricyclic benzoxabolol compound, production method and use thereof | |
Zhang et al. | Synthesis and antigastric ulcer activity of novel 5-isoproyl-3, 8-dimethylazulene derivatives | |
TW201602065A (en) | Hydroxamic acid derivative | |
KR20160026856A (en) | Anti-bacterial siderophore-aminopenicillin conjugates | |
WO2015056800A1 (en) | Hydroxamic acid derivative | |
CA3022102A1 (en) | Benzoylglycine derivatives and methods of making and using same | |
JP6487333B2 (en) | Spiroisoxazoline compounds having activity to enhance the activity of antibiotics | |
JP2023166378A (en) | Metabolically stable n-acylaminooxadiazoles useful as antibacterial agents | |
TW201602064A (en) | Hydroxamic acid derivative | |
JP2020508999A (en) | Ciprofloxacin derivative antibacterial drug | |
JP2014114278A (en) | Antibacterial agent | |
CN107531613B (en) | Benzo-aliphatic ring-substituted alkylamine compound and application thereof | |
WO2014049356A1 (en) | Erythromycin ketolide derivatives bearing c-10 modifications | |
Muhammad et al. | Synthesis, antibacterial activity and molecular docking studies of N’-benzylidene/N’-(1-phenylethylidene) hexa-2, 4-dienehydrazide derivatives | |
KR20170036106A (en) | C-4''-substituted macrolide compound | |
JP2016199497A (en) | Medicine containing hydroxamic acid derivative | |
JP2016199499A (en) | Crystal forms of compounds having (2s)-2-methylamino-n-hydroxy-n',2-dimethylpropanediamide and production method thereof | |
Yıldız et al. | Discovery of quinolinequinones with N-phenylpiperazine by conversion of hydroxyquinoline as a new class of antimicrobial agents targeting resistant pathogenic microorganisms | |
CN110437177B (en) | Pleuromutilin derivative and preparation method and application thereof | |
EP3546454B1 (en) | Benzoheterocyclyl alkylamine compound and use thereof | |
CN109121411B (en) | Pyrimido-isoquinoline-quinone derived compounds, pharmaceutical compositions containing them and their use in the treatment of bacterial diseases |