JP5984925B2 - オキサゾロ[5,4−b]ピリジン環を有するカルボン酸誘導体 - Google Patents
オキサゾロ[5,4−b]ピリジン環を有するカルボン酸誘導体 Download PDFInfo
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- JP5984925B2 JP5984925B2 JP2014517829A JP2014517829A JP5984925B2 JP 5984925 B2 JP5984925 B2 JP 5984925B2 JP 2014517829 A JP2014517829 A JP 2014517829A JP 2014517829 A JP2014517829 A JP 2014517829A JP 5984925 B2 JP5984925 B2 JP 5984925B2
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 title description 8
- BFPLMTPHDFFMTG-UHFFFAOYSA-N [1,3]oxazolo[5,4-b]pyridine Chemical group C1=CN=C2OC=NC2=C1 BFPLMTPHDFFMTG-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 223
- -1 cyano, hydroxycarbonyl Chemical group 0.000 claims description 210
- 150000003839 salts Chemical class 0.000 claims description 73
- 125000001424 substituent group Chemical group 0.000 claims description 70
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 51
- 239000000203 mixture Substances 0.000 claims description 48
- 125000004432 carbon atom Chemical group C* 0.000 claims description 46
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 42
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 31
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- 239000012453 solvate Substances 0.000 claims description 28
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 238000009472 formulation Methods 0.000 claims description 12
- 239000000017 hydrogel Substances 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 230000029663 wound healing Effects 0.000 claims description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 3
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 208000008960 Diabetic foot Diseases 0.000 claims description 2
- 230000005961 cardioprotection Effects 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 235000002639 sodium chloride Nutrition 0.000 description 46
- 238000006243 chemical reaction Methods 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 238000000034 method Methods 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 25
- 125000000623 heterocyclic group Chemical group 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 229910052799 carbon Inorganic materials 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 238000001819 mass spectrum Methods 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- 102100025750 Sphingosine 1-phosphate receptor 1 Human genes 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000003054 catalyst Substances 0.000 description 18
- 229910052801 chlorine Inorganic materials 0.000 description 17
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 125000000217 alkyl group Chemical group 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 239000003446 ligand Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 11
- 125000000304 alkynyl group Chemical group 0.000 description 11
- 125000001153 fluoro group Chemical group F* 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 10
- 235000011121 sodium hydroxide Nutrition 0.000 description 10
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 239000012528 membrane Substances 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 101000693265 Homo sapiens Sphingosine 1-phosphate receptor 1 Proteins 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
- 238000001994 activation Methods 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 229910052796 boron Inorganic materials 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- 125000000524 functional group Chemical group 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- 239000012442 inert solvent Substances 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 8
- LIQVWYAAXVFXJA-UHFFFAOYSA-N 2-[4-[5-(2-fluorophenoxy)-[1,3]oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenoxy]-2-methylpropanoic acid Chemical compound CC1=C(OC(C)(C)C(O)=O)C(C)=CC(C=2OC3=NC(OC=4C(=CC=CC=4)F)=CC=C3N=2)=C1 LIQVWYAAXVFXJA-UHFFFAOYSA-N 0.000 description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 229930195733 hydrocarbon Natural products 0.000 description 7
- 150000002430 hydrocarbons Chemical class 0.000 description 7
- 125000004043 oxo group Chemical group O=* 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000007363 ring formation reaction Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 101001021281 Homo sapiens Protein HEXIM1 Proteins 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 230000019491 signal transduction Effects 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 239000008096 xylene Substances 0.000 description 6
- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 5
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 5
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 5
- BRIOKNPDCPJCOD-UHFFFAOYSA-N [1,3]oxazolo[5,4-d]pyrimidine Chemical group N1=CN=C2OC=NC2=C1 BRIOKNPDCPJCOD-UHFFFAOYSA-N 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 239000012131 assay buffer Substances 0.000 description 5
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 5
- 229910052802 copper Inorganic materials 0.000 description 5
- 239000010949 copper Substances 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 238000000752 ionisation method Methods 0.000 description 5
- 210000004698 lymphocyte Anatomy 0.000 description 5
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 5
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 5
- 229960002216 methylparaben Drugs 0.000 description 5
- 125000006574 non-aromatic ring group Chemical group 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 239000011574 phosphorus Substances 0.000 description 5
- 235000011118 potassium hydroxide Nutrition 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 5
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 5
- 229960003415 propylparaben Drugs 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000010626 work up procedure Methods 0.000 description 5
- 229910052727 yttrium Inorganic materials 0.000 description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 4
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-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 4
- AYJIDLATWFNCIJ-UHFFFAOYSA-N 4-[5-(2-fluorophenoxy)-[1,3]oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenol Chemical compound CC1=C(O)C(C)=CC(C=2OC3=NC(OC=4C(=CC=CC=4)F)=CC=C3N=2)=C1 AYJIDLATWFNCIJ-UHFFFAOYSA-N 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 4
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical class [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 125000003277 amino group Chemical class 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 229960001681 croscarmellose sodium Drugs 0.000 description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 4
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229910000510 noble metal Inorganic materials 0.000 description 4
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 4
- 239000000137 peptide hydrolase inhibitor Substances 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
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- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
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- A—HUMAN NECESSITIES
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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Description
Xは、(C1−C6)−アルカンジイル、(C2−C6)−アルケンジイル、(C2−C6)−アルキンジイル、(C3−C7)−シクロアルカンジイル、(C1−C6)−アルカンジイルオキシ及び(C3−C7)−シクロアルカンジイルオキシから成るグループから選択され;それらの全ては、場合により、フッ素及びヒドロキシルから成るグループから選択される一つ又はそれ以上の同一又は異なる置換基で置換され、ここで、(C1−C6)−アルカンジイルオキシ及び(C3−C7)−シクロアルカンジイルオキシ基の酸素原子が基Yに結合し;
Yは、フェニレン、及びN、O及びSから成るグループから選択される、1、2又は3個の同一又は異なる環ヘテロ原子を含む芳香族5員環又は6員環の単環ヘテロ環の二価の基からなるグループから選択され、ここで、環内窒素原子の一つが、水素原子又は置換基R4を保有し(carry)、そしてここで、フェニレン及び二価の芳香族ヘテロ環基は、場合により、同一又は異なる置換基R5で一つ又はそれ以上の環炭素原子に置換され;
R1は、水素及び(C1−C4)−アルキルから成るグループから選択され;
R2及びR3は、互いに独立して、H、ハロゲン、ヒドロキシル、(C1−C4)−アルキル−、(C1−C4)−アルキルオキシ、(C1−C4)−アルキル−S(O)m−、アミノ、ニトロ、シアノ、ヒドロキシカルボニル、(C1−C4)−アルキルオキシカルボニル、アミノカルボニル及びアミノスルホニル、(C3−C7)−シクロアルキル−CwH2w−及びオキシから成るグループから選択され、ここで、wは、0、1及び2から成るグループから選択され;
R4は、(C1−C4)−アルキル、(C3−C7)−シクロアルキル−CwH2w−及びオキシから成るグループから選択され、ここで、wは、0、1及び2から成るグループから選択され;
R5は、ハロゲン、ヒドロキシル、(C1−C4)−アルキル−、(C3−C5)−シクロアルキル−CzH2z−、(C1−C4)−アルキルオキシ、(C1−C4)−アルキル−S(O)m−、アミノ、ニトロ、シアノ、ヒドロキシカルボニル、(C1−C4)−アルキルオキシカルボニル、アミノカルボニル及びアミノスルホニルから成るグループから選択され、ここで、zは、0、1及び2から成るグループから選択され;
mは、0、1及び2から成るグループから選択される、
の化合物を提供する。
Xは、C1−C6)−アルカンジイルオキシ基の酸素原子が基Yに結合する、(C1−C6)−アルカンジイルオキシであり;
Yは、フェニレンが、場合により、同一の又は異なる置換基R5により一つ又はそれ以上の環炭素原子に置換されている、フェニレンであり;
R1は、水素又は(C1−C4)−アルキルであり;
R2及びR3は、互いに独立して、H、ハロゲン、ヒドロキシル、(C1−C4)−アルキル−、(C1−C4)−アルキルオキシ、(C1−C4)−アルキル−S(O)m−、アミノ、ニトロ、シアノ、ヒドロキシカルボニル、(C1−C4)−アルキルオキシカルボニル、アミノカルボニル及びアミノスルホニル、(C3−C7)−シクロアルキル−CwH2w−及びオキシから成るグループから選択され、ここでwは0、1及び2から成るグループから選択され;
R5は、ハロゲン、ヒドロキシル、(C1−C4)−アルキル−、(C3−C5)−シクロアルキル−CzH2z−、(C1−C4)−アルキルオキシ、(C1−C4)−アルキル−S(O)m−、アミノ、ニトロ、シアノ、ヒドロキシカルボニル、(C1−C4)−アルキルオキシカルボニル、アミノカルボニル及びアミノスルホニルから成るグループから選択され、ここで、zは、0、1及び2から成るグループから選択され;
mは0、1及び2から成るグループから選択される;
を有する。
Xは、(C1−C6)−アルカンジイルオキシの酸素原子が基Yに結合する、(C1−C6)−アルカンジイルオキシであり;
Yは、フェニレンは、場合により、一つ又はそれ以上の環炭素原子に、同一又は異なる置換基R5で置換される、フェニレンであり;
R1は、水素又は(C1−C4)−アルキルであり;
R2及びR3は、互いに独立して、H、ハロゲン、ヒドロキシル、(C1−C4)−アルキル−、(C1−C4)−アルキルオキシ、(C1−C4)−アルキル−S(O)m−、アミノ、ニトロ、シアノ、ヒドロキシカルボニル、(C1−C4)−アルキルオキシカルボニル、アミノカルボニル及びアミノスルホニル、(C3−C7)−シクロアルキル−CwH2w−及びオキシから成るグループから選択され、ここで、wは、0、1及び2から成るグループから選択され;
R5は、(C1−C4)−アルキルであり;
mは、0、1及び2から成るグループから選択される;
を有する化合物に関する。
Xは、(C1−C4)アルカンジイルオキシの酸素原子が、基Yに結合する、(C1−C4)アルカンジイルオキシであり;
Yは、フェニレンが、場合により、同一の又は異なる置換基R5により一つ又はそれ以上の環炭素原子に置換されている、フェニレンであり;
R1は、水素であり;
R2及びR3は、互いに独立して、H、ハロゲンから成るグループから選択され;
R5は、(C1−C4)−アルキルである;
を有する化合物に関する。
製剤例1
式Iの化合物:0.0004%;
グリセロール85%:10%;
メチルパラベン:0.2%;
プロピルパラベン:0.03%;
クロスカルメロース−ナトリウム:4%:
HCl/NaOH:qs(pH7.5に調整するため)
水:ad 100%;
製剤例2
式Iの化合物:0.04%;
グリセロール85%:10%;
メチルパラベン:0.2%;
プロピルパラベン:0.03%;
クロスカルメロース−ナトリウム:4%:
HCl/NaOH:qs(pH7.5に調整するため)
水:ad 100%;
製剤3
式Iの化合物:0.0004%;
PGA400:10%;
メチルパラベン:0.2%;
プロピルパラベン:0.03%;
クロスカルメロース−ナトリウム:4%:
HCl/NaOH:qs(pH7.5に調整するため)
水:ad 100%;
製剤4
式Iの化合物:0.04%;
PGA400:10%;
メチルパラベン:0.2%;
プロピルパラベン:0.03%;
クロスカルメロース−ナトリウム:4%:
HCl/NaOH:qs(pH7.5に調整するため)
水:ad 100%;
カラム:Phenomenex製:4μM、10×2mm、1.7μm;流速:1.1 ml/min;溶出液A:水+0.05%トリフルオロ酢酸;溶出液B:アセトニトリル;傾斜溶出条件:93%A+7%B〜5%A+95%B、1.2分間、その後、5%A+95%B、0.2分間;MSイオン化法:ESI+
カラム:UPLC BEH C18製:50×2.1mm、1.7μm;流速:0.9ml/min;溶出液A:水+0.1%ギ酸;溶出液B:アセトニトリル+0.08%ギ酸;傾斜溶出条件:95%A+5%B〜5%A+95%B、1.1分間、その後、5%A+95%B、0.6分間;MSイオン化法:ESI+
カラム:UPLC BEH C18製:50×2.1mm、1.7μm;流速:0.9ml/min;溶出液A:水+0.05%ギ酸;溶出液B:アセトニトリル+0.035%ギ酸;傾斜溶出条件:95%A+5%B〜5%A+95%B、1.1分間、その後、5%A+95%B、0.6分間;MSイオン化法:ESI+
LC/MS(方法LC1):Rt=0.99min;m/z=325.00 [M+H]+。
LC/MS(方法LC2):Rt=1.41 min;m/z=289.07 [M+H]+。
LC/MS(方法LC3):Rt=1.23min;m/z=365.16 [M+H]+。
LC/MS(方法LC2):Rt=1.37min;m/z=351.10 [M+H]+。
LC/MS(方法LC2):Rt=1.34min;m/z=465.20 [M+H]+
LC/MS(方法LC2):Rt=1.32min;m/z=409.14 [M+H]+。
2−{4−[5−(2−フルオロフェノキシ)オキサゾロ[5,4−b]ピリジン−2−イル]−2,6−ジメチルフェノキシ}プロピオン酸
LC/MS(方法LC2):Rt=1.35min;m/z=423.19 [M+H]+
LC/MS(方法LC2):Rt=1.52min;m/z=493.27 [M+H]+。
LC/MS(方法LC2):Rt=1.36min;m/z=437.19 [M+H]+。
LC/MS(方法LC2):Rt=1.53min;m/z=541.37 [M+H]+。
LC/MS(方法LC2):Rt=1.40min;m/z=451.21 [M+H]+。
A)ヒトEdg1受容体を用いるGTP−γ−Sアッセイ
本発明の化合物によるEdg1受容体活性化を測定するために、ヒトEdg1受容体を構成的に過剰発現するCHOFlp−In細胞株由来の細胞膜製剤を用いて、シンチレーション近接アッセイ原理に基づくGタンパク質共役受容体結合の、GTP−γ−S((GTP−γ−S=グアノシン5’−[チオ]トリホスファート)アッセイを使用した。
Flp−In(商標)発現システム (Invitrogen, cat.no.K6010−01) は、関心のある遺伝子が、pOG44発現プラスミドによってコード化されたFlpリコンビナーゼを用いてFlp組換標的(FRT)部位と呼ばれる特異的ゲノム位置における相同組換を通して組み込まれている、安定な哺乳動物細胞株の生成を可能にする。Flp−In宿主細胞株ゲノムへのpcDNA5/FRT発現構成物の組み込みは、関心のある遺伝子の転写をもたらす。安定的トランスフェクト化細胞はヒグロマイシン耐性となる。
膜製剤は、前述のヒトEdg1受容体を構成的に過剰発現するCHOFlp−In細胞株から標準方法によって得た。簡潔には、凍結保存細胞は、培養で取り入れ、そしてT175細胞培養フラスコ(Becton Dickinson,cat.no.35 5001)において密集まで増殖した。細胞培養は、無カルシウムリン酸緩衝生理食塩水(PBS; Gibco,cat.no.14190)で洗浄することによって停止し、そして細胞は、プロテアーゼ阻害剤カクテル(完全プロテアーゼ阻害剤; Roche, cat.no.1697498;1錠/50ml)で補充した4℃の冷却及び無カルシウムPBS中においてゴム−ポリスマンで回収し、そしてその後4℃で15分間1100xg(Heraeus Minifuge T)で遠心分離した。細胞溶解のために、ペレットは、細胞が氷上で更に15分間保存されたプロテアーゼ阻害剤カクテル(上記)で補充した5mMのHEPES(Sigma-Aldrich, cat.no.H−0981)、1mMのEDTA(ジナトリウム塩; Merck, cat.No.8418) から成る4℃の冷却低張緩衝液中で再懸濁した。溶解後、細胞は4℃で10分間400x g(Heraeus Minifuge T)で遠心分離した。ペレットは、Dounceホモジナイザ中で破壊し、既遠心分離の上清で希釈し、そして主として上清中に存在する膜から核及び尚インタクト細胞を分離するために、4℃で10分間500xg(Heraeus Minifuge T)で遠心分離した。次いで上清は、低張緩衝液で希釈し、そして4℃において凡そ18600xgで2時間遠心分離(Beckmann, Avanti J251)した。遠心分離後、膜ペレットは、プロテアーゼ阻害剤カクテル(上記)で補充した20mMのHEPES; 150mMのNaCl(Merck, cat.no.6400)、1mMのEDTAから成る保存緩衝液中で再懸濁した。膜製剤は等分しそして−80℃で保存した。膜製剤のタンパク質濃度は市販のタンパク質アッセイ(Bio-Rad, DC Protein Assay, cat.nos.500−0113、500−0114、500−0115)を用いてサンプルで測定した。
(b)で得たEdg1膜製剤は、シンチレーションビーズに結合されている、受容体含有膜への35S−放射性標識GTP−γ−Sのリガンド誘導結合が、光の放射を刺激しそしてEdg1アゴニスト化合物のインビトロ活性を定量化することができる、Amersham Biosciences/GE Healthcare (コードRPNQ0210)からのGタンパク質共役受容体結合用の市販シンチレーション近接アッセイ(SPA)キットで用いられた。このアッセイは、実質的にメーカー使用説明書により96ウェルプレートで行った。実験の開始前に、シンチレーションビーズを、0.1%(w/v)ナトリウムアジドで補充したTris−HCl(pH 7.4)から成る再構成緩衝液中に再懸濁し、そして続いて30mg/mlの最終ビーズ濃度になるまでアッセイ緩衝液(20mMHEPES、100mMNaCl、1mMEDTA(上記)、1mMジチオトレイトール(DTT)から成り、pH7.4に調整した)により氷上で希釈した。
Claims (13)
- 任意の立体異性体の形態の、又は任意の比率での立体異性体の形態の混合物である式Iの化合物、又は生理学的に許容可能なその塩、又はそのような化合物若しくはそのような塩の生理学的に許容可能な溶媒和物。
Xは、(C1−C6)−アルカンジイル、(C2−C6)−アルケンジイル、(C2−C6)−アルキンジイル、(C3−C7)−シクロアルカンジイル、(C1−C6)−アルカンジイルオキシ及び(C3−C7)−シクロアルカンジイルオキシから成るグループから選択され;それらの全ては、場合により、フッ素及びヒドロキシルから成るグループから選択される一つ又はそれ以上の同一又は異なる置換基で置換され、ここで、(C1−C6)−アルカンジイルオキシ及び(C3−C7)−シクロアルカンジイルオキシの酸素原子が基Yに結合し;
Yは、フェニレン、及びN、O及びSから成るグループから選択される1、2又は3個の同一又は異なる環ヘテロ原子を含む芳香族5員環又は6員環の単環ヘテロ環の二価の基から成るグループから選択され、ここで、環窒素原子の一つは、水素原子又は置換基R4を保有してもよく、そしてここで、フェニレン及び芳香族ヘテロ環の二価の基は、場合により、同一又は異なる置換基R5で一つ又はそれ以上の環炭素原子に置換され;
R1は、水素及び(C1−C4)−アルキルから成るグループから選択され;
R2及びR3は、互いに独立して、H、ハロゲン、ヒドロキシル、(C1−C4)−アルキル−、(C1−C4)−アルキルオキシ、(C1−C4)−アルキル−S(O)m−、アミノ
、ニトロ、シアノ、ヒドロキシカルボニル、(C1−C4)−アルキルオキシカルボニル、アミノカルボニル及びアミノスルホニル、(C3−C7)−シクロアルキル−CwH2w−及
びオキシから成るグループから選択され、ここでwは、0、1及び2から成るグループか
ら選択され;
R4は、(C1−C4)−アルキル、(C3−C7)−シクロアルキル−CwH2w−及びオキシから成るグループから選択され、ここでwは、0、1及び2から成るグループから選択され;
R5は、ハロゲン、ヒドロキシル、(C1−C4)−アルキル−、(C3−C5)−シクロアルキル−CzH2z−、(C1−C4)−アルキルオキシ、(C1−C4)−アルキル−S(O)m−、アミノ、ニトロ、シアノ、ヒドロキシカルボニル、(C1−C4)−アルキルオキシカルボニル、アミノカルボニル及びアミノスルホニルから成るグループから選択され、ここでzは、0、1及び2から成るグループから選択され;
mは、0、1及び2から成るグループから選択される] - 任意の立体異性体の形態の、又は任意の比率での立体異性体の形態の混合物である請求項1に記載の式Iの化合物、又は生理学的に許容可能なその塩、又はそのような化合物若しくはそのような塩の生理学的に許容可能な溶媒和物であって、
Xは、(C1−C6)−アルカンジイルオキシ基の酸素原子が基Yに結合している、(C1−C6)−アルカンジイルオキシであり;
Yは、フェニレンが、場合により、同一の又は異なる置換基R5により一つ又はそれ以
上の環炭素原子で置換されている、フェニレンであり;
R1は、水素又は(C1−C4)−アルキルであり;
R2及びR3は、互いに独立して、H、ハロゲン、ヒドロキシル、(C1−C4)−アルキル−、(C1−C4)−アルキルオキシ、(C1−C4)−アルキル−S(O)m−、アミノ
、ニトロ、シアノ、ヒドロキシカルボニル、(C1−C4)−アルキルオキシカルボニル、アミノカルボニル及びアミノスルホニル、(C3−C7)−シクロアルキル−CwH2w−及
びオキシから成るグループから選択され、ここでwは、0、1及び2から成るグループから選択され;
R5は、ハロゲン、ヒドロキシル、(C1−C4)−アルキル−、(C3−C5)−シクロ
アルキル−CzH2z−、(C1−C4)−アルキルオキシ、(C1−C4)−アルキル−S(
O)m−、アミノ、ニトロ、シアノ、ヒドロキシカルボニル、(C1−C4)−アルキルオ
キシカルボニル、アミノカルボニル及びアミノスルホニルから成るグループから選択され、ここでzは、0、1及び2から成るグループから選択され;
mは、0、1及び2から成るグループから選択される、
ことを特徴とする上記化合物。 - 任意の立体異性体の形態の、又は任意の比率での立体異性体の形態の混合物である請求項1又は2に記載の式Iの化合物、又は生理学的に許容可能なその塩、又はそのような化合物若しくはそのような塩の生理学的に許容可能な溶媒和物であって、
Xは、(C1−C6)−アルカンジイルオキシ基の酸素原子が基Yに結合している、(C1−C6)−アルカンジイルオキシであり;
Yは、フェニレンが、場合により、同一の又は異なる置換基R5により一つ又はそれ以
上の環炭素原子で置換されている、フェニレンであり;
R1は、水素又は(C1−C4)−アルキルであり;
R2及びR3は、互いに独立して、H、ハロゲン、ヒドロキシル、(C1−C4)−アルキル−、(C1−C4)−アルキルオキシ、(C1−C4)−アルキル−S(O)m−、アミノ
、ニトロ、シアノ、ヒドロキシカルボニル、(C1−C4)−アルキルオキシカルボニル、アミノカルボニル及びアミノスルホニル、(C3−C7)−シクロアルキル−CwH2w−及
びオキシから成るグループから選択され、ここでwは、0、1及び2から成るグループから選択され;
R5は、(C1−C4)−アルキルであり;
mは、0、1及び2から成るグループから選択される、
ことを特徴とする、上記化合物。 - 任意の立体異性体の形態の、又は任意の比率での立体異性体の形態の混合物である請求項1〜3の一つ又はそれ以上に記載の式Iの化合物、又は生理学的に許容可能なその塩、又はそのような化合物若しくはそのような塩の生理学的に許容可能な溶媒和物であって、
Xは、(C1−C4)−アルカンジイルオキシ基の酸素原子が基Yに結合している、(C1−C4)−アルカンジイルオキシであり;
Yは、フェニレンが、場合により、同一の又は異なる置換基R5により一つ又はそれ以
上の環炭素原子で置換されている、フェニレンであり;
R1は、水素であり;
R2及びR3は、互いに独立して、H,ハロゲンから成るグループから選択され;
R5は、(C1−C4)−アルキルである、
ことを特徴とする、上記化合物。 - 請求項1〜4のいずれかに記載の式Iの少なくとも一つの化合物、又は生理学的に許容可能なその塩、又はそのような化合物若しくはそのような塩の生理学的に許容可能な溶媒和物、及び薬学的に許容可能な担体を含んでなる、薬学的組成物。
- 薬学的組成物がヒドロゲル製剤であることを特徴とする、請求項5に記載の薬学的組成物。
- 薬剤として使用するための、請求項1〜4のいずれかに記載の式Iの化合物、又は生理学的に許容可能なその塩、又はそのような化合物若しくはそのような塩の生理学的に許容可能な溶媒和物。
- 創傷治癒障害の処置のための、請求項1〜4のいずれかに記載の式Iの化合物、又は生理学的に許容可能なその塩、又はそのような化合物若しくはそのような塩の生理学的に許容可能な溶媒和物。
- 創傷治癒のための、請求項1〜4のいずれかに記載の式Iの化合物、又は生理学的に許容可能なその塩、又はそのような化合物若しくはそのような塩の生理学的に許容可能な溶媒和物。
- 糖尿病患者における創傷治癒のための、請求項1〜4のいずれかに記載の式Iの化合物、又は生理学的に許容可能なその塩、又はそのような化合物若しくはそのような塩の生理学的に許容可能な溶媒和物。
- 糖尿病性足症候群の処置のための、請求項1〜4のいずれかに記載の式Iの化合物、又は生理学的に許容可能なその塩、又はそのような化合物若しくはそのような塩の生理学的に許容可能な溶媒和物。
- 心血管系障害の処置のための、請求項1〜4のいずれかに記載の式Iの化合物、又は生理学的に許容可能なその塩、又はそのような化合物若しくはそのような塩の生理学的に許容可能な溶媒和物。
- 心臓保護のための、請求項1〜4のいずれかに記載の式Iの化合物、又は生理学的に許容可能なその塩、又はそのような化合物若しくはそのような塩の生理学的に許容可能な溶媒和物。
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EP12305525.3 | 2012-05-11 | ||
PCT/EP2012/063297 WO2013004826A1 (de) | 2011-07-07 | 2012-07-06 | Carbonsäurederivate mit einem oxazolo[5,4-b]pyridinring |
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US20130023557A1 (en) | 2013-01-24 |
KR20140061384A (ko) | 2014-05-21 |
EP2729473B1 (de) | 2015-11-25 |
WO2013004826A1 (de) | 2013-01-10 |
CA2841220C (en) | 2019-07-30 |
US8580816B2 (en) | 2013-11-12 |
CY1117390T1 (el) | 2017-04-26 |
PL2729473T3 (pl) | 2016-05-31 |
CN103781790B (zh) | 2016-04-27 |
RU2609002C2 (ru) | 2017-01-30 |
CA2841220A1 (en) | 2013-01-10 |
AU2012280206B2 (en) | 2016-07-28 |
HUE026432T2 (en) | 2016-05-30 |
HRP20160167T1 (hr) | 2016-03-11 |
AU2012280206A1 (en) | 2014-01-23 |
JP2014518247A (ja) | 2014-07-28 |
PT2729473E (pt) | 2016-03-22 |
DK2729473T3 (en) | 2016-02-29 |
MX2014000024A (es) | 2014-02-27 |
HK1192239A1 (zh) | 2014-08-15 |
EP2729473A1 (de) | 2014-05-14 |
RU2014104232A (ru) | 2015-08-20 |
ES2562852T3 (es) | 2016-03-08 |
CN103781790A (zh) | 2014-05-07 |
MY164133A (en) | 2017-11-30 |
MX365931B (es) | 2019-06-20 |
SI2729473T1 (sl) | 2016-03-31 |
BR112014000100A2 (pt) | 2017-01-10 |
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