JP4226005B2 - Ppar活性化化合物及びこれを含有する医薬組成物 - Google Patents
Ppar活性化化合物及びこれを含有する医薬組成物 Download PDFInfo
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- JP4226005B2 JP4226005B2 JP2005513668A JP2005513668A JP4226005B2 JP 4226005 B2 JP4226005 B2 JP 4226005B2 JP 2005513668 A JP2005513668 A JP 2005513668A JP 2005513668 A JP2005513668 A JP 2005513668A JP 4226005 B2 JP4226005 B2 JP 4226005B2
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- Prior art keywords
- phenoxy
- group
- compound
- aminomethyl
- acid
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- 150000001875 compounds Chemical class 0.000 title claims description 127
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 title description 16
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 title description 16
- 230000003213 activating effect Effects 0.000 title description 4
- -1 benzoxazol-2-yl Chemical group 0.000 claims description 418
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 194
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 137
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 135
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 104
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 74
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 62
- 235000019260 propionic acid Nutrition 0.000 claims description 52
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 52
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 239000004480 active ingredient Substances 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 229940124597 therapeutic agent Drugs 0.000 claims description 14
- 206010012601 diabetes mellitus Diseases 0.000 claims description 10
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 10
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 9
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 9
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 208000002249 Diabetes Complications Diseases 0.000 claims description 8
- 206010012655 Diabetic complications Diseases 0.000 claims description 8
- 208000019622 heart disease Diseases 0.000 claims description 8
- 206010061218 Inflammation Diseases 0.000 claims description 7
- 230000004054 inflammatory process Effects 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 3
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 189
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 180
- 238000003786 synthesis reaction Methods 0.000 description 176
- 230000015572 biosynthetic process Effects 0.000 description 175
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 144
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
- 239000002904 solvent Substances 0.000 description 121
- 238000005160 1H NMR spectroscopy Methods 0.000 description 117
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 117
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 112
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 90
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 90
- 230000002829 reductive effect Effects 0.000 description 83
- 238000006243 chemical reaction Methods 0.000 description 81
- 238000003756 stirring Methods 0.000 description 73
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 70
- 239000000243 solution Substances 0.000 description 65
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 64
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
- 239000000203 mixture Substances 0.000 description 63
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 55
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 52
- 238000004519 manufacturing process Methods 0.000 description 52
- 239000002253 acid Substances 0.000 description 50
- 150000002148 esters Chemical group 0.000 description 50
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 50
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 49
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 48
- 238000009835 boiling Methods 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- 229910001868 water Inorganic materials 0.000 description 46
- 238000010898 silica gel chromatography Methods 0.000 description 44
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 41
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 36
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 36
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 33
- 239000012044 organic layer Substances 0.000 description 32
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 31
- 238000001816 cooling Methods 0.000 description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 27
- 229910052938 sodium sulfate Inorganic materials 0.000 description 27
- 235000011152 sodium sulphate Nutrition 0.000 description 27
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 25
- 125000004432 carbon atom Chemical group C* 0.000 description 25
- 239000011734 sodium Substances 0.000 description 25
- 235000002639 sodium chloride Nutrition 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 description 21
- 238000010438 heat treatment Methods 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 19
- 239000002585 base Substances 0.000 description 18
- 238000000605 extraction Methods 0.000 description 18
- 150000007530 organic bases Chemical class 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 17
- 239000012298 atmosphere Substances 0.000 description 16
- 125000004494 ethyl ester group Chemical group 0.000 description 16
- 238000000034 method Methods 0.000 description 16
- BBVQDWDBTWSGHQ-UHFFFAOYSA-N 2-chloro-1,3-benzoxazole Chemical compound C1=CC=C2OC(Cl)=NC2=C1 BBVQDWDBTWSGHQ-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 102000023984 PPAR alpha Human genes 0.000 description 15
- 125000000217 alkyl group Chemical group 0.000 description 15
- 150000007529 inorganic bases Chemical class 0.000 description 15
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 15
- 239000011261 inert gas Substances 0.000 description 14
- 230000004913 activation Effects 0.000 description 13
- 239000012230 colorless oil Substances 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 108010015181 PPAR delta Proteins 0.000 description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 239000012190 activator Substances 0.000 description 12
- 239000003513 alkali Substances 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 description 10
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 10
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 10
- 239000003755 preservative agent Substances 0.000 description 10
- 239000003381 stabilizer Substances 0.000 description 10
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 9
- 0 C*(C)(*c1ccccc1)N(*)*C1NC(I)=C(*)*1 Chemical compound C*(C)(*c1ccccc1)N(*)*C1NC(I)=C(*)*1 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 102000001708 Protein Isoforms Human genes 0.000 description 9
- 108010029485 Protein Isoforms Proteins 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 238000007796 conventional method Methods 0.000 description 9
- 230000002335 preservative effect Effects 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 239000000654 additive Substances 0.000 description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 8
- 150000004702 methyl esters Chemical class 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- 230000003301 hydrolyzing effect Effects 0.000 description 7
- 239000007951 isotonicity adjuster Substances 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 7
- 239000003002 pH adjusting agent Substances 0.000 description 7
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 7
- 229940126062 Compound A Drugs 0.000 description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 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 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 102000000536 PPAR gamma Human genes 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 239000004094 surface-active agent Substances 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
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- 208000008589 Obesity Diseases 0.000 description 5
- 108010016731 PPAR gamma Proteins 0.000 description 5
- 210000001789 adipocyte Anatomy 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 5
- 150000004820 halides Chemical class 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 235000020824 obesity Nutrition 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 238000012746 preparative thin layer chromatography Methods 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 206010022489 Insulin Resistance Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000003449 preventive effect Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 4
- 235000010262 sodium metabisulphite Nutrition 0.000 description 4
- 239000001488 sodium phosphate Substances 0.000 description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
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- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000346 polystyrene-polyisoprene block-polystyrene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 210000002363 skeletal muscle cell Anatomy 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- WPTJBFNYRRZIDZ-UHFFFAOYSA-M sodium;2-phenoxyacetate Chemical compound [Na+].[O-]C(=O)COC1=CC=CC=C1 WPTJBFNYRRZIDZ-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- CPPYPSYKADNWFW-UHFFFAOYSA-N tert-butyl 2-[2-[2-(1,3-benzoxazol-2-ylamino)ethyl]phenoxy]-2-methylpropanoate Chemical compound CC(C)(C)OC(=O)C(C)(C)OC1=CC=CC=C1CCNC1=NC2=CC=CC=C2O1 CPPYPSYKADNWFW-UHFFFAOYSA-N 0.000 description 1
- KWLYRFVBPXLHNG-UHFFFAOYSA-N tert-butyl 2-[2-[3-[2-(4-chlorophenoxy)ethylamino]-3-oxopropyl]phenoxy]-2-methylpropanoate Chemical compound CC(C)(C)OC(=O)C(C)(C)OC1=CC=CC=C1CCC(=O)NCCOC1=CC=C(Cl)C=C1 KWLYRFVBPXLHNG-UHFFFAOYSA-N 0.000 description 1
- RQHBEUNFQVWXPN-UHFFFAOYSA-N tert-butyl 2-[3-[(3-hydroxypropylamino)methyl]phenoxy]butanoate Chemical compound CC(C)(C)OC(=O)C(CC)OC1=CC=CC(CNCCCO)=C1 RQHBEUNFQVWXPN-UHFFFAOYSA-N 0.000 description 1
- ODDBBPCRJYHONU-UHFFFAOYSA-N tert-butyl 2-[3-[[3-(2-phenyl-1,3-dioxolan-2-yl)propylamino]methyl]phenoxy]butanoate Chemical compound CC(C)(C)OC(=O)C(CC)OC1=CC=CC(CNCCCC2(OCCO2)C=2C=CC=CC=2)=C1 ODDBBPCRJYHONU-UHFFFAOYSA-N 0.000 description 1
- CHZSVBPZFCSRGO-UHFFFAOYSA-N tert-butyl 2-[4-(cyanomethyl)phenoxy]-2-methylpropanoate Chemical compound CC(C)(C)OC(=O)C(C)(C)OC1=CC=C(CC#N)C=C1 CHZSVBPZFCSRGO-UHFFFAOYSA-N 0.000 description 1
- CVAWKJKISIPBOD-UHFFFAOYSA-N tert-butyl 2-bromopropanoate Chemical compound CC(Br)C(=O)OC(C)(C)C CVAWKJKISIPBOD-UHFFFAOYSA-N 0.000 description 1
- JAELLLITIZHOGQ-UHFFFAOYSA-N tert-butyl propanoate Chemical compound CCC(=O)OC(C)(C)C JAELLLITIZHOGQ-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LZGVDNRJCGPNDS-UHFFFAOYSA-N trinitromethane Chemical compound [O-][N+](=O)C([N+]([O-])=O)[N+]([O-])=O LZGVDNRJCGPNDS-UHFFFAOYSA-N 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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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
- A61K31/4164—1,3-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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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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- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
しかしながら、特許文献2に開示される化合物はα、γ及びδのいずれのサブタイプに対しても作用しており、PPARα選択的であるとは言い難く、特許文献3に開示される化合物もPPARδ選択的であることが望まれており、さらに試験結果の開示が無くPPARα選択的であるとは言えない。
Nature,347,pp645−650,1990. Cell,68,pp879−887,1992. Cell,97,pp161−163,1999. Biochim.Biophys.Acta.,1302,pp93−109,1996. Journal of Medicinal Chemistry,43,pp527−550,2000. Journal of the National Cancer Institute,90,pp1702−1709,1998. Current Opinion in Lipidology,10,pp245−257,1999. Journal of Atherosclerosis and Thrombosis,3,pp81−89,1996. Current Pharmaceutical Design,3,pp1−14,1997. Current Opinion in Lipidology,10,pp151−159,1999. Current Opinion in Lipidology,10,pp245−257,1999. The Lancet,354,pp141−148,1999. Journal of Medicinal Chemistry,43,pp527−550,2000. Journal of Cardiovascular Risk,8,pp195−201,2001. Journal of Biological Chemistry,270,pp12953−12956,1995. Endocrinology,137,pp4189−4195,1996. Trends Endocrinol.Metab.,10,pp9−13,1999. J.Clin.Invest.,101,pp1354−1361,1998. The Lancet,349,p952,1997. Proc.Natl.Acad.Sci.,96,pp6102−6106,1999. The Journal of Biological Chemistry,275,pp1873−1877,2000. J.Clin.Invest.,108,pp1001−1013,2001. Diabetes,46,pp1319−1327,1997. Journal of Medicinal Chemistry,43,pp527−550,2000. Proc.Natl.Acad.Sci.,98,pp5306−5311,2001. Cell,113,pp159−170,2003. Journal of Biological Chemistry,276,pp44258−44265,2001. Proc.Natl.Acad.Sci.,99,pp303−308,2002.
で表わされる化合物又はその塩を提供するものである。
また、本発明は、上記一般式(1)で表わされる化合物又はその塩を有効成分とする高脂血症治療剤を提供するものである。
また、本発明は、上記一般式(1)で表わされる化合物又はその塩を有効成分とする糖尿病治療剤を提供するものである。
また、本発明は、上記一般式(1)で表わされる化合物又はその塩を有効成分とする糖尿病合併症治療剤を提供するものである。
また、本発明は、上記一般式(1)で表わされる化合物又はその塩を有効成分とする炎症治療剤を提供するものである。
また、本発明は、上記一般式(1)で表わされる化合物又はその塩を有効成分とする心疾患治療剤を提供するものである。
更に本発明は上記一般式(1)で表わされる化合物又はその塩、及び薬学的に許容される担体を含有する医薬組成物を提供するものである。
更にまた本発明は、上記一般式(1)で表わされる化合物又はその塩の、医薬製造のための使用を提供するものである。
更にまた本発明は、上記一般式(1)で表される化合物又はその塩の、有効量を投与することを特徴とする高脂血症、動脈硬化症、糖尿病、糖尿病合併症、炎症及び心疾患から選ばれる疾患の処置方法を提供するものである。
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノメチル]フェノキシ]酪酸、
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−2−(4−フルオロフェノキシ)エチル]アミノメチル]フェノキシ]酪酸、
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]プロピオン酸、
3−[[N−(ベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ酢酸、
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]酪酸、
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸、
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸
又はこれらの塩が挙げられる。
(なお以下の式中のR1、R2、R3a、R3b、R4a、R4b、R5、m、n、X、Y、Zは前記と同じであり、R6はC1−4アルキル基、トリアルキルシリル基等の水酸基を保護できる置換基(Protective Groups in Organic Synthesis(John Wiley & Sons,Inc)等の書誌を参考)を示し、R7はC1−4アルキル基を示し、R3はR3a及びR3bを示し、R4はR4a及びR4bを示し、Halはハロゲン原子を示し、pは1又は2の数を示す。)
第5工程(H−5)は、反応工程式A−3と同様の方法で達成することができる。
なお、本合成ルートでは、R6が水素の場合においても合成可能であり、R6=HではJ−3の工程を必要としない。
2−(3−ホルミルフェノキシ)酪酸エチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.10(t,J=7Hz,3H),1.26(t,J=7Hz,3H),1.99−2.06(m,2H),4.23(q,J=7Hz,2H),4.65(t,J=6Hz,1H),7.17−7.22(m,1H),7.35(s,1H),7.45−7.49(m,2H),9.95(s,1H).
2−[3−[N−[3−(4−フルオロフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸エチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.07(t,J=7Hz,3H),1.24(t,J=7Hz,3H),1.93−2.01(m,4H),2.80(t,J=7Hz,2H),3.77(s,2H),4.00(t,J=6Hz,2H),4.21(q,J=7Hz,2H),4.55(t,J=6Hz,1H),6.74−6.84(m,3H),6.89−6.98(m,4H),7.21(t,J=8Hz,1H)
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸エチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.05(t,J=7Hz,3H),1.17(t,J=7Hz,3H),1.96(quintet,J=7Hz,2H),2.14(quintet,J=6Hz,2H),3.70(t,J=7Hz,2H),4.00(t,J=6Hz,2H),4.12(q,J=7Hz,2H),4.51(t,J=6Hz,1H),4.72(d,J=16Hz,1H),4.77(d,J=16Hz,1H),6.75−6.81(m,3H),6.86−7.00(m,4H),7.01(t,J=8Hz,1H),7.17(t,J=8Hz,1H),7.19−7.23(m,2H),7.36(d,J=7Hz,1H)
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸の合成
1H−NMR(400MHz,CDCl3)δ ppm:1.04(t,J=7Hz,3H),1.95(quintet,J=7Hz,2H),2.04(quintet,J=6Hz,2H),3.56−3.64(m,2H),3.87(t,J=6Hz,2H),4.50(t,J=6Hz,1H),4.62(d,J=16Hz,1H),4.68(d,J=16Hz,1H),6.73−6.93(m,7H),6.99(t,J=8Hz,1H),7.10−7.20(m,3H),7.34(d,J=8Hz,1H)
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−2−(4−フルオロフェノキシ)エチル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−2−(4−メトキシフェノキシ)エチル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[4−[[N−(ベンズオキサゾール−2−イル)−N−2−(3−ジメチルアミノフェノキシ)エチル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−メタンスルホニルオキシフェノキシ)プロピル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[4−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−メタンスルホニルオキシフェノキシ)プロピル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
1H−NMR(400MHz,CDCl3)δ ppm:1.61(s,6H),2.03(brs,2H),3.08(s,3H),3.56(brs,2H),3.88(brs,2H),4.64(s,2H),6.81−6.83(m,4H),7.01(t,J=7Hz,1H),7.08(d,J=8Hz,2H),7.14−1.18(m,4H),7.46(d,J=8Hz,1H)
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
3−[[N−(ベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ酢酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−クロロフェノキシ)プロピル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[4−[[N−(ベンズオキサゾール−2−イル)−N−3−(3−ジメチルアミノフェノキシ)プロピル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−(3−ジメチルアミノフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[4−[[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[2−[[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル)]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−2−(3−ジメチルアミノフェノキシ)エチル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−(3−ジメチルアミノフェノキシ)プロピル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[4−[[N−(ベンズオキサゾール−2−イル)−N−2−(4−メトキシフェノキシ)エチル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[4−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[4−[[N−(ベンズオキサゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[4−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−クロロフェノキシ)プロピル]アミノメチル]フェノキシ]−2−メチルプロピオン酸の合成
N−2−フェノキシエチル−3−ヒドロキシフェニルアセトアミドの合成
1H−NMR(400MHz,CDCl3)δ ppm:3.38(s,2H),3.61(q,J=5Hz,2H),4.00(t,J=5Hz,2H),5.97(br,1H),6.71−6.86(m,4H),6.96(t,J=8Hz,1H),7.07−7.30(m,4H).
2−[3−(N−2−フェノキシエチルアミノカルボニルメチル)フェノキシ]プロピオン酸tert−ブチルの合成
2−[3−[2−(N−2−フェノキシエチル)アミノエチル]フェノキシ]プロピオン酸tert−ブチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.43(s,9H,)1.56(d,J=7Hz,3H),2.79(t,J=7Hz,2H),2.93(t,J=7Hz,2H),3.01(t,J=5Hz,2H),4.05(t,J=5Hz,2H),4.60(q,J=7Hz,1H),6.69(dd,J=2,8Hz,1H),6.75(s,1H),6.82(d,J=8Hz,1H),6.86−6.97(m,3H),7.18(t,J=8Hz,1H),7.25−7.29(m,2H).
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノエチル]フェノキシ]プロピオン酸tert−ブチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.43(s,9H)1.57(d,J=8Hz,3H),3.02(t,J=8Hz,2H),3.82−3.90(m,4H),4.20(t,J=5Hz,2H),4.60(q,J=7Hz,1H),6.69(dd,J=2,8Hz,1H),6.72−7.02(m,6H),7.18(t,J=8Hz,1H),7.14−7.29(m,4H),7.36(d,J=8Hz,1H).
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノエチル]フェノキシ]プロピオン酸の合成
1H−NMR(400MHz,CDCl3)δ ppm:1.60(d,J=7Hz,3H),3.02(t,J=6Hz,2H),3.68−4.19(m,6H),4.60(q,J=7Hz,1H),6.58(s,1H),6.79(d,J=8Hz,1H),6.85(d,J=8Hz,2H),6.90−6.97(m,2H),7.12(t,J=8Hz,1H),7.20−7.28(m,5H),7.44(d,J=8Hz,1H)
2−[3−[3−[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノプロピル]フェノキシ]−2−メチルプロピオン酸の合成
2−[4−[3−[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノプロピル]フェノキシ]−2−メチルプロピオン酸の合成
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−2−(4−フルオロフェノキシ)エチル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(5−フルオロベンズオキサゾール−2−イル)−N−2−(4−フルオロフェノキシ)エチル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(5−クロロベンズオキサゾール−2−イル)−N−2−(4−フルオロフェノキシ)エチル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−2−(4−フルオロフェノキシ)エチル−N−(5−メトキシベンズオキサゾール−2−イル)]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(5−フルオロベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(5−クロロベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(5−メトキシベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(5−フルオロベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(5−メトキシベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−2−(4−メトキシフェノキシ)エチル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(5−フルオロベンズオキサゾール−2−イル)−N−2−(4−メトキシフェノキシ)エチル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(5−クロロベンズオキサゾール−2−イル)−N−2−(4−メトキシフェノキシ)エチル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(5−メトキシベンズオキサゾール−2−イル)−N−2−(4−メトキシフェノキシ)エチル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(5−フルオロベンズオキサゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−3−(4−フルオロフェノキシ)プロピル−N−(5−メトキシベンズオキサゾール−2−イル)]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−3−(4−クロロフェノキシ)プロピル−N−(5−メトキシベンズオキサゾール−2−イル)]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−3−(4−クロロフェノキシ)プロピル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(5−クロロベンズオキサゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−2−(4−クロロフェノキシ)エチル−N−(5−メトキシベンズオキサゾール−2−イル)]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(ベンゾチアゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノエチル]フェノキシ]酪酸の合成
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−2−(4−メトキシフェノキシ)エチル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(5−フルオロベンズオキサゾール−2−イル)−N−2−(4−メトキシフェノキシ)エチル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(5−クロロベンズオキサゾール−2−イル)−N−2−(4−メトキシフェノキシ)エチル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(5−メトキシベンズオキサゾール−2−イル)−N−2−(4−メトキシフェノキシ)エチル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(5−フルオロベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(5−クロロベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(5−メトキシベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−3−(4−クロロフェノキシ)プロピル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−3−(4−クロロフェノキシ)プロピル−N−(5−フルオロベンズオキサゾール−2−イル)]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(5−クロロベンズオキサゾール−2−イル)−N−3−(4−クロロフェノキシ)プロピル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−3−(4−クロロフェノキシ)プロピル−N−(5−メトキシベンズオキサゾール−2−イル)]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(5−フルオロベンズオキサゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−(5−クロロベンズオキサゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノエチル]フェノキシ]プロピオン酸の合成
2−[3−[2−[N−3−(4−フルオロフェノキシ)プロピル−N−(5−メトキシベンズオキサゾール−2−イル)]アミノエチル]フェノキシ]プロピオン酸の合成
N−(4−クロロフェノキシエチル)−3−(2−メトキシフェニル)プロパンアミドの合成
1H−NMR(400MHz,CDCl3)δ ppm:2.50(t,J=8Hz,2H),2.95(t,J=8Hz,2H),3.59−3.63(m,2H),3.81(s,3H),3.91(t,J=5Hz,2H),5.87(brs,1H),6.75−6.84(m,4H),7.12(d,J=7Hz,2H),7.23(d,J=9Hz,2H)
N−(4−クロロフェノキシエチル)−3−(2−ヒドロキシフェニル)プロパンアミドの合成
1H−NMR(400MHz,CDCl3)δ ppm:2.64(t,J=6Hz,2H),2.92(t,J=6Hz,2H,),3.61−3.65(m,2H),3.94(t,J=5Hz,2H),5.99(brs,1H),6.75(d,J=9Hz,2H),6.82(t,J=7Hz,1H),6.88(d,J=7Hz,1H),7.04(d,J=7Hz,1H),7.07(t,J=7Hz,1H),7.21(d,J=9Hz,2H),8.66(s,1H)
2−[2−[2−[N−2−(4−クロロフェノキシ)エチルアミノカルボニル]エチル]フェノキシ]−2−メチルプロピオン酸tert−ブチルの合成
2−[2−[3−[N−2−(4−クロロフェノキシ)エチル]アミノプロピル]フェノキシ]−2−メチルプロピオン酸tert−ブチル合成
1H−NMR(400MHz,CDCl3)δ ppm:1.40(s,9H),1.58(s,6H),1.83(quintet,J=7Hz,2H),2.67(t,J=8Hz,2H),2.70(t,J=7Hz,2H),2.99(t,J=5Hz,2H),4.03(t,J=5Hz,2H),6.68(d,J=8Hz,1H),6.82(t,J=9Hz,2H),6.84−6.88(m,1H),7.05(t,J=8Hz,1H),7.12(d,J=8Hz,1H),7.22(d,J=9Hz,2H)
2−[2−[3−[N−(ベンズオキサゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノプロピル]フェノキシ]−2−メチルプロピオン酸tert−ブチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.37(s,9H),1.57(s,6H),2.02−2.10(m,2H),2.71(t,J=8Hz,2H),3.70(t,J=8Hz,2H),3.93(t,J=6Hz,2H),4.22(t,J=5Hz,2H),6.68(d,J=8Hz,1H),6.78(t,J=9Hz,2H),6.87(t,J=8Hz,1H),7.00(t,J=8Hz,1H),7.04−7.22(m,3H),7.20(d,J=9Hz,2H),7.23(d,J=8Hz,1H),7.35(d,J=8Hz,1H)
2−[2−[3−[N−(ベンズオキサゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノプロピル]フェノキシ]−2−メチルプロピオン酸の合成
1H−NMR(400MHz,CDCl3)δ ppm:1.61(s,6H),1.94−2.14(br,2H),2.69(t,J=8Hz,2H),3.64(t,J=8Hz,2H),3.85(t,J=5Hz,2H),4.09(t,5Hz,2H),6.70(d,J=9Hz,2H),6.81(d,J=8Hz,1H),6.89(t,J=7Hz,1H),7.00(t,J=7Hz,1H),7.10−7.19(m,3H),7.16(d,J=9Hz,2H),7.21(d,J=8Hz,1H),7.35(d,J=8Hz,1H)
減圧濃縮を行い、ヘキサンを加え得られた固体を精製し、白色アモルファス状粉末2.7g(81%)を得た。
1H−NMR(400MHz,CDCl3)δ ppm:1.35(s,6H),1.80−2.00(br,2H),2.48−2.60(br,2H),3.45−3.60(br,2H),3.80(brs,2H),4.05−4.13(br,2H),6.70(d,J=9Hz,2H),6.75−6.80(m,2H),6.87−7.01(m,3H),7.08(t,J=8Hz,1H),7.13−7.18(m,1H),7.14(d,J=9Hz,2H),7.28(t,J=8Hz,1H)
MS(FAB)m/z:533[(M++1)+2],531(M++1)
2−[2−[3−[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノプロピル]フェノキシ]−2−メチルプロピオン酸の合成
2−[4−(シアノメチル)フェノキシ]−2−メチルプロピオン酸tert−ブチルの合成
2−[4−(2−アミノエチル)フェノキシ]−2−メチルプロピオン酸tert−ブチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.45(s,9H),1.55(s,6H),2.67(t,J=7Hz,2H),2.92(t,J=7Hz,2H),6.80(dt,J=9,3Hz,2H),7.05(dt,J=9,3Hz,2H).
2−[4−[2−N−(ベンズオキサゾール−2−イル)アミノエチル]フェノキシ]−2−メチルプロピオン酸tert−ブチルの合成
2−[4−[2−[N−(ベンズオキサゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノエチル]フェノキシ]−2−メチルプロピオン酸tert−ブチル
2−[4−[2−[N−(ベンズオキサゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノエチル]フェノキシ]−2−メチルプロピオン酸の合成
MS(FAB)m/z:495(M++1)
2−[4−[2−[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノエチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノエチル]フェノキシ]−2−メチルプロピオン酸の合成
2−[3−[2−[N−(ベンズオキサゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノエチル]フェノキシ]−2−メチルプロピオン酸の合成
2−メトキシフェニルアセトアミドの合成
2−ヒドロキシフェニルアセトアミドの合成
2−[2−(アミノカルボニルメチル)フェノキシ]−2−メチルプロピオン酸tert−ブチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.43(s,9H),1.65(s,6H),3.59(s,2H),6.10−6.35(br,2H),6.75(d,J=8Hz,1H),6.94(t,J=7Hz,1H),7.17(t,J=8Hz,1H),7.25(d,J=7Hz,1H)
2−[2−(2−アミノエチル)フェノキシ]−2−メチルプロピオン酸tert−ブチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.43(s,9H),1.65(s,6H),2.09(brs.,2H),2.79(t,J=7Hz,2H),2.97(t,J=7Hz,2H),6.69(d,J=8Hz,1H),6.88(t,J=7Hz,1H),7.07(d,J=8Hz,1H),7.14(d,J=7Hz,1H)
2−[2−[2−(N−ベンズオキサゾール−2−イル)アミノエチル]フェノキシ]−2−メチルプロピオン酸tert−ブチルの合成
2−[2−[2−[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノエチル]フェノキシ]−2−メチルプロピオン酸tert−ブチルの合成
2−[2−[2−[N−(ベンズオキサゾール−2−イル)−N−2−フェノキシエチル]アミノエチル]フェノキシ]−2−メチルプロピオン酸の合成
MS(m/z):460(M+)
2−[2−[2−[N−(ベンズオキサゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノエチル]フェノキシ]−2−メチルプロピオン酸の合成
3−tert−ブチルジメチルシリルオキシベンズアルデヒドの合成
1H−NMR(400MHz,CDCl3)δ ppm:0.00(s,6H),0.77(s,9H),6.88(d,J=8Hz,1H),7.10(s,1H),7.18(t,J=8Hz,1H),7.25(d,J=8Hz,1H),9.73(s,1H)
N−3−(4−メトキシフェノキシ)プロピル−3−tert−ブチルジメチルシリルオキシベンジルアミンの合成
1H−NMR(400MHz,CDCl3)δ ppm:0.00(s,6H),0.73(s,9H),1.81(m,2H),2.66(br.s,2H),3.58(s,3H),3.61(s,2H),3.81(t,J=6Hz,2H),6.55(d,J=7Hz,1H),6.63(br.s,5H),6.73(d,J=7Hz,1H),6.99(t,J=7Hz,1H)
N−(ベンズオキサゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル−3−tert−ブチルジメチルシリルオキシベンジルアミンの合成
1H−NMR(400MHz,CDCl3)δ ppm:0.05(s,9H),0.85(s,6H),1.97−2.03(m,2H),3.60(t,J=7Hz,2H),3.67(s,3H),3.87(t,J=6Hz,2H),4.63(s,2H),6.65−6.80(m,7H),6.91(t,J=7Hz,1H),7.05−7.09(m,2H),7.12(d,J=8Hz,1H),7.27(d,J=8Hz,1H)
N−(ベンズオキサゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル−3−ヒドロキシベンジルアミンの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.98(quintet,J=7Hz,2H),3.37(t,=7Hz,2H),3.75(s,3H),3.86(t,J=6Hz,2H),4.61(s,2H),6.65−6.81(m,7H),6.90−7.13(m,5H)
(R)−2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸エチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.16(t,J=7Hz,3H),1.56(d,J=7Hz,3H),2.12(quintet,J=7Hz,2H),3.67(t,J=7Hz,2H),3.74(s,3H),3.94(t,J=6Hz,2H),4.07−4.18(m,2H),4.68(q,J=7Hz,1H),4.72(s,2H),6.75(d,J=8Hz,1H),6.79(s,4H),6.83(br.s,1H),6.88(d,J=8Hz,1H),6.99(t,J=8Hz,1H),7.14(t,J=8Hz,1H),7.18−7.22(m,2H),7.35(d,J=8Hz,1H)
(R)−2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸の合成
1H−NMR(400MHz,CDCl3)δ ppm:1.40(br.s,3H),1.98−2.03(m,2H),3.58(t,J=7Hz,2H),3.70(s,3H),3.84(t,J=6Hz,2H),4.55(br.s,1H),4.59(s,2H),6.70−6.81(m,7H),6.93(t,J=8Hz,1H),7.03−7.14(m,3H),7.31(d,J=8Hz,1H)
(R)−2−[[3−[N−(ベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]酪酸の合成
(R)−2−[[3−[N−(ベンズオキサゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノメチル]フェノキシ]酪酸の合成
(R)−2−[[3−[N−(ベンズオキサゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸の合成
(R)−2−[[3−[N−(ベンズオキサゾール−2−イル)−N−2−(4−フルオロフェノキシ)エチル]アミノメチル]フェノキシ]酪酸の合成
(R)−2−[[3−[N−(ベンズオキサゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸の合成
(R)−2−[[3−[N−(ベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]プロピオン酸の合成
3−[[3−[N−(ベンズオキサゾール−2−イル)−N−3−フェニルスルフィニルプロピル]アミノメチル]フェノキシ]プロピオン酸エチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.19(t,J=7Hz,3H),1.58(d,J=7Hz,3H),1.97−2.16(m,2H),2.72−2.91(m,2H),3.55−3.69(m,2H),4.12−4.21(m,2H),4.64−4.74(m,3H),6.78(d,J=8Hz,1H),6.81(s,1H),6.86(d,J=8Hz,1H),7.03(t,J=8Hz,1H),7.16−7.27(m,3H),7.35(d,J=8Hz,1H),7.47−7.56(m,5H).
3−[[3−[N−(ベンズオキサゾール−2−イル)−N−3−フェニルスルフィニルプロピル]アミノメチル]フェノキシ]プロピオン酸の合成
1H−NMR(400MHz,CD3OD)δ ppm:1.53(d,J=7Hz,3H),1.89−2.10(m,2H),2.81−3.10(m,2H),3.61(t,J=7Hz,2H),4.63−4.75(m,3H),6.79−6.86(m,3H),7.04(t,J=8Hz,1H),7.17(t,J=8Hz,1H),7.19(t,J=8Hz,1H),7.27(d,J=8Hz,1H),7.31(d,J=8Hz,1H),7.52−7.61(m,5H).
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−ベンゼンスルフィニルプロピル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−ベンゼンスルフォニルプロピル]アミノメチル]フェノキシ]プロピオン酸の合成
4−アジドブチロフェノンの合成
1H−NMR(400MHz,CDCl3)δ ppm:2.05(quintet,J=7Hz,2H),3.09(t,J=7Hz,2H),3.43(t,J=7Hz,2H),7.48(t,J=8Hz,2H),7.58(t,J=8Hz,2H),7.97(dd,J=6,1Hz,1H).
4,4−エチレンジオキシ−4−フェニルブチルアジドの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.67(quintet,J=7Hz,2H),1.94−1.98(m,2H),3.26(t,J=7Hz,2H),3.78(t,J=7Hz,2H),4.02(t,J=7Hz,2H),7.31−7.37(m,3H),7.45(dd,J=7,1Hz,2H).
4,4−エチレンジオキシ−4−フェニルブチルアミンの合成
1H−NMR(270MHz,CDCl3)δ ppm:1.47(quintet,J=7Hz,2H),1.89(t,J=7Hz,2H),2.14(br.s,2H),2.63(t,J=7Hz,2H),3.57−3.83(m,2H),3.85−4.10(m,2H),7.26−7.67(m,5H).
2−[3−[N−(4,4−エチレンジオキシ−4−フェニルブチル)アミノメチル]フェノキシ]酪酸tert−ブチルの合成
1H−NMR(270MHz,CDCl3)δ ppm:1.06(t,J=7Hz,3H),1.42(s,9H),1.56(quintet,J=7Hz,2H),1.81−2.05(m,4H),2.24(br.s,1H),2.59(t,J=7Hz,2H),3.62−3.82(m,4H),3.99(s,2H),4.43(t,J=6Hz,1H),6.70−6.89(m,3H),7.15−7.41(m,6H).
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−(4,4−エチレンジオキシ−4−フェニルブチル)]アミノメチル]フェノキシ]酪酸tert−ブチルの合成
1H−NMR(270MHz,CDCl3)δ ppm:(t,J=7Hz,3H),1.38(s,9H),1.70−1.95(m,6H),3.48(t,J=7Hz,2H),3.68−3.72(m,2H),3.92−4.04(m,2H),4.40(t,J=7Hz,1H),4.69(s,2H),6.74−6.85(m,3H),7.00(t,J=7Hz,1H),7.12−7.43(m,9H).
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−(4−オキソ−4−フェニルブチル)]アミノメチル]フェノキシ]酪酸tert−ブチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.03(t,J=7Hz,3H),1.35(s,9H),1.91(quintet,J=7Hz,2H),2.12(quintet,J=7Hz,2H),2.99(t,J=7Hz,2H),3.59(t,J=7Hz,2H),4.39(t,J=6Hz,1H),4.74(dd,J=16,20Hz,2H),6.75(d,J=8Hz,1H),6.85(s,1H),6.90(d,J=8Hz,1H),6.96(t,J=8Hz,1H),7.12(t,J=8Hz,2H),7.19(t,J=8Hz,1H),7.31(d,J=8Hz,1H),7.38(t,J=8Hz,2H),7.49(t,J=8Hz,1H),7.87(d,J=7Hz,2H).
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−(4−オキソ−4−フェニルブチル)]アミノメチル]フェノキシ]酪酸の合成
1H−NMR(400MHz,CD3OD)δ ppm:0.93(t,J=7Hz,3H),1.76−1.84(m,2H),1.98(quintet,J=7Hz,2H),2.95(t,J=7Hz,2H),3.50(t,J=7Hz,2H),4.40(t,J=6Hz,1H),4.64(s,2H),6.72(d,J=7Hz,1H),6.81(d,J=7Hz,2H),6.89(t,J=8Hz,1H),7.03(t,J=8Hz,1H),7.11(t,J=8Hz,3H),7.31(t,J=8Hz,2H),7.42(t,J=7Hz,1H),7.80(d,J=8Hz,2H).
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−(4−オキソ−4−フェニルブチル)]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[N−(3−ヒドロキシプロピル)アミノメチル]フェノキシ]酪酸tert−ブチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.43(s,9H),1.57(d,J=7Hz,3H),1.73(quintet,J=6Hz,2H),2.88(t,J=7Hz,2H),3.77−3.80(m,4H),4.29(br.s,2H),4.63(q,J=7Hz,1H),6.75(dd,J=8,3Hz,1H),6.84(s,1H),6.91(d,J=8Hz,1H),7.22(t,J=8Hz,1H).
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−ヒドロキシプロピル]アミノメチル]フェノキシ]酪酸tert−ブチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.38(s,9H),1.55(d,J=7Hz,3H),1.74(quintet,J=6Hz,2H),3.58(t,J=5Hz,2H),3.68(t,J=6Hz,2H),4.60(q,J=7Hz,1H),4.67(s,2H),4.92(br.s,1H),6.77(d,J=8Hz,1H),6.83(s,1H),6.89(d,J=8Hz,1H),7.02(t,J=8Hz,1H),7.16(t,J=8Hz,1H),7.21−7.26(m,2H),7.32(d,J=8Hz,1H).
2−[3−[[N−(ベンズオキサゾール−2−イル)−N−3−フタルイミドプロピル]アミノメチル]フェノキシ]酪酸tert−ブチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.38(s,9H),1.55(d,J=7Hz,3H),2.07(quintet,J=7Hz,2H),3.57(t,J=7Hz,2H),3.74(t,J=7Hz,2H),4.58(q,J=7Hz,1H),4.78(s,2H),6.73(d,J=8Hz,1H),6.82(s,1H),6.86(d,J=8Hz,1H),6.99(t,J=8Hz,1H),7.12−7.20(m,3H),7.29(t,J=8Hz,1H),7.70−7.76(m,2H),7.81−7.87(m,2H).
2−[3−[[N−3−アミノプロピル−N−(ベンズオキサゾール−2−イル)]アミノメチル]フェノキシ]酪酸tert−ブチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.42(s,9H),1.57(d,J=7Hz,3H),1.88−1.98(m,2H),3.20−3.33(m,4H),4.62(q,J=7Hz,1H),4.69(s,2H),5.80(br.s,2H),6.74(d,J=7Hz,2H),6.81(s,1H),6.80−7.02(m,3H),7.22−7.26(m,2H).
2−[3−[[N−(ベンズオキサゾール−2−イル)]−N−3−(N’,N’−ビス(ベンゼンスルフォニル)アミノ)プロピル]アミノメチル]フェノキシ]酪酸tert−ブチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.44(s,9H),1.60(d,J=7Hz,3H),2.11(quintet,J=7Hz,2H),3.19(t,J=7Hz,2H),3.74(t,J=7Hz,2H),4.48(dd,J=15,24Hz,2H),4.71(q,J=7Hz,1H),6.72−6.80(m,3H),6.89(s,1H),7.03(t,J=8Hz,2H),7.08(dt,J=7,2Hz,1H),7.15(d,J=7Hz,2H),7.21(t,J=8Hz,2H),7.28(t,J=8Hz,2H),7.35−7.42(m,2H),7.56(t,J=8Hz,1H),7.69(d,J=7Hz,2H).
2−[3−[[N−(ベンズオキサゾール−2−イル)]−N−3−(N’,N’−ビス(ベンゼンスルフォニル)アミノ)プロピル]アミノメチル]フェノキシ]酪酸の合成
1H−NMR(400MHz,CD3OD)δ ppm:1.52(d,J=7Hz,3H),1.78(quintet,J=7Hz,2H),2.88(t,J=6Hz,2H),3.49(t,J=7Hz,2H),4.61(q,J=7Hz,1H),4.66(s,2H),6.73−6.83(m,4H),6.91−6.98(m,1H),7.06(t,J=8Hz,1H),7.15−7.32(m,6H),7.46(t,J=8Hz,2H),7.54(t,J=7Hz,1H),7.67−7.70(m,1H),7.79(d,J=8Hz,2H).
2−[3−[[N−3−ベンゼンスルフォニルアミドプロピル−N−(ベンズオキサゾール−2−イル)]アミノメチル]フェノキシ]酪酸の合成
1H−NMR(400MHz,CD3OD)δ ppm:1.43(d,J=7Hz,3H),1.69(quintet,J=7Hz,2H),2.78(t,J=7Hz,2H),3.40(t,J=7Hz,2H),4.54(q,J=7Hz,1H),4.57(s,2H),6.70−6.75(m,3H),6.95(t,J=7Hz,1H),7.08(t,J=7Hz,1H),7.11(t,J=8Hz,1H),7.18(d,J=7Hz,1H),7.22(d,J=8Hz,1H),7.37(t,J=7Hz,2H),7.45(t,J=7Hz,1H),7.70(d,J=7Hz,2H).
2−[3−[[N−3−ベンゼンスルホンアミドプロピル−N−(ベンズオキサゾール−2−イル)]アミノメチル]フェノキシ]プロピオン酸の合成
3−[[N−2−ヨウドフェニルアミノカルボニル−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノールの合成
1H−NMR(400MHz,CDCl3)δ ppm:2.25(quintet,J=7Hz,2H),3.74(s,3H),3.97−4.05(m,4H),5.10(s,2H),6.77(s,5H),6.91−6.95(m,3H),7.22−7.26(m,1H),7.31(t,J=8Hz,1H),7.53(d,J=8Hz,1H),7.78(d,J=8Hz,1H).
3−[[N−(ベンゾチアゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノールの合成
1H−NMR(400MHz,CDCl3)δ ppm:2.08(quintet,J=7Hz,2H),3.53(t,J=7Hz,2H),3.76(s.3H),3.91(t,J=6Hz,2H),4.67(s,2H),6.96−6.83(m,7H),7.04(t,J=8Hz,1H),7.15(t,J=8Hz,1H),7.23(t,J=8Hz,1H),7.46(d,J=8Hz,2H).
3−[[3−N−(ベンゾチアゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸エチルの合成
1H−NMR(400MHz,CDCl3)δ ppm:1.57(d,J=7Hz,3H),2.16(quintet,J=7Hz,2H),3.70(t,J=7Hz,2H),3.76(s,3H),3.96(t,J=6Hz,2H),4.07−4.17(m,2H),4.68(q,J=7Hz,2H),4.74(s,2H),6.75(dd,J=9,2Hz,1H),6.81−6.83(m,5H),6.89(d,J=7Hz,1H),7.05(dt,J=7,1Hz,1H),7.21(t,J=8Hz,1H),7.28(dt,J=7,1Hz,1H),7.55(dd,J=7,1Hz,2H).
3−[[3−N−(ベンゾチアゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸の合成
1H−NMR(400MHz,CDCl3)δ ppm:1.53(d,J=7Hz,3H),2.04(br,2H),3.61(br,2H),3.72(s,3H),3.86(br,2H),4.56(br,1H),4.62(s,2H),6.72−6.81(m,7H),7.00(t,J=8Hz,1H),7.08(br,1H),7.24(t,J=8Hz,1H),7.50(d,J=8Hz,2H).
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−2−フェノキシエチル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−2−(4−フルオロフェノキシ)エチル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−2−(4−メトキシフェノキシ)エチル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−2−フェノキシエチル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−2−(4−フルオロフェノキシ)エチル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−2−(4−メトキシフェノキシ)エチル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−3−(4−クロロフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(ベンゾチアゾール−2−イル)−N−3−(4−クロロフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−2−ニトロフェニルアミノカルボニル−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸エチルの合成
1H−NMR(400MHz,CDCl−3)δ ppm:1.21(t,J=7Hz,3H),1.60(d,J=7Hz,3H),2.14(quintet,J=7Hz,2H),3.64(t,J=7Hz,2H),3.76(s,3H),3.99(t,J=7Hz,2H),4.18(q,J=7Hz,2H),4.63(s,2H),4.74(q,J=7Hz,1H),6.76−6.93(m,7H),7.04(t,J=8Hz,1H),7.25(t,J=8Hz,1H),7.59(t,J=7Hz,1H),8.17(d,J=8Hz,1H),8.68(d,J=9Hz,1H),10.21(s,1H)
2−[3−[[N−2−アミノフェニルアミノカルボニル−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸エチルの合成
1H−NMR(400MHz,CDCl−3)δ ppm:1.22(t,J=7Hz,3H),1.61(d,J=7Hz,3H),2.04(quintet,J=6Hz,2H),3.60(t,J=7Hz,2H),3.76(s,3H),3.80(brs.,2H),4.02(t,J=6Hz,2H),4.17−4.22(m,2H),4.55(d,J=16Hz,1H),4.75(d,J=16Hz,1H),6.65−6.97(m,12H),7.26(t,J=8Hz,1H)
2−[3−[[N−(ベンズイミダゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸エチルの合成
1H−NMR(400MHz,CDCl−3)δ ppm:1.16(t,J=7Hz,3H),1.58(d,J=7Hz,3H),1.97−2.00(m,2H),3.62−3.65(m,2H),3.78(s,3H),4.03−4.13(m,2H),4.69(q,J=7Hz,2H),4.72(d,J=16Hz,1H),4.82(d,J=16Hz,1H),6.76(dd,J=16,3Hz,1H),6.84−6.95(m,10H),7.21(t,J=8Hz,1H)
2−[3−[[N−(1−メチルベンズイミダゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸エチルの合成
1H−NMR(400MHz,CDCl−3)δ ppm:1.21(t,J=7Hz,3H),1.58(d,J=7Hz,3H),2.02(quintet,J=6Hz,2H),3.44(t,J=7Hz,2H),3.63(s,3H),3.74(s,3H),3.88(t,J=6Hz,2H),4.13−4.18(m,2H),4.45(s,2H),4.68(q,J=7Hz,1H),6.68−6.77(m,5H),6.91(s,1H),6.96(d,J=8Hz,1H),7.14−7.21(m,4H),7.58−7.61(m,1H)
2−[3−[[N−(1−メチルベンズイミダゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸の合成
1H−NMR(400MHz,CD−3OD)δ ppm:1.38(d,J=7Hz,3H),1.89(quintet,J=7Hz,2H),3.37(t,J=6Hz,2H),3.55(s,3H),3.57(s,3H),3.78(t,J=6Hz,2H),4.35(s,2H),4.39(q,J=7Hz,1H),6.55−6.61(m,4H),6.68(dd,J=8,2Hz,1H),6.75(d,J=8Hz,1H),6.80(s,1H),7.02−7.07(m,3H),7.14−7.17(m,1H),7.29−7.32(m,1H)
2−[3−[[N−(ベンズイミダゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンズイミダゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(1−メタンスルホニルベンズイミダゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(1−メタンスルホニルベンズイミダゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(ベンズイミダゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(ベンズイミダゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(ベンズイミダゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(ベンズイミダゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸の合成
2−[3−][N−(1−メチルベンズイミダゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(1−メチルベンズイミダゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]酪酸の合成
2−[3−[[N−(1−メチルベンズイミダゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸の合成
2−[3−[[N−(1−メチルベンズイミダゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸の合成
式(1)で示される本発明化合物及び比較化合物としてWO02/46176に記載の化合物(以下、それぞれ化合物A、化合物B、化合物Cと記載する)のPPAR受容体活性化作用を以下の方法で測定した。(Proc.Natl.Acad.Sci.,92,pp7297−7301,1995、Journal of Lipid Research,40,pp2099−2110,1999、Proc.Natl.Acad.Sci,98,pp5306−5311,2001)
トランスフェクションアッセイ
すべてのトランスフェクションアッセイはアフリカミドリザルの腎由来細胞株であるCOS細胞を用いて行った。COS細胞の培養は5%のCO2濃度で行い、培養液には10%のウシ胎児血清、グルタミン酸および抗生物質を含有するDMEM培地を用いた。
発現ベクターは酵母の転写因子であるGal4のDNA結合領域とヒトPPARのリガンド結合領域を融合したキメラ体を用いた。各アイソフォームのキメラ体はGal4転写因子の1から147番目のアミノ酸およびヒトPPARαは166から467番目のアミノ酸、ヒトPPARγ2は182から505番目のアミノ酸、ヒトPPARδは137から441番目のアミノ酸をそれぞれ融合したものを用いた。またレポーターベクターはホタルルシフェラーゼを用い、そのプロモーター領域には5個のGal4の認識配列が含まれている。細胞へのプラスミドのトランスフェクションはリポフェクトアミンを用いた方法により行った。更にβ−ガラクトシダーゼの発現ベクターを内部標準として用いた。
細胞へのトランスフェクションの後、化合物を添加したDMEM培地(0.2%血清含有)に交換し、更に16時間の培養を行った。その後、細胞溶解液中のルシフェラーゼ活性及びβ−ガラクトシダーゼ活性を測定した。
なお、本実験では化合物の溶解・希釈にはジメチルスルホキシド(DMSO)を用い、細胞への処理の際はDMEM培地(0.2%血清含有)にDMSO濃度が0.1%になるように調整した。陽性化合物としてPPARαにはWY14643を、PPARγにはトログリタゾンを(Journal of Medicinal Chemistry,43,pp527−550,2000)、PPARδにはGW501516(Proc.Natl.Acad.Sci,98,pp5306−5311,2001)を用いた。
表9にhPPARα、hPPARγ、hPPARδアゴニスト活性測定結果を示す。
また、一例として図1から図5に本発明化合物(実施例1及び実施例2)及び比較化合物(化合物A、化合物B及び化合物C)のhPPARαを活性化するEC50値の濃度と、その10倍の濃度における各アイソフォームの活性化倍率をまとめた。なお、活性化倍率は、化合物を含まない溶媒(DMSO)のみを処理した時の活性値をコントロールとし、コントロールに対する倍率で示した。本結果より、化合物Aと化合物BはhPPARαを活性化するEC50値の10倍の濃度において、hPPARγ及びδを強く活性化しているのに対し、実施例1及び実施例2の化合物は何れもhPPARαを活性化するEC50値の濃度の10倍の濃度においても、hPPARγ及びδを殆ど活性化しないことがわかる。また化合物Cに至っては、hPPARの全てのアイソフォームに対し活性化を示さなかった。以上の結果より、本発明化合物は、優れたhPPARα選択的活性化剤である。
Claims (11)
- 次の一般式(1)
- Xが酸素原子であり、ZがCHである請求項1記載の化合物又はその塩。
- 2−[3−[[ N−(ベンズオキサゾール−2−イル)−N−3−(4−フルオロフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸、
2−[3−[[ N−(ベンズオキサゾール−2−イル)−N−2−(4−クロロフェノキシ)エチル]アミノメチル]フェノキシ]酪酸、
2−[3−[[ N−(ベンズオキサゾール−2−イル)−N−2−(4−フルオロフェノキシ)エチル]アミノメチル]フェノキシ]酪酸、
2−[3−[[ N−(ベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]プロピオン酸、
3−[[ N−(ベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ酢酸、
2−[3−[[ N−(ベンズオキサゾール−2−イル)−N−3−フェノキシプロピル]アミノメチル]フェノキシ]酪酸、
2−[3−[[ N−(ベンズオキサゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]酪酸、
2−[3−[[ N−(ベンズオキサゾール−2−イル)−N−3−(4−メトキシフェノキシ)プロピル]アミノメチル]フェノキシ]プロピオン酸及びこれらの塩から選ばれる化合物。 - 請求項1〜3のいずれか1項記載の化合物又はその塩を有効成分とする医薬。
- 請求項1〜3のいずれか1項記載の化合物又はその塩を有効成分とする高脂血症治療剤。
- 請求項1〜3のいずれか1項記載の化合物又はその塩を有効成分とする動脈硬化症治療剤。
- 請求項1〜3のいずれか1項記載の化合物又はその塩を有効成分とする糖尿病治療剤。
- 請求項1〜3のいずれか1項記載の化合物又はその塩を有効成分とする糖尿病合併症治療剤。
- 請求項1〜3のいずれか1項記載の化合物又はその塩を有効成分とする炎症治療剤。
- 請求項1〜3のいずれか1項記載の化合物又はその塩を有効成分とする心疾患治療剤。
- 請求項1〜3のいずれか1項記載の化合物又はその塩及び薬学的に許容される担体を含有する医薬組成物。
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JP4914827B2 (ja) * | 2005-03-01 | 2012-04-11 | 興和株式会社 | 光学活性ppar活性化化合物中間体及びその製造法 |
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