WO2004018453A1 - Derive de proline - Google Patents
Derive de proline Download PDFInfo
- Publication number
- WO2004018453A1 WO2004018453A1 PCT/JP2003/010548 JP0310548W WO2004018453A1 WO 2004018453 A1 WO2004018453 A1 WO 2004018453A1 JP 0310548 W JP0310548 W JP 0310548W WO 2004018453 A1 WO2004018453 A1 WO 2004018453A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- compound
- pyrrolidine
- methyl
- piperazinyl
- Prior art date
Links
- 150000003147 proline derivatives Chemical class 0.000 title claims abstract description 31
- 150000001875 compounds Chemical class 0.000 claims abstract description 213
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 70
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 28
- 125000005843 halogen group Chemical group 0.000 claims abstract description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 27
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 22
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 21
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 13
- 241000894006 Bacteria Species 0.000 claims abstract description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 10
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- -1 sulfonyloxy group Chemical group 0.000 claims description 158
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 134
- 239000000203 mixture Substances 0.000 claims description 68
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 59
- 125000003277 amino group Chemical group 0.000 claims description 37
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 125000006239 protecting group Chemical group 0.000 claims description 24
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 15
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 14
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- 239000003242 anti bacterial agent Substances 0.000 claims description 13
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000002947 alkylene group Chemical group 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 4
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 239000000470 constituent Substances 0.000 claims description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 4
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 150000005676 cyclic carbonates Chemical group 0.000 claims description 3
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical group O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 229910052751 metal Chemical class 0.000 claims description 3
- 239000002184 metal Chemical class 0.000 claims description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 4
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 16
- 229940124350 antibacterial drug Drugs 0.000 abstract 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 80
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 238000004519 manufacturing process Methods 0.000 description 47
- 239000000243 solution Substances 0.000 description 44
- 230000002829 reductive effect Effects 0.000 description 43
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
- 229910052739 hydrogen Inorganic materials 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 38
- 238000005481 NMR spectroscopy Methods 0.000 description 38
- 239000002904 solvent Substances 0.000 description 35
- 238000000034 method Methods 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000012044 organic layer Substances 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 239000013078 crystal Substances 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 238000001816 cooling Methods 0.000 description 18
- 239000012043 crude product Substances 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 17
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 230000000844 anti-bacterial effect Effects 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 206010041925 Staphylococcal infections Diseases 0.000 description 11
- 208000015181 infectious disease Diseases 0.000 description 11
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 11
- 239000002994 raw material Substances 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- 241000191967 Staphylococcus aureus Species 0.000 description 7
- 125000003282 alkyl amino group Chemical group 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- YZBOVSFWWNVKRJ-UHFFFAOYSA-M 2-butoxycarbonylbenzoate Chemical compound CCCCOC(=O)C1=CC=CC=C1C([O-])=O YZBOVSFWWNVKRJ-UHFFFAOYSA-M 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000012267 brine Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- 229940126062 Compound A Drugs 0.000 description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 125000004193 piperazinyl group Chemical group 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-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
- 241000193998 Streptococcus pneumoniae Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- AILAQOYFPLQIFN-UHFFFAOYSA-N butyl piperazine-1-carboxylate Chemical compound CCCCOC(=O)N1CCNCC1 AILAQOYFPLQIFN-UHFFFAOYSA-N 0.000 description 3
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 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
- 238000000354 decomposition reaction Methods 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000194033 Enterococcus Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound 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
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000003113 dilution method Methods 0.000 description 2
- 231100000676 disease causative agent Toxicity 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
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- REOJLIXKJWXUGB-UHFFFAOYSA-N mofebutazone Chemical group O=C1C(CCCC)C(=O)NN1C1=CC=CC=C1 REOJLIXKJWXUGB-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- HNHVTXYLRVGMHD-UHFFFAOYSA-N n-butyl isocyanate Chemical compound CCCCN=C=O HNHVTXYLRVGMHD-UHFFFAOYSA-N 0.000 description 1
- KDGKTJGPFXIBEB-UHFFFAOYSA-N n-hydroxyformamide Chemical compound ONC=O KDGKTJGPFXIBEB-UHFFFAOYSA-N 0.000 description 1
- XNLBCXGRQWUJLU-UHFFFAOYSA-N naphthalene-2-carbonyl chloride Chemical compound C1=CC=CC2=CC(C(=O)Cl)=CC=C21 XNLBCXGRQWUJLU-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical group C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- HNACNYOQQGUSRD-UHFFFAOYSA-N o-[(2,4-dimethoxyphenyl)methyl]hydroxylamine Chemical compound COC1=CC=C(CON)C(OC)=C1 HNACNYOQQGUSRD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940115458 pantolactone Drugs 0.000 description 1
- SIEVQTNTRMBCHO-UHFFFAOYSA-N pantolactone Natural products CC1(C)OC(=O)CC1O SIEVQTNTRMBCHO-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000004894 pentylamino group Chemical group C(CCCC)N* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- XQCHMGAOAWZUPI-UHFFFAOYSA-M sodium;butane-1-sulfonate Chemical compound [Na+].CCCCS([O-])(=O)=O XQCHMGAOAWZUPI-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000011232 storage material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Inorganic materials O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a novel proline derivative useful as a medicine and an intermediate for producing the same. More specifically, the present invention relates to a proline derivative or a salt thereof, a production intermediate thereof, a medicament, and a pharmaceutical composition having an excellent antibacterial activity, particularly against multidrug-resistant bacteria.
- MRSA Methicilin-resistant Staphylococcus aureus
- MRSA infectious disease 196 Intractable postoperative infection, first reported in the UK in 1961, in the respiratory and gastrointestinal tracts.
- MRSA infectious disease prevailed in Europe and the United States in the late 1960s and late 1970s, and in Japan in the 1980s, attracted public attention as the main causative agent of hospital-acquired infections. It spread nationwide in the late 990s, and MRSA is now highly resistant to multiple drugs and resistant to the antibacterial agents Vancomycin and Arbekacin in MRSA infections. Strains have also emerged.
- multidrug-resistant bacteria that have attracted a great deal of interest in the medical community include Penicillin-Resistant Streptococcus pneumoniae (PRSP) and Vancomycin-Resistant Enterococcus faeciwn
- PRSP Penicillin-Resistant Streptococcus pneumoniae
- Vancomycin-Resistant Enterococcus faeciwn pneumococcus is a pneumonia-causing bacterium that is feared for its virulence
- enterococci are systemic infections and Z or urine that may be clinically isolated with MRSA.
- new antibacterial agents such as quinoquinone and oxazolidinone are used, but their antibacterial activities are not so strong. The emergence of strains resistant to these antibiotics has also been reported.
- the present inventors searched for a compound having a strong antibacterial activity against these multidrug-resistant bacteria, particularly MRSA, and succeeded in selecting a proline derivative described later, thus completing the present invention.
- the present invention relates to a proline derivative represented by the following formula or a salt thereof.
- ring A has 1 to 4 hetero atoms as ring constituent atoms, and is a halogen atom. It is a 5- to 6-membered heterocyclic group that may be condensed with an optionally substituted benzene ring.
- p1 is an integer of 0 or 1
- p2 is an integer of 0 or 1
- p3 is an integer of 0 or 1.
- Ri, R 2 and R 3 are bonded at any position on the A ring, and are the same or different and each has 1 to 3 halogen atoms or hydroxy groups (the hydroxy groups are protected with an acyl group). May be substituted with a lower alkyl group, a hydrogen atom, a lower alkoxy group, a lower alkylthio group, a halogen atom, a hydroxy group, an amino group, or an aminocarbonyl group (the amino group is protected or lower alkyl).
- a saturated cyclic group (a) which is directly bonded to the A ring, or bonded via a carbonyl group, an imino lower alkylene or an oxy lower alkylene; It may contain two hetero atoms, and the cyclic group (a) may be substituted with a lower alkyl group optionally substituted with a halogen atom or a halogen atom.
- T represents a single bond, a methylene group or a heptonyl group.
- R 4 and R 5 may be the same or different and each may be a hydrogen atom or a lower alkyl group, or both bonded to the same carbon atom may be combined to form an oxo group.
- n is an integer of 1 or 2.
- R 6 and R 7 are the same or different and are a hydrogen atom, a hydroxy group, a halogen atom, a lower alkyl group, a phenyl group, a lower alkoxy group, a phenyl lower alkyloxy group, an amino group which may be protected, Both may combine to form a saturated cyclic group.
- X is a carbon atom (CH 2 , CH, C), a zeo atom or an oxygen atom, and n is an integer of 1 or 2.
- Y is a hydrogen atom or an amino protecting group or a group (b) represented by the following formula.
- R 8 is an alkyl group or a cycloalkyl lower alkyl group
- R 9 is a hydrogen atom or a hydroxy protecting group, or R 9a .
- R 9a is R 9al -CO-
- R 9a2 -0- CO-
- R 9al is a lower alkyl group (the lower alkyl group is a phenyl group, Or a mono-lower alkyl-substituted amino group, or substituted with a 6-membered saturated cyclic amino group.
- a saturated cyclic amino group which may 6 membered and has, optionally substituted by hydroxyl C 6 - C io Ariru group in which force ,, or a benzene ring condensed with or 5-6 membered also It means a saturated or unsaturated heterocyclic group.
- R 9a2 represents a lower alkyl group, a power which is a cycloalkyl group which may be substituted with lower alkyl, or a 5-membered saturated cyclic ester residue which may be substituted with lower alkyl.
- R 9 a3 represents a 5-membered saturated or unsaturated cyclic ester residue or cyclic carbonate residue which may be substituted with lower alkyl or condensed with a benzene ring, and p is 0 or 1. It is an integer. )
- the compound (I) of the present invention can be divided into two groups having a common main structure but different characteristics.
- the first group is a proline derivative represented by the following formula (I-A) or a salt thereof, wherein Y is a substituent W (hydrogen atom or amino protecting group).
- w is a hydrogen atom or an amino protecting group, and the definitions of other substituents and symbols are the same as those defined above.
- the second group is a proline derivative (IB) or a salt thereof, wherein Y is represented by the formula (b). '
- Compound (I-A) is an intermediate for producing compound (I_B), and among compounds (I-B), compounds in which R 9 is H or R 9a [hereinafter, referred to as compound (I-B) ' Has a strong antibacterial effect, especially against multidrug-resistant bacteria such as MRSA, and is useful as an antibacterial agent.
- the structural features of the compound (IB) include (i) the presence of ring A, (ii) having at least three heterocyclic groups consisting of ring A, ring B, and ring C, (Iii) ring A and ring B are linked via T; (iv) N-formyl-N- ⁇ R 9 _ amine moiety; (V) substituent R 8 is present And the combination of these, especially (i), (ii) and (iii), above all, (i) is the essence of the feature.
- a compound suitable as an antibacterial agent is represented by the following general formula (I-C) wherein R 9 in the general formula (I-B) is H and ring A is a ring. It is a phosphorus derivative or a salt thereof represented.
- R 2 , R 3 , R 4 , R 5 , n, 1, p 2, p 3 and R 8 are the same as those defined in claim 1, and the ring has 1 to 3 rings.
- Z 2 , Z 3 and Z 4 are the same or different and are atoms selected from a carbon atom (CH 2 , CH or C), a nitrogen atom (NH or N), a zeolite atom and an oxygen atom.
- Z 1 Z 2 , Z 3 and Z 4 may be absent, and Ri, R 2 and R 3 may be bonded to any of the ring-forming carbon or nitrogen atoms. shall have.
- R 6al and R 7Al are the same or different, a hydrogen atom, a lower alkyl group, a c androgenic atom or a lower alkoxy group, X al is TansoHara (CH 2, CH or C) means or an oxygen atom.)
- a compound particularly suitable as an antibacterial agent is a proline derivative represented by the following general formula (I-D) or a salt thereof.
- R 8 is the same as defined above, U is a nitrogen atom or a sulfur atom, R la is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and the two parts of Z are (It means the absence of a single bond, a double bond or a bond, so the Ala ring is 5 or 6 members.)
- the compound (IE) in which R 9 is R 9a and salts thereof also have excellent antibacterial activity.
- Ring A in compound (I) of the present invention has 1 to 4 heteroatoms as ring-constituting atoms, and may be condensed with a benzene ring which may be substituted with a halogen atom.
- the hetero atom is selected from, for example, a nitrogen atom, an iodine atom or an oxygen atom, and preferably contains at least one nitrogen atom.
- Ring A may be saturated, but is preferably unsaturated.
- Ring A and ring B are linked via T, but nitrogen atom on ring B and carbon atom on ring A And a direct bond (hereinafter, referred to as an “N—C bond”, in which case T is a single bond).
- Ring A Specific examples of the 5- to 6-membered heterocyclic group represented by Ring A include, but are not limited to, for example, pyridyl, pyrael, chenyl, furyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, piperidyl, tetrahydrofuryl and the like.
- a condensed heterocyclic group obtained by condensing a heterocyclic group and a benzene ring is exemplified. Examples of such a fused heterocyclic group include isoquinolyl, quinolyl, quinoxalinyl, naphthyridinyl, benzothiazolyl, and benzoxazo
- a nitrogen atom which is a hetero atom
- the most preferred examples of such a heterocyclic group include pyrimidinyl and thiazolyl.
- R 2 and R 3 in the compound (I) of the present invention may be substituted at any position of the ring A, but preferably binds to a carbon atom on the ring A.
- R 2 and R 3 include, as one substituent, a lower alkyl group which may be substituted with 1 to 3 halogen atoms or a hydroxy group (the hydroxy group may be protected with acyl).
- the term “lower” means that the hydrocarbon moiety of the group to which this term is attached has 1 to 6 carbon atoms, unless otherwise specified.
- lower alkyl examples include straight or branched ones such as methyl, ethyl, propylyl, isopropyl, butyl, isobutyl, -butyl, pentyl, and hexyl.
- halogen atom means fluorine, chlorine, bromine, and iodine.
- the “lower alkyl group substituted with 1 to 3 halogen atoms” includes, for example, trifluoromethyl.
- acyl examples include lower aliphatic acyl groups such as acetyl, propionyl, and piperoyl.
- lower alkoxy is a lower alkyloxy group whose lower alkyl moiety has the above-mentioned meaning, and includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.
- the “lower alkylthio group” is a lower alkylthio group in which the lower alkyl moiety has the above-mentioned meaning, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, monobutylthio, pentylthio, and hexylthio. And straight-chain or branched ones.
- the “mono-lower alkylamino” is a mono-lower alkylamino group whose lower alkyl moiety has the above-mentioned meaning, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isoptylamino, —butylamino, pentylamino. And linear or branched ones such as hexylamino.
- the “di-lower alkylamino” is a di-lower alkylamino group in which the lower alkyl moiety has the above-mentioned meaning, for example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino. And linear or branched ones such as, di-butylamino, dipentylamino, and dihexylamino.
- mono-lower alkylaminocarbonyl is a mono-lower alkylaminocarbonyl group having a lower alkyl moiety having the above-mentioned meaning, for example, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl.
- examples thereof include linear or branched ones such as bonyl, isopropylaminocarbonyl, butylaminocarbonyl, isobutylaminocarbonyl, t-butylaminocarbonyl, pentylaminocarbonyl, and hexylaminocarbonyl.
- di-lower alkylaminocarbonyl is a di-lower alkylaminocarbonyl group in which the lower alkyl moiety has the above-mentioned meaning, for example, dimethylaminocarbonyl, getylaminocarbonyl, dipropylamino Minocarbonyl, diisopropylaminocarbonyl, dibutylaminopropyl, diiso Linear or branched ones such as butylaminopropyl, di-pentylaminopropyl, dipentylaminopropyl, dihexylaminocarbonyl and the like can be mentioned.
- hydroxy lower alkylamino is a hydroxy lower alkylamino group whose lower alkyl moiety has the above-mentioned meaning, for example, hydroxymethylamino, 2-hydroxyethylamino, 3-hydroxy Propylamino, 2-hydroxy-1-methyl-1-ethaneamine, 4-hydroxybutylamino, 2-hydroxy-1-methyl-1-propanamine, 2-hydroxy-1,1,1-dimethyl-1-ethaneamine, 5-hydroxypentylamino And linear or branched ones such as 6-hydroxyhexylamino.
- lower alkoxycarbonyl is a lower alkoxycarbonyl group whose lower alkyl moiety has the above-mentioned meaning, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, Examples thereof include linear or branched ones such as butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.
- lower alkylcarbonyloxy refers to a lower alkylcarbonyloxy having a lower alkyl moiety having the above-mentioned meaning, and includes methylcaplonoxy, ethylcarbonyloxy, propylcarbonyloxy, and isopropoxy. Examples thereof include linear or branched ones such as pyroxycarbonyl, butylcarbonyloxy, isobutylcarbonyloxy, -butylcarbonyloxy, pentylcarbonyloxy, and hexylcarbonyloxy.
- the “lower alkylsulfonyloxy group” is a lower alkylsulfonyloxy group in which the lower alkyl moiety has the above-mentioned meaning, such as methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, and isopropanol. Examples thereof include linear or branched ones such as pyrsulfonyloxy, butylsulfonyloxy, isoptylsulfonyloxy, -butylsulfonyloxy, pentylsulfonyloxy, and hexylsulfonyloxy.
- the “lower alkylsulfonyloxy group substituted with 1 to 3 halogen atoms” includes trifluoro A methylsulfonyloxy group is exemplified.
- examples of the “imino lower alkylene group” include —NH (CH 2 ) q — (Q is an integer of 1 to 6)
- an iminomethylene group is preferable.
- examples of the “oxy lower alkylene group” include 1 O (CH 2 ) g ⁇ (q is an integer of 1 to 6), and an oxymethylene group is preferable.
- phenyl lower alkyloxy group is a phenyl lower alkyloxy group whose lower alkyl moiety has the above-mentioned meaning, and is a linear or branched such as benzyloxy, phenethyloxy, 3_phenylpropyloxy and the like.
- Examples of the saturated cyclic group formed by combining R 6 and R 7 include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
- the terms “the amino group is protected”, “optionally protected amino group” or “amino protecting group” are used.
- protecting group for amino group those commonly used in the field of chemistry, particularly in the field of peptide chemistry are used.
- Examples of the “protecting group for an amino group” include those capable of reductive elimination and those capable of hydrolytic elimination.
- Examples of the "protecting group for an amino group” that can be reductively eliminated include an arylsulfonyl group such as P-toluenesulfonyl; a methyl group substituted by phenyl or benzyloxy such as benzyl, trityl and benzyloxymethyl; Benzyloxycarbonyl ⁇ arylmethoxycarbonyl such as P-methoxybenzyloxycarbonyl; halogenoethoxycarbonyl groups such as 2,2,2-trichloromouth ethoxycarbonyl and 2-thioethoxycarbonyl.
- the “protecting group for the amino group” that can be hydrolytically removed includes ethoxycarponyl ⁇ B0C ⁇ butoxycarbonyl, benzyloxycarponyl, ⁇ -methoxybenzyloxycarponyl, vinyloxycarponyl And oxycarbonyl groups such as 2-tosylethoxycarbonyl; carbonyl groups such as formyl, acetyl, 1, and rifluoroacetyl; and ⁇ -ditrophenylsulfenyl, 1, rimethylsilyl.
- Tetrahydropi Ranyl, diphenylphosphinyl and the like are exemplified.
- amino group protecting group When two amino groups are present in the same molecule, one is an “amino group protecting group” that can be hydrolytically eliminated, and the other is an “amino group protecting group” that can be reductively eliminated. It is a good idea to adopt it.
- the “protecting group for the amino group” in the “amino group or aminolponyl group (the amino group is protected)” for R 2 or R 3 those that can be reductively eliminated are used. It is preferable to select a “protecting group for an amino group” that can be hydrolytically eliminated as an amino protecting group for Y.
- Examples of the “5- to 6-membered saturated or unsaturated cyclic group (a)” for R 3 include, but are not limited to, phenyl, adamantyl, pyridyl, piperazinyl, morpholinyl, morpholino, pyrazinyl, tetrahydro Examples thereof include a furyl group and the like, and these cyclic groups (a) may be substituted with a lower alkyl group such as methyl or ethyl or a halogen atom. These cyclic groups (a) are bonded to the ring A via a direct bond; a carboxylic acid; an imino lower alkylene such as iminomethylene; or an oxy lower alkylene such as oxymethylene.
- alkyl group defined as R 8 may be linear or branched as long as it has 2 to 10 carbon atoms, but is preferably linear. Preferred alkyl groups are those having 4 to 7 carbon atoms, particularly preferably 13-butyl or 3-pentyl. Examples of cycloalkyl in “cycloalkyl lower alkyl” defined as R 8 include those having 4 to 7, preferably 5 or 6 carbon atoms, and lower alkyl having 1 to 4 carbon atoms. , Preferably methyl or ethyl. Accordingly, specific examples of suitable “cycloalkyl lower alkyl” include a cyclobenzylmethyl group and a cyclohexylmethyl group.
- the “hydroxy protecting group” defined as R 9 is not particularly limited as long as it can be eliminated by chemical means, and examples include benzyl and 2,4-dimethoxyphenylmethyl. Of these, 2,4-dimethoxyphenylmethyl which is easily desorbed is preferred.
- the compound having a hydroxy protecting group (I-B) has no antibacterial activity.
- a lower alkyl group defined as R 9al (the lower alkyl group may be one or two selected from a phenyl group, a protected amino group and a carbonyl group); May be substituted with a group) ”, for example, include a methyl group, a -butyl group, a 3-force propyloxy group, a 2-phenyl-1-(-butoxycarponyl) aminoethyl group, and the like.
- R 9al Specific examples of the “mono-lower alkyl-substituted amino group” or the “6-membered saturated cyclic amino group which may be substituted with a 6-membered saturated cyclic amino group” for R 9al include -butylamino, 4-piperidinyl-1- And a piperidinyl group. Specific examples of the "C 6 -C 10 aryl group optionally substituted with a hydroxyl group” for R 9al include a phenyl group, a 2-hydroxyphenyl group, a 1- or 2-naphthyl group, and the like.
- 5- or 6-membered saturated or unsaturated heterocyclic group which may be condensed with a ring
- 3-pyridyl 2-pyrrolyl, 3-quinolyl, 2-indolyl
- 2- Examples include a phenyl group, a 3-furyl group, and a morpholino group.
- lower alkyl group and the “cycloalkyl group optionally substituted with lower alkyl” for R 9a2 include isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-isopropyl-5 -Methylcyclohexyl group.
- a group represented by the following formula (c) is substituted with “lower alkyl” in R 9a3 .
- Examples of the 5-membered saturated or unsaturated cyclic ester residue or cyclic carbonate residue which may be condensed with a benzene ring include groups represented by the following formulas (d) and (e). Is mentioned.
- the compound (I) of the present invention can form an acid addition salt between a basic nitrogen atom in the molecule and an acid.
- the acid addition salt include salts with an organic acid such as tartaric acid, fumaric acid, acetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, dalconic acid, and aspartic acid, or hydrochloric acid And salts with inorganic acids such as phosphoric acid and the like.
- a metal salt such as sodium, potassium or calcium may be formed.
- the compound (I) of the present invention sometimes exists as a hydrate or solvate, or as a stereoisomer such as an optical isomer or a mixture thereof, and all of them are included in the present invention. Is done.
- Step 1 is a step of reacting compound (1) with compound (2) (amidation reaction) to form a new compound (IA-1).
- This step can be performed according to a conventional method for peptide production. For example, this step is carried out in the presence of a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) and a reaction accelerator such as 1-hydroxybenzotriazole. It can be carried out by mixing and stirring both starting compounds in a solvent such as methylene.
- the reaction is preferably performed in the presence of a base such as triethylamine. This step is performed at -10 ° C to 45 ° C for 1 hour to 3 days.
- the compound (1) is known, and the compound (2) is mostly known, and can be easily prepared from a known compound by a known method.
- Step 2 is a step of removing the amino protecting group W ′ of the compound (I-A-1) produced in Step 1 to give the compound (I-A-2).
- Elimination can be carried out reductively or hydrolytically, depending on the nature of the amino protecting group W '. Usually, it is preferably carried out by hydrolysis, preferably by acid decomposition, and it is good to select an amino protecting group W ′ suitable for acid decomposition. Boc is suitable as W ′ suitable for acid decomposition.
- the elimination of the amino-protecting group W 'by acidolysis can be carried out by contacting the compound (I-A-1) with an acid in a solvent at ⁇ 10 ° C. to 100 ° C., preferably 0 ° C. to room temperature. Can be implemented.
- the acid include hydrogen chloride and trifluoroacetic acid
- examples of the solvent include ethyl acetate, 1,4-dioxane, and methylene chloride.
- Step 3 can be carried out by reacting compound (3) with compound (I-A-2) in the same manner as in step 1 (amidation reaction) to give compound (IB-1).
- Compound (3) can be advantageously produced by the method described in Reference Examples below or a method analogous thereto.
- Step 4 is to remove the hydroxyl-protecting group R 9 ′ of compound (I-B-1)
- This step is carried out by adding an acid such as trifluoroacetic acid to the compound (I-B-1) in a solvent such as methylene chloride and mixing and stirring at 110 ° C. to 45 ° C. for 1 to 20 hours. it can.
- Step 5 is a step of modifying the hydroxy group of (I-B-2) to give compound (I-E).
- This step is a base such as the presence of pyridine, to (I- B- 2), for example, 9aR to ⁇ - teeth 1, J 9a2'0- C 0 "C 1, Rg a 3- ( by H 2 Bruno p - 1 (i ⁇ 9al, R9a2, ⁇ 3 and ⁇ are as defined above) or an alkylating agent such as an alkyl halide;
- the compound of the present invention thus prepared can be converted to another compound of the present invention as appropriate, for example, by protecting Ri, R 2 , R 3 , R 6 or R 7 with “protection”.
- the compounds produced in each step are characterized by 30 OMHz iH-NMR.
- Compounds produced in Series D are amorphous unless otherwise specified and must be subjected to high performance liquid chromatography under the following conditions.
- the physical properties may be clarified by the retention time of the raffle (the time from the injection of the compound of the present invention to the silica gel column to the discharge thereof).
- 2,4,6-Triclo 1,1,3,5-triazine 2.04 g (11.1 mmo 1) of acetonitrile solution in 100 ml of acetonitrile solution 60 ml of an acetonitrile solution containing 6 mmo 1) and 2.5 g (25.2 mmo 1) of triethylamine was added dropwise and stirred at room temperature for 3 hours. After concentration, the mixture was extracted with chloroform to obtain 3.7 g of crude crystals.
- the filtrate was concentrated under reduced pressure, a mixed solvent of diisopropyl ether and hexane was added to the obtained residue, and the mixture was stirred gently while cooling with ice, and the precipitated crystals were collected by filtration.
- the filtrate was concentrated under reduced pressure to obtain 138.4 g of a crude product.
- Example D 11 A compound (903 mg, 2.Ommo 1) was dissolved in 60 ml of ethyl acetate, and 4 molno 1000 ml of HC1 ethyl acetate solution 1.2 ml was dissolved in ice under ice-cooling. I got it. After concentration under reduced pressure, the precipitate was collected by filtration and dried to give 914 mg (91%) of the desired product.
- Example D_1-1 The following compounds were obtained in the same manner as in the method described in Example D_1-1 or Example D-12.
- the compound of Example D-2-1-1 was produced according to the method described in Example D-1-1-1.
- Example D_1-1 The following compounds were obtained in the same manner as described in Example D_1-1 or Example D-11-10. However, D-4_3 was manufactured according to the method described in D-1-15, and D-16-3 was manufactured according to the method described in D-1-2. Further, the metal salt compound was produced according to the method described in Example D_1-1-1.
- Example D A compound of 16-1 15 Omg (0.314 mmol), triethylamine 881 (0.63 mmol) and toluene 2. A mixture of Oml at room temperature was added with butyl isocyanate 43 1 (0.38 mm 0 1) was added, and the mixture was stirred at the same temperature for 23 hours.
- Example D_1-1 The following compounds were obtained in the same manner as described in Example D_1-1 or Example D-11-14.
- the compound of Example D- 25- 1- is the same as Example D-1-1 It was manufactured according to the method described.
- Example D-110 To the compound 15 Omg (0.25 lmmo 1) obtained in Example D-110, 5 ml of ethanol and 20% Pd (OH) 2 -C 3 Omg were added, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. .
- the compound (I-B) ′ of the present invention thus obtained has an excellent antibacterial activity and is useful as an antibacterial agent.
- Antibacterial activity in vitro (MIC: gZm 1): The minimum inhibitory concentration (MIC: g / m 1) was measured according to the standard method defined by The National Committee for Clinical Laboratory Standards (NCCLS). 40 results were obtained.
- NCCLS National Committee for Clinical Laboratory Standards
- Strain M Mor axel la (B.) catarrhal is K1209 3 ' 4
- Compound A has the structure described in Section 2 of the present specification and is a comparative control compound disclosed in Example 12 of WO99 / 39704 pamphlet.
- Compound B is a commercially available pyridonecarboxylic acid antibacterial agent (ciprofloxacin) having the following structure.
- This strain is a clinical isolate.
- This strain is a Gram-negative bacterium, the others are Gram-positive.
- the strains H to K were measured by the microfluidic dilution method, and the other strains were measured by the agar plate dilution method.
- Experimental example 2 Effect on mouse systemic infection:
- mice ICR-strain male mice (body weight about 20 g) in 50% infection lethal dose of about 50 times the amount of the pathogen per animal (A to The live bacteria of C) were intraperitoneally administered (ip) to cause infection, and the test compound dissolved in physiological saline was subcutaneously administered (sc) twice at 1 hour and 4 hours after infection, and 7 days after infection Was calculated by the probit method from the survival rate of the mice.
- the results are shown in Table 41. Antibacterial action on the table 41 systemic infections (ED 5:. Mg / kg / do se)
- Table 40 refers to the same strain from ⁇ above, salts among, which 9 is hydrogen atom or 1 9 £ 1 Dearu compound (1 -B) 'or a physiologically acceptable compounds of the present invention It has excellent antibacterial activity and low toxicity.
- the compound of the present invention has better antibacterial activity in vitro than compound A, and also has a strong antibacterial activity in vivo.
- D-1-1, D-3-1, D-7-1, D-14, D-15, D-16-1, D-17, D-25 _ 1 and D-54 The acute toxicity values (LD50, iV) for the compounds in mice are all> 100 mg / kg, and these compounds are non-toxic or extremely low.
- the compound (I-B) ′ of the present invention or a physiologically acceptable salt thereof is useful as an antibacterial agent for humans and animals.
- the dose of the compound (I_B) 'of the present invention varies depending on the administration method, symptoms, age, etc., but is usually about 2 to 5000 mg, preferably about 5 to 500 mg, particularly preferably about 5 to 500 mg per 60 kg of body weight per day. 30-30 Omg.
- the route of administration may be oral, but parenteral, especially intravenous, is recommended.
- the compound (I-B) ′ of the present invention is generally administered in the form of a preparation. These preparations can be prepared by mixing the compound (I-B) 'with the components to be formulated.
- a solvent such as water or physiological saline is an essential component, and in addition, a tonicity agent, a soothing agent, a pH regulator, a buffer, a storage agent, and the like.
- auxiliary components such as agents are appropriately blended.
- Liquid preparations such as injections can be prepared by dissolving compound (I-B) 'in a solvent such as physiological saline for injection, and adding other auxiliary components before or after dissolution as required.
- Lyophilized formulations can be prepared by lyophilizing such solutions and redissolving them upon administration.
- the compound (IB) ′ of the present invention or a physiologically acceptable salt thereof has an excellent action on multidrug-resistant bacteria and is useful as an antibacterial agent. Further, the compound (IA) or a salt thereof of the present invention is useful as a direct intermediate for producing the compound (IB).
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Abstract
Priority Applications (1)
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AU2003257637A AU2003257637A1 (en) | 2002-08-23 | 2003-08-21 | Proline derivatives |
Applications Claiming Priority (6)
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JP2002/242795 | 2002-08-23 | ||
JP2002242795A JP2006052138A (ja) | 2002-08-23 | 2002-08-23 | プロリン誘導体 |
JP2002339200A JP2006052139A (ja) | 2002-11-22 | 2002-11-22 | プロリン誘導体 |
JP2002/339200 | 2002-11-22 | ||
JP2003/27010 | 2003-02-04 | ||
JP2003027010A JP2006052140A (ja) | 2003-02-04 | 2003-02-04 | プロリン誘導体 |
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WO2004018453A1 true WO2004018453A1 (fr) | 2004-03-04 |
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PCT/JP2003/010548 WO2004018453A1 (fr) | 2002-08-23 | 2003-08-21 | Derive de proline |
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AU (1) | AU2003257637A1 (fr) |
TW (1) | TW200410956A (fr) |
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2006032322A1 (fr) * | 2004-09-20 | 2006-03-30 | 4Sc Ag | NOUVEAUX INHIBITEURS HÉTÉROCYCLIQUES DU NF-κB |
JP2007517010A (ja) * | 2003-12-24 | 2007-06-28 | プロシディオン・リミテッド | Gpcr受容体作動薬としてのヘテロ環誘導体 |
JP2008513499A (ja) * | 2004-09-20 | 2008-05-01 | ゼノン・ファーマシューティカルズ・インコーポレイテッド | ステアロイル−CoAデサチュラーゼ酵素によって媒介される疾患の処置のための複素環誘導体 |
JP2009502948A (ja) * | 2005-07-26 | 2009-01-29 | イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー | 殺菌・殺カビ性カルボキサミド |
US7601745B2 (en) | 2004-09-27 | 2009-10-13 | 4Sc Ag | Heterocyclic NF-kB inhibitors |
US7723349B2 (en) | 2003-04-24 | 2010-05-25 | Incyte Corporation | Aza spiro alkane derivatives as inhibitors of metalloproteases |
US7812041B2 (en) | 2004-09-20 | 2010-10-12 | 4Sc Ag | Heterocyclic NF-κB inhibitors |
US8680114B2 (en) | 2003-11-21 | 2014-03-25 | Array Biopharma, Inc. | AKT protein kinase inhibitors |
AU2011265309B2 (en) * | 2003-11-21 | 2014-06-05 | Array Biopharma, Inc. | AKT protein kinase inhibitors |
CN104119296A (zh) * | 2013-04-25 | 2014-10-29 | 苏州科捷生物医药有限公司 | 一种2-三氟甲基-5-哌嗪基-噻二唑的合成方法 |
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WO1999039704A1 (fr) * | 1998-02-07 | 1999-08-12 | British Biotech Pharmaceuticals Limited | Agents antibacteriens |
WO2000058294A1 (fr) * | 1999-03-29 | 2000-10-05 | British Biotech Pharmaceuticals Limited | Agents antibacteriens |
WO2002083628A1 (fr) * | 2001-04-13 | 2002-10-24 | Boehringer Ingelheim Pharmaceuticals, Inc. | Composes benzo-fusionnes a disubstitution en positions 1,4 |
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2003
- 2003-08-21 AU AU2003257637A patent/AU2003257637A1/en not_active Abandoned
- 2003-08-21 WO PCT/JP2003/010548 patent/WO2004018453A1/fr not_active Application Discontinuation
- 2003-08-22 TW TW092123113A patent/TW200410956A/zh unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1999039704A1 (fr) * | 1998-02-07 | 1999-08-12 | British Biotech Pharmaceuticals Limited | Agents antibacteriens |
WO2000058294A1 (fr) * | 1999-03-29 | 2000-10-05 | British Biotech Pharmaceuticals Limited | Agents antibacteriens |
WO2002083628A1 (fr) * | 2001-04-13 | 2002-10-24 | Boehringer Ingelheim Pharmaceuticals, Inc. | Composes benzo-fusionnes a disubstitution en positions 1,4 |
Cited By (19)
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US7723349B2 (en) | 2003-04-24 | 2010-05-25 | Incyte Corporation | Aza spiro alkane derivatives as inhibitors of metalloproteases |
US9801877B2 (en) | 2003-04-24 | 2017-10-31 | Incyte Corporation | AZA spiro alkane derivatives as inhibitors of metalloproteases |
US9403775B2 (en) | 2003-04-24 | 2016-08-02 | Incyte Corporation | AZA spiro alkane derivatives as inhibitors of metalloproteases |
US10226459B2 (en) | 2003-04-24 | 2019-03-12 | Incyte Holdings Corporation | Aza spiro alkane derivatives as inhibitors of metalloproteases |
AU2011265309B2 (en) * | 2003-11-21 | 2014-06-05 | Array Biopharma, Inc. | AKT protein kinase inhibitors |
US8680114B2 (en) | 2003-11-21 | 2014-03-25 | Array Biopharma, Inc. | AKT protein kinase inhibitors |
JP2007517010A (ja) * | 2003-12-24 | 2007-06-28 | プロシディオン・リミテッド | Gpcr受容体作動薬としてのヘテロ環誘導体 |
WO2006032322A1 (fr) * | 2004-09-20 | 2006-03-30 | 4Sc Ag | NOUVEAUX INHIBITEURS HÉTÉROCYCLIQUES DU NF-κB |
US7812041B2 (en) | 2004-09-20 | 2010-10-12 | 4Sc Ag | Heterocyclic NF-κB inhibitors |
EP2289510A1 (fr) * | 2004-09-20 | 2011-03-02 | Xenon Pharmaceuticals Inc. | Dérivés hétérocycliques pour le traitement des maladies induites par des enzymes stearoyl-coa desaturase |
US8106048B2 (en) | 2004-09-20 | 2012-01-31 | 4Sc Ag | Heterocyclic NF-κB inhibitors |
EP1830837B1 (fr) * | 2004-09-20 | 2013-09-04 | Xenon Pharmaceuticals Inc. | Derives heterocycliques pour le traitement de maladies induites par des enzymes stearoyl-coadesaturases |
EA012607B1 (ru) * | 2004-09-20 | 2009-10-30 | 4Сц Аг | НОВЫЕ ГЕТЕРОЦИКЛИЧЕСКИЕ ИНГИБИТОРЫ NF-κB |
JP2008513499A (ja) * | 2004-09-20 | 2008-05-01 | ゼノン・ファーマシューティカルズ・インコーポレイテッド | ステアロイル−CoAデサチュラーゼ酵素によって媒介される疾患の処置のための複素環誘導体 |
JP2008513386A (ja) * | 2004-09-20 | 2008-05-01 | 4エスシー アーゲー | 新規な複素環式NF−κB阻害剤 |
US7601745B2 (en) | 2004-09-27 | 2009-10-13 | 4Sc Ag | Heterocyclic NF-kB inhibitors |
JP2009502948A (ja) * | 2005-07-26 | 2009-01-29 | イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー | 殺菌・殺カビ性カルボキサミド |
US8586611B2 (en) | 2005-07-26 | 2013-11-19 | E. I. Du Pont De Nemours And Company | Fungicidal carboxamides |
CN104119296A (zh) * | 2013-04-25 | 2014-10-29 | 苏州科捷生物医药有限公司 | 一种2-三氟甲基-5-哌嗪基-噻二唑的合成方法 |
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TW200410956A (en) | 2004-07-01 |
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