JP2002167371A - Phenylpropionic acid derivative - Google Patents
Phenylpropionic acid derivativeInfo
- Publication number
- JP2002167371A JP2002167371A JP2001285989A JP2001285989A JP2002167371A JP 2002167371 A JP2002167371 A JP 2002167371A JP 2001285989 A JP2001285989 A JP 2001285989A JP 2001285989 A JP2001285989 A JP 2001285989A JP 2002167371 A JP2002167371 A JP 2002167371A
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- propionic acid
- aminooxy
- ethylidene
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical class OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 title abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 150000002148 esters Chemical class 0.000 claims abstract description 29
- 125000005843 halogen group Chemical group 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 114
- 125000004432 carbon atom Chemical group C* 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- VRHLYBWEHSZLRO-PMERELPUSA-N (2s)-2-(4-fluorophenoxy)-3-[4-[2-[1-(4-phenylphenyl)ethylideneamino]oxyethoxy]phenyl]propanoic acid Chemical compound O([C@@H](CC1=CC=C(C=C1)OCCON=C(C)C=1C=CC(=CC=1)C=1C=CC=CC=1)C(O)=O)C1=CC=C(F)C=C1 VRHLYBWEHSZLRO-PMERELPUSA-N 0.000 claims description 2
- ZAHUVJWLJMYWNG-LJAQVGFWSA-N (2s)-2-(4-fluorophenoxy)-3-[4-[2-[1-(4-pyridin-2-ylphenyl)ethylideneamino]oxyethoxy]phenyl]propanoic acid Chemical compound O([C@@H](CC1=CC=C(C=C1)OCCON=C(C)C=1C=CC(=CC=1)C=1N=CC=CC=1)C(O)=O)C1=CC=C(F)C=C1 ZAHUVJWLJMYWNG-LJAQVGFWSA-N 0.000 claims description 2
- QPMCGLFQMNSIQY-HKBQPEDESA-N (2s)-2-(4-fluorophenoxy)-3-[4-[2-[1-[4-(4-methoxyphenyl)phenyl]ethylideneamino]oxyethoxy]phenyl]propanoic acid Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C(C)=NOCCOC=2C=CC(C[C@H](OC=3C=CC(F)=CC=3)C(O)=O)=CC=2)C=C1 QPMCGLFQMNSIQY-HKBQPEDESA-N 0.000 claims description 2
- JIMWXDDMOQBHGD-HKBQPEDESA-N (2s)-2-(4-methylphenoxy)-3-[4-[2-[1-(4-phenylphenyl)ethylideneamino]oxyethoxy]phenyl]propanoic acid Chemical compound O([C@@H](CC1=CC=C(C=C1)OCCON=C(C)C=1C=CC(=CC=1)C=1C=CC=CC=1)C(O)=O)C1=CC=C(C)C=C1 JIMWXDDMOQBHGD-HKBQPEDESA-N 0.000 claims description 2
- JWEPGRFZQLSYRR-PMERELPUSA-N (2s)-2-(4-methylphenoxy)-3-[4-[2-[1-(4-pyridin-2-ylphenyl)ethylideneamino]oxyethoxy]phenyl]propanoic acid Chemical compound O([C@@H](CC1=CC=C(C=C1)OCCON=C(C)C=1C=CC(=CC=1)C=1N=CC=CC=1)C(O)=O)C1=CC=C(C)C=C1 JWEPGRFZQLSYRR-PMERELPUSA-N 0.000 claims description 2
- PPOPGSRZFIYHPX-XIFFEERXSA-N (2s)-2-(4-tert-butylphenoxy)-3-[4-[2-[1-(4-phenylphenyl)ethylideneamino]oxyethoxy]phenyl]propanoic acid Chemical compound O([C@@H](CC1=CC=C(C=C1)OCCON=C(C)C=1C=CC(=CC=1)C=1C=CC=CC=1)C(O)=O)C1=CC=C(C(C)(C)C)C=C1 PPOPGSRZFIYHPX-XIFFEERXSA-N 0.000 claims description 2
- JRHZDGGCMACSIU-YTTGMZPUSA-N (2s)-2-(4-tert-butylphenoxy)-3-[4-[2-[1-(4-pyridin-2-ylphenyl)ethylideneamino]oxyethoxy]phenyl]propanoic acid Chemical compound O([C@@H](CC1=CC=C(C=C1)OCCON=C(C)C=1C=CC(=CC=1)C=1N=CC=CC=1)C(O)=O)C1=CC=C(C(C)(C)C)C=C1 JRHZDGGCMACSIU-YTTGMZPUSA-N 0.000 claims description 2
- LSVOPITXABSOSL-UHFFFAOYSA-N 2-(4-chlorophenoxy)-3-[4-[2-[1-(4-pyridin-2-ylphenyl)ethylideneamino]oxyethoxy]phenyl]propanoic acid Chemical compound C=1C=C(C=2N=CC=CC=2)C=CC=1C(C)=NOCCOC(C=C1)=CC=C1CC(C(O)=O)OC1=CC=C(Cl)C=C1 LSVOPITXABSOSL-UHFFFAOYSA-N 0.000 claims description 2
- CIQXPMBQNIBJTR-UHFFFAOYSA-N 2-(4-fluorophenoxy)-3-[4-[2-[1-[4-(4-fluorophenyl)phenyl]ethylideneamino]oxyethoxy]phenyl]propanoic acid Chemical compound C=1C=C(C=2C=CC(F)=CC=2)C=CC=1C(C)=NOCCOC(C=C1)=CC=C1CC(C(O)=O)OC1=CC=C(F)C=C1 CIQXPMBQNIBJTR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 201000001421 hyperglycemia Diseases 0.000 abstract description 8
- 208000031226 Hyperlipidaemia Diseases 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 126
- -1 1-methylpentyl Chemical group 0.000 description 124
- 239000000243 solution Substances 0.000 description 61
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 60
- 238000006243 chemical reaction Methods 0.000 description 49
- 238000005160 1H NMR spectroscopy Methods 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- 230000002829 reductive effect Effects 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 239000013078 crystal Substances 0.000 description 26
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 125000002344 aminooxy group Chemical group [H]N([H])O[*] 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 19
- 239000008280 blood Substances 0.000 description 19
- 210000004369 blood Anatomy 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 18
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 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 16
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000003480 eluent Substances 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 14
- 235000019260 propionic acid Nutrition 0.000 description 13
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 11
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 11
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 10
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 208000002705 Glucose Intolerance Diseases 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 208000004104 gestational diabetes Diseases 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 7
- 206010033645 Pancreatitis Diseases 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- 239000008101 lactose Substances 0.000 description 7
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 7
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- 206010003210 Arteriosclerosis Diseases 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 208000001132 Osteoporosis Diseases 0.000 description 6
- 208000011775 arteriosclerosis disease Diseases 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 208000002177 Cataract Diseases 0.000 description 5
- 208000002249 Diabetes Complications Diseases 0.000 description 5
- 206010012655 Diabetic complications Diseases 0.000 description 5
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 5
- 206010020772 Hypertension Diseases 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 5
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- 206010022489 Insulin Resistance Diseases 0.000 description 5
- 201000004681 Psoriasis Diseases 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- AIKVCUNQWYTVTO-UHFFFAOYSA-N nicardipine hydrochloride Chemical compound Cl.COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 AIKVCUNQWYTVTO-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- 206010006895 Cachexia Diseases 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 208000004930 Fatty Liver Diseases 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 206010019708 Hepatic steatosis Diseases 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 4
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 235000020824 obesity Nutrition 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 231100000240 steatosis hepatitis Toxicity 0.000 description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 4
- OJOFMLDBXPDXLQ-VIFPVBQESA-N (4s)-4-benzyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@H]1CC1=CC=CC=C1 OJOFMLDBXPDXLQ-VIFPVBQESA-N 0.000 description 3
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- ZNGINKJHQQQORD-UHFFFAOYSA-N 2-trimethylsilylethanol Chemical compound C[Si](C)(C)CCO ZNGINKJHQQQORD-UHFFFAOYSA-N 0.000 description 3
- ZTLPPYBMNJAROV-UHFFFAOYSA-N 2-trimethylsilylethyl propanoate Chemical compound CCC(=O)OCC[Si](C)(C)C ZTLPPYBMNJAROV-UHFFFAOYSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 201000011152 Pemphigus Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 235000012211 aluminium silicate Nutrition 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、高脂血症、高血糖
症、肥満症、耐糖能不全状態、インスリン抵抗性非耐糖
能不全状態、高血圧症、骨粗鬆症、膵炎、悪液質、脂肪
肝、糖尿病合併症、動脈硬化症、妊娠糖尿病、多嚢胞卵
巣症候群のようなインスリン抵抗性に起因する疾病、乾
癬、自己免疫疾患等の治療剤または予防剤として有用な
フェニルプロピオン酸誘導体並びにその薬理上許容され
る塩及びその薬理上許容されるエステルに関する。The present invention relates to hyperlipidemia, hyperglycemia, obesity, glucose intolerance, insulin-resistant non-glucose intolerance, hypertension, osteoporosis, pancreatitis, cachexia, fatty liver Phenylpropionic acid derivative useful as a therapeutic or prophylactic agent for diseases caused by insulin resistance such as diabetic complications, arteriosclerosis, gestational diabetes, polycystic ovary syndrome, psoriasis, autoimmune diseases, and the like; It relates to an acceptable salt and a pharmacologically acceptable ester thereof.
【０００２】[0002]
【従来の技術】WO97/37970（EP916651A）には、構造
上、本願発明の化合物と共通部分を有する化合物が記載
されている。2. Description of the Related Art WO 97/37970 (EP916651A) describes a compound having a structurally common part with the compound of the present invention.
【０００３】しかしながら、上記先行技術中には、本願
発明の化合物の物性が具体的に記載されていないのみな
らず、化学構造や化学名も具体的には記載されていな
い。さらに、本願発明の化合物は、上記先行技術に具体
的に記載された化合物に比べて、強い薬理活性と高い安
全性を有し、優れた血中トリグリセリド降下作用を示
す。However, the above prior art does not specifically describe the physical properties of the compound of the present invention, nor does it specifically describe the chemical structure or chemical name. Furthermore, the compound of the present invention has stronger pharmacological activity and higher safety than the compounds specifically described in the above prior art, and shows an excellent blood triglyceride lowering action.
【０００４】[0004]
【発明が解決しようとする課題】本発明者らは強い活性
と安全性の極めて高い、高脂血症、高血糖症、肥満症、
耐糖能不全状態、インスリン抵抗性非耐糖能不全状態、
インスリン抵抗性、悪液質、乾癬、糖尿病合併症、動脈
硬化症、高血圧症、骨粗鬆症、膵炎、多嚢胞卵巣症候
群、脂肪肝及び妊娠糖尿病等を改善し、更にアルドース
還元酵素阻害作用を有するフェニルプロピオン酸誘導体
並びにその薬理上許容される塩及びそのエステルについ
て鋭意研究を行ない、本発明を完成した。DISCLOSURE OF THE INVENTION The present inventors have found that hyperlipidemia, hyperglycemia, obesity,
Glucose intolerance, insulin resistant non-glucose intolerance,
Phenylpropion which improves insulin resistance, cachexia, psoriasis, diabetic complications, arteriosclerosis, hypertension, osteoporosis, pancreatitis, polycystic ovary syndrome, fatty liver and gestational diabetes mellitus, and further has an aldose reductase inhibitory action The present inventors have made intensive studies on acid derivatives and their pharmaceutically acceptable salts and esters, and have completed the present invention.
【０００５】即ち、本発明は、高脂血症、高血糖症、肥
満症、耐糖能不全（impaired glucose tolerance： IG
T）状態、インスリン抵抗性非耐糖能不全（insulin res
istant non-IGT: NGT）状態、高血圧症、骨粗鬆症、膵
炎、悪液質、脂肪肝、糖尿病合併症（例えば網膜症、腎
症、白内障、冠動脈疾患等）、動脈硬化症、白内障、妊
娠糖尿病（gestational diabetes mellitus: GDM）、多
嚢胞卵巣症候群（polycystic ovary syndrome:PCOS）の
ようなインスリン抵抗性に起因する疾病、炎症性疾患
（例えば骨関節炎、疼痛、発熱、炎症性腸炎等）、アク
ネ、日焼け、乾癬、湿疹、アレルギー性疾患、喘息、Ｇ
Ｉ潰瘍、心血管性疾患（例えば虚血性心疾患等）、アテ
ローム性動脈硬化症および虚血性疾患により惹起される
細胞損傷（例えば卒中により惹起される脳損傷等）、自
己免疫疾患（例えば全身性エリテマトーデス、慢性関節
リウマチ、若年性関節リウマチ、シェーグレン症候群、
全身性強皮症、混合型結合組織病、皮膚筋炎、橋本病、
原発性粘液水腫、甲状腺中毒症、悪性貧血、潰瘍性大腸
炎、自己免疫性萎縮性胃炎、特発性Ａｄｄｉｓｏｎ病、
男性不妊症、Ｇｏｏｄｐａｓｔｕｒｅ症候群、急性進行
性糸球体腎炎、重症筋無力症、多発性筋炎、尋常性天疱
瘡、水疱性類天疱瘡、交感性眼炎、多発性硬化症、自己
免疫性溶血性貧血、特発性血小板減少性紫斑病、心筋梗
塞後症候群、リウマチ熱、ルポイド肝炎、原発性胆汁性
肝硬変症、ベーチェット病、ＣＲＥＳＴ症候群等）等の
治療薬または予防薬として有用なフェニルプロピオン酸
誘導体並びにその薬理上許容される塩及びその薬理上許
容されるエステルを提供する。[0005] That is, the present invention relates to hyperlipidemia, hyperglycemia, obesity, impaired glucose tolerance (IG).
T) state, insulin resistance non-glucose intolerance (insulin res
istant non-IGT: NGT) condition, hypertension, osteoporosis, pancreatitis, cachexia, fatty liver, diabetic complications (eg retinopathy, nephropathy, cataract, coronary artery disease, etc.), arteriosclerosis, cataract, gestational diabetes ( Diseases caused by insulin resistance, such as gestational diabetes mellitus (GDM), polycystic ovary syndrome (PCOS), inflammatory diseases (eg, osteoarthritis, pain, fever, inflammatory enteritis, etc.), acne, sunburn , Psoriasis, eczema, allergic diseases, asthma, G
I ulcer, cardiovascular disease (eg, ischemic heart disease), cell damage caused by atherosclerosis and ischemic disease (eg, brain damage caused by stroke), autoimmune disease (eg, systemic disease) Lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, Sjogren's syndrome,
Systemic scleroderma, mixed connective tissue disease, dermatomyositis, Hashimoto's disease,
Primary myxedema, thyrotoxicosis, pernicious anemia, ulcerative colitis, autoimmune atrophic gastritis, idiopathic Addison's disease,
Male infertility, Goodpasture syndrome, acute progressive glomerulonephritis, myasthenia gravis, polymyositis, pemphigus vulgaris, bullous pemphigoid, sympathetic ophthalmitis, multiple sclerosis, autoimmune hemolytic anemia Phenylpropionic acid derivatives useful as therapeutics or prophylactics for idiopathic thrombocytopenic purpura, post-myocardial infarction syndrome, rheumatic fever, lupus hepatitis, primary biliary cirrhosis, Behcet's disease, CREST syndrome, etc.) Provided are pharmacologically acceptable salts and pharmacologically acceptable esters thereof.
【０００６】[0006]
【課題を解決するための手段】本発明は、（１）下記一
般式（Ｉ）According to the present invention, there is provided (1) a compound represented by the following general formula (I):
【０００７】[0007]
【化２】 Embedded image
【０００８】（式中、ＸはＣＨ又はＮを示し、Ｒ1は水
素原子、炭素数１乃至６個の直鎖若しくは分岐鎖のアル
キル基、炭素数１乃至６個の直鎖若しくは分岐鎖のアル
コキシ基又はハロゲン原子を示し、Ｒ2は炭素数１乃至
６個の直鎖若しくは分岐鎖のアルキル基、炭素数１乃至
６個の直鎖若しくは分岐鎖のアルコキシ基又はハロゲン
原子を示す。）で表わされる化合物又はその薬理上許容
される塩若しくはエステル、（２）上記（１）におい
て、ＸがＮである化合物、（３）上記（１）又は（２）
において、Ｒ1が水素原子、炭素数１乃至６個の直鎖若
しくは分岐鎖のアルコキシ基又はハロゲン原子である化
合物、（４）上記（１）又は（２）において、Ｒ1が水
素原子である化合物、（５）上記（１）乃至（４）にお
いて、Ｒ2が炭素数１乃至６個の直鎖若しくは分岐鎖の
アルキル基又はハロゲン原子である化合物、（６）上記
（１）乃至（５）に記載の化合物の薬理上許容される
塩、（７）上記（１）乃至（５）に記載の化合物の薬理
上許容されるエステル、（８）2-(4-クロロフェノキシ)
-3-[4-[2-[[1-[4-(2-ピリジル)フェニル]エチリデン]ア
ミノオキシ]エトキシ]フェニル]プロピオン酸、3-[4-[2
-[[1-(4'-フルオロ-4-ビフェニリル)エチリデン]アミノ
オキシ]エトキシ]フェニル]-2-(4-フルオロフェノキシ)
プロピオン酸、(S)-3-[4-[2-[[1-(4-ビフェニリル)エチ
リデン]アミノオキシ]エトキシ]フェニル]-2-(4-メチル
フェノキシ)プロピオン酸、(S)-2-(4-メチルフェノキ
シ)-3-[4-[2-[[1-[4-(2-ピリジル)フェニル]エチリデ
ン]アミノオキシ]エトキシ]フェニル]プロピオン酸、
(S)-3-[4-[2-[[1-(4-ビフェニリル)エチリデン]アミノ
オキシ]エトキシ]フェニル]-2-(4-t-ブチルフェノキシ)
プロピオン酸、(S)-2-(4-t-ブチルフェノキシ)-3-[4-[2
-[[1-[4-(2-ピリジル)フェニル]エチリデン]アミノオキ
シ]エトキシ]フェニル]プロピオン酸、(S)-3-[4-[2-[[1
-(4-ビフェニリル)エチリデン]アミノオキシ]エトキシ]
フェニル]-2-(4-フルオロフェノキシ)プロピオン酸、
(S)-2-(4-フルオロフェノキシ)-3-[4-[2-[[1-(4'-メト
キシ-4-ビフェニリル)エチリデン]アミノオキシ]エトキ
シ]フェニル]プロピオン酸、若しくは、(S)-2-(4-フル
オロフェノキシ)-3-[4-[2-[[1-[4-(2-ピリジル)フェニ
ル]エチリデン]アミノオキシ]エトキシ]フェニル]プロ
ピオン酸、又はその薬理上許容される塩若しくはエステ
ルである。本発明において、「炭素数１乃至６個の直鎖
又は分岐鎖のアルキル基」とは、炭素原子を１個乃至６
個有する直鎖状又は分枝鎖状のアルキル基であり、例え
ば、メチル、エチル、プロピル、イソプロピル、ブチ
ル、イソブチル、ｓ−ブチル、ｔ−ブチル、ペンチル、
１−メチルブチル、２−メチルブチル、３−メチルブチ
ル、１，１−ジメチルプロピル、１，２−ジメチルプロ
ピル、２，２−ジメチルプロピル、１−エチルプロピ
ル、ヘキシル、１−メチルペンチル、２−メチルペンチ
ル、３−メチルペンチル、４−メチルペンチル、１，１
−ジメチルブチル、１，２−ジメチルブチル、１，３−
ジメチルブチル、２，２−ジメチルブチル、２，３−ジ
メチルブチル、３，３−ジメチルブチル、１−エチルブ
チル、２−エチルブチル、１，１，２−トリメチルプロ
ピル、１，２，２−トリメチルプロピルを挙げることが
できる。Ｒ1においては、好適にはメチル基である。Ｒ2
においては、好適にはメチル基又はｔ−ブチル基であ
り、最も好適にはｔ−ブチル基である。Wherein X represents CH or N, and R 1 is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched alkyl group having 1 to 6 carbon atoms. Represents an alkoxy group or a halogen atom, and R 2 represents a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms or a halogen atom. A compound represented by the formula: or a pharmacologically acceptable salt or ester thereof, (2) a compound in which X is N in the above (1), (3) a compound (1) or (2) above
Wherein R 1 is a hydrogen atom, a linear or branched alkoxy group having 1 to 6 carbon atoms or a halogen atom, or (4) in the above (1) or (2), R 1 is a hydrogen atom A compound, (5) a compound of the above (1) to (4), wherein R 2 is a linear or branched alkyl group or a halogen atom having 1 to 6 carbon atoms; A) a pharmacologically acceptable salt of the compound of the above, (7) a pharmacologically acceptable ester of the compound of the above (1) to (5), (8) 2- (4-chlorophenoxy)
-3- [4- [2-[[1- [4- (2-pyridyl) phenyl] ethylidene] aminooxy] ethoxy] phenyl] propionic acid, 3- [4- [2
-[[1- (4'-Fluoro-4-biphenylyl) ethylidene] aminooxy] ethoxy] phenyl] -2- (4-fluorophenoxy)
Propionic acid, (S) -3- [4- [2-[[1- (4-biphenylyl) ethylidene] aminooxy] ethoxy] phenyl] -2- (4-methylphenoxy) propionic acid, (S) -2 -(4-methylphenoxy) -3- [4- [2-[[1- [4- (2-pyridyl) phenyl] ethylidene] aminooxy] ethoxy] phenyl] propionic acid,
(S) -3- [4- [2-[[1- (4-biphenylyl) ethylidene] aminooxy] ethoxy] phenyl] -2- (4-t-butylphenoxy)
Propionic acid, (S) -2- (4-t-butylphenoxy) -3- [4- [2
-[[1- [4- (2-pyridyl) phenyl] ethylidene] aminooxy] ethoxy] phenyl] propionic acid, (S) -3- [4- [2-[[1
-(4-Biphenylyl) ethylidene] aminooxy] ethoxy]
Phenyl] -2- (4-fluorophenoxy) propionic acid,
(S) -2- (4-fluorophenoxy) -3- [4- [2-[[1- (4′-methoxy-4-biphenylyl) ethylidene] aminooxy] ethoxy] phenyl] propionic acid or ( S) -2- (4-Fluorophenoxy) -3- [4- [2-[[1- [4- (2-pyridyl) phenyl] ethylidene] aminooxy] ethoxy] phenyl] propionic acid or pharmacologically thereof It is an acceptable salt or ester. In the present invention, “a linear or branched alkyl group having 1 to 6 carbon atoms” means 1 to 6 carbon atoms.
A linear or branched alkyl group having, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl,
1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1
-Dimethylbutyl, 1,2-dimethylbutyl, 1,3-
Dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl Can be mentioned. R 1 is preferably a methyl group. R 2
Is preferably a methyl group or a t-butyl group, and most preferably a t-butyl group.
【０００９】本発明において、「炭素数１乃至６個の直
鎖又は分岐鎖のアルコキシ基」とは、炭素原子を１個乃
至６個有する直鎖状又は分枝鎖状のアルキル基が酸素原
子と結合した基であり、例えば、メトキシ、エトキシ、
プロポキシ、イソプロポキシ、ブトキシ、イソブトキ
シ、ｓ−ブトキシ、ｔ−ブトキシ、ペンチルオキシ、１
−メチルブトキシ、２−メチルブチルオキシ、３−メチ
ルブチルオキシ、１，１−ジメチルプロポキシ、１，２
−ジメチルプロポキシ、２，２−ジメチルプロポキシ、
１−エチルプロポキシ、ヘキシルオキシ、１−メチルペ
ンチルオキシ、２−メチルペンチルオキシ、３−メチル
ペンチルオキシ、４−メチルペンチルオキシ、１，１−
ジメチルブトキシ、１，２−ジメチルブトキシ、１，３
−ジメチルブトキシ、２，２−ジメチルブトキシ、２，
３−ジメチルブトキシ、３，３−ジメチルブトキシ、１
−エチルブチルオキシ、２−エチルブチルオキシ、１，
１，２−トリメチルプロポキシ、１，２，２−トリメチ
ルプロポキシを挙げることができる。Ｒ1においては、
好適にはメトキシ基である。Ｒ2においては、好適には
メトキシ基又はｔ−ブトキシ基である。In the present invention, "a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. And a group bonded to, for example, methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, 1
-Methylbutoxy, 2-methylbutyloxy, 3-methylbutyloxy, 1,1-dimethylpropoxy, 1,2
-Dimethylpropoxy, 2,2-dimethylpropoxy,
1-ethylpropoxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1,1-
Dimethylbutoxy, 1,2-dimethylbutoxy, 1,3
-Dimethylbutoxy, 2,2-dimethylbutoxy, 2,
3-dimethylbutoxy, 3,3-dimethylbutoxy, 1
-Ethylbutyloxy, 2-ethylbutyloxy, 1,
Examples thereof include 1,2-trimethylpropoxy and 1,2,2-trimethylpropoxy. In R 1 ,
Preferably it is a methoxy group. R 2 is preferably a methoxy group or a t-butoxy group.
【００１０】本発明において、「ハロゲン原子」とは、
フッ素原子、塩素原子、臭素原子又は沃素原子である。
Ｒ1においては、好適にはフッ素原子である。Ｒ2におい
ては、好適にはフッ素原子又は塩素原子であり、最も好
適にはフッ素原子である。本発明において、Ｘは、好適
には、Ｎである。In the present invention, “halogen atom” is
It is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
R 1 is preferably a fluorine atom. R 2 is preferably a fluorine atom or a chlorine atom, and most preferably a fluorine atom. In the present invention, X is preferably N.
【００１１】本発明において、Ｒ1は、好適には、水素
原子、炭素数１乃至６個の直鎖又は分岐鎖のアルコキシ
基又はハロゲン原子であり、最も好適には、水素原子で
ある。In the present invention, R 1 is preferably a hydrogen atom, a linear or branched alkoxy group having 1 to 6 carbon atoms or a halogen atom, and most preferably a hydrogen atom.
【００１２】本発明において、Ｒ2は、好適には、炭素
数１乃至６個の直鎖又は分岐鎖のアルキル基又はハロゲ
ン原子であり、更に好適には、炭素数１乃至６個の直鎖
又は分岐鎖のアルキル基である。本発明の前記一般式
（Ｉ）を有するフェニルプロピオン酸誘導体は、常法に
従って塩基性基を有する場合は酸付加塩にすることがで
きる。そのような塩としては、例えばフッ化水素酸、塩
酸、臭化水素酸、沃化水素酸のようなハロゲン化水素酸
の塩；硝酸塩、過塩素酸塩、硫酸塩、燐酸塩のような無
機酸塩；メタンスルホン酸、トリフルオロメタンスルホ
ン酸、エタンスルホン酸のような低級アルカンスルホン
酸の塩；ベンゼンスルホン酸、ｐ−トルエンスルホン酸
のようなアリールスルホン酸の塩；グルタミン酸、アス
パラギン酸のようなアミノ酸の塩；酢酸、フマール酸、
酒石酸、蓚酸、マレイン酸、リンゴ酸、コハク酸、安息
香酸、マンデル酸、アスコルビン酸、乳酸、グルコン
酸、クエン酸のようなカルボン酸の塩を挙げることがで
きる。好適にはハロゲン化水素酸の塩である。In the present invention, R 2 is preferably a linear or branched alkyl group having 1 to 6 carbon atoms or a halogen atom, and more preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Or a branched alkyl group. When the phenylpropionic acid derivative having the general formula (I) of the present invention has a basic group according to a conventional method, it can be converted into an acid addition salt. Examples of such salts include salts of hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid; inorganic salts such as nitrates, perchlorates, sulfates and phosphates. Acid salts; salts of lower alkanesulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid; salts of arylsulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid; such as glutamic acid and aspartic acid Amino acid salts; acetic acid, fumaric acid,
Examples thereof include salts of carboxylic acids such as tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and citric acid. Preferably, it is a salt of hydrohalic acid.
【００１３】更に、前記一般式（Ｉ）を有するフェニル
プロピオン酸誘導体は、カルボキシル基を有するため、
常法に従って金属塩にすることができる。そのような塩
としては、例えばリチウム、ナトリウム、カリウムのよ
うなアルカリ金属塩；カルシウム、バリウム、マグネシ
ウムのようなアルカリ土類金属塩；アルミニウム塩をあ
げることができる。好適にはアルカリ金属塩である。Further, since the phenylpropionic acid derivative having the general formula (I) has a carboxyl group,
It can be converted into a metal salt according to a conventional method. Examples of such salts include alkali metal salts such as lithium, sodium and potassium; alkaline earth metal salts such as calcium, barium and magnesium; and aluminum salts. Preferably, it is an alkali metal salt.
【００１４】本発明の前記一般式（Ｉ）を有するフェニ
ルプロピオン酸誘導体は、常法に従って薬理上許容され
るエステルにすることができる。そのようなエステルと
しては、前記一般式（Ｉ）を有するフェニルプロピオン
酸誘導体と比べて、医学的に使用され、薬理上受け入れ
られるものであれば特に限定はない。The phenylpropionic acid derivative having the general formula (I) of the present invention can be converted into a pharmacologically acceptable ester according to a conventional method. Such an ester is not particularly limited as long as it is used medically and is pharmacologically acceptable as compared with the phenylpropionic acid derivative having the general formula (I).
【００１５】本発明の前記一般式（Ｉ）を有するフェニ
ルプロピオン酸誘導体のエステルは、例えば炭素数１乃
至６個を有する直鎖状若しくは分枝鎖状のアルキル基
（当該アルキル基は、トリアルキルシリル基により置換
されていてもよい）、炭素数７乃至１９個を有するアラ
ルキル基、炭素数１乃至６個を有する直鎖状若しくは分
枝鎖状のアルカノイルオキシが置換した炭素数１乃至５
個を有する直鎖状若しくは分枝鎖状のアルキル基、炭素
数１乃至６個を有する直鎖状若しくは分枝鎖状のアルキ
ルオキシカルボニルオキシが置換した炭素数１乃至５個
を有する直鎖状若しくは分枝鎖状のアルキル基、炭素数
５乃至７個を有するシクロアルキルカルボニルオキシが
置換した炭素数１乃至５個を有する直鎖状若しくは分枝
鎖状のアルキル基、炭素数５乃至７個を有するシクロア
ルキルオキシカルボニルオキシが置換した炭素数１乃至
５個を有する直鎖状若しくは分枝鎖状のアルキル基、炭
素数６乃至１０個を有するアリールカルボニルオキシが
置換した炭素数１乃至５個を有する直鎖状若しくは分枝
鎖状のアルキル基、炭素数６乃至１０個を有するアリー
ルオキシカルボニルオキシが置換した炭素数１乃至５個
を有する直鎖状若しくは分枝鎖状のアルキル基、５位に
置換分として炭素数１乃至６個を有する直鎖状若しくは
分枝鎖状のアルキルを有する２−オキソ−１，３−ジオ
キソレン−４−イル基を挙げることができる。The ester of the phenylpropionic acid derivative having the general formula (I) of the present invention is, for example, a linear or branched alkyl group having 1 to 6 carbon atoms (the alkyl group is a trialkyl (Optionally substituted by a silyl group), an aralkyl group having 7 to 19 carbon atoms, and a linear or branched alkanoyloxy having 1 to 6 carbon atoms, which has 1 to 5 carbon atoms.
Linear or branched alkyl group having 1 to 6 carbon atoms, linear or branched alkyloxycarbonyloxy having 1 to 6 carbon atoms, and linear chain having 1 to 5 carbon atoms substituted with Or a branched alkyl group, a linear or branched alkyl group having 1 to 5 carbon atoms substituted with a cycloalkylcarbonyloxy having 5 to 7 carbon atoms, 5 to 7 carbon atoms A linear or branched alkyl group having 1 to 5 carbon atoms substituted with cycloalkyloxycarbonyloxy having 1 to 5 carbon atoms substituted with arylcarbonyloxy having 6 to 10 carbon atoms Or a straight-chain or branched alkyl group having 1 to 5 carbon atoms substituted with an aryloxycarbonyloxy having 6 to 10 carbon atoms. Or a branched alkyl group or a 2-oxo-1,3-dioxolen-4-yl group having a linear or branched alkyl having 1 to 6 carbon atoms as a substituent at the 5-position. Can be mentioned.
【００１６】ここで、炭素数１乃至６個を有する直鎖状
若しくは分枝鎖状のアルキル基としては、例えばメチ
ル、エチル、プロピル、イソプロピル、ブチル、イソブ
チル、ｓ−ブチル、ｔ−ブチル、ペンチル、１−メチル
ブチル、２−メチルブチル、３−メチルブチル、１，１
−ジメチルプロピル、１，２−ジメチルプロピル、２，
２−ジメチルプロピル、１−エチルプロピル、ヘキシ
ル、１−メチルペンチル、２−メチルペンチル、３−メ
チルペンチル、４−メチルペンチル、１，１−ジメチル
ブチル、１，２−ジメチルブチル、１，３−ジメチルブ
チル、２，２−ジメチルブチル、２，３−ジメチルブチ
ル、３，３−ジメチルブチル、１−エチルブチル、２−
エチルブチル、１，１，２−トリメチルプロピル又は
１，２，２−トリメチルプロピルを挙げることができ、
好適には炭素数１乃至４個を有する直鎖状若しくは分枝
鎖状のアルキル基であり、更に好適にはメチル、エチ
ル、プロピル、イソプロピル、ブチル又はイソブチルで
あり、最適にはメチル又はエチルである。The linear or branched alkyl group having 1 to 6 carbon atoms includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl , 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1
-Dimethylpropyl, 1,2-dimethylpropyl, 2,
2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3- Dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-
Ethylbutyl, 1,1,2-trimethylpropyl or 1,2,2-trimethylpropyl,
Preferably it is a linear or branched alkyl group having 1 to 4 carbon atoms, more preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl, most preferably methyl or ethyl. is there.
【００１７】炭素数７乃至１９個を有するアラルキル基
としては、例えばベンジル、フェネチル、３−フェニル
プロピル、４−フェニルブチル、１−ナフチルメチル、
２−ナフチルメチル又はジフェニルメチルを挙げること
ができ、好適にはベンジルである。Examples of the aralkyl group having 7 to 19 carbon atoms include benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl,
Examples include 2-naphthylmethyl or diphenylmethyl, preferably benzyl.
【００１８】炭素数５乃至７個を有するシクロアルキル
基としては、例えばシクロペンチル、シクロヘキシル、
シクロヘプチルを挙げることができ、好適にはシクロヘ
キシルである。Examples of the cycloalkyl group having 5 to 7 carbon atoms include cyclopentyl, cyclohexyl,
Cycloheptyl can be mentioned, preferably cyclohexyl.
【００１９】炭素数６乃至１０個を有するアリール基と
しては、例えばフェニル又はナフチルを挙げることがで
き、好適にはフェニルである。The aryl group having 6 to 10 carbon atoms includes, for example, phenyl or naphthyl, and is preferably phenyl.
【００２０】好適なエステル残基の具体例としては、例
えばメチル、エチル、プロピル、イソプロピル、ブチ
ル、イソブチル、ｔ−ブチル、ベンジル、アセトキシメ
チル、１−（アセトキシ）エチル、プロピオニルオキシ
メチル、１−（プロピオニルオキシ）エチル、ブチリル
オキシメチル、１−（ブチリルオキシ）エチル、イソブ
チリルオキシメチル、１−（イソブチリルオキシ）エチ
ル、バレリルオキシメチル、１−（バレリルオキシ）エ
チル、イソバレリルオキシメチル、１−（イソバレリル
オキシ）エチル、ピバロイルオキシメチル、１−（ピバ
ロイルオキシ）エチル、メトキシカルボニルオキシメチ
ル、１−（メトキシカルボニルオキシ）エチル、エトキ
シカルボニルオキシメチル、１−（エトキシカルボニル
オキシ）エチル、プロポキシカルボニルオキシメチル、
１−（プロポキシカルボニルオキシ）エチル、イソプロ
ポキシカルボニルオキシメチル、１−（イソプロポキシ
カルボニルオキシ）エチル、ブトキシカルボニルオキシ
メチル、１−（ブトキシカルボニルオキシ）エチル、イ
ソブトキシカルボニルオキシメチル、１−（イソブトキ
シカルボニルオキシ）エチル、ｔ−ブトキシカルボニル
オキシメチル、１−（ｔ−ブトキシカルボニルオキシ）
エチル、シクロペンタンカルボニルオキシメチル、１−
（シクロペンタンカルボニルオキシ）エチル、シクロヘ
キサンカルボニルオキシメチル、１−（シクロヘキサン
カルボニルオキシ）エチル、シクロペンチルオキシカル
ボニルオキシメチル、１−（シクロペンチルオキシカル
ボニルオキシ）エチル、シクロヘキシルオキシカルボニ
ルオキシメチル、１−（シクロヘキシルオキシカルボニ
ルオキシ）エチル、ベンゾイルオキシメチル、１−（ベ
ンゾイルオキシ）エチル、フェノキシカルボニルオキシ
メチル、１−（フェノキシカルボニルオキシ）エチル、
（５−メチル−２−オキソ−１，３−ジオキソレン−４
−イル）メチル又は２−トリメチルシリルエチルであ
る。なお、前記一般式（Ｉ）を有するフェニルプロピオ
ン酸誘導体は、種々の異性体を有する。例えばカルボン
酸のα位炭素の不斉に由来する光学異性体が存在する。
前記一般式（Ｉ）においては、これら不斉炭素原子に基
づく立体異性体及びこれら異性体の等量及び非等量混合
物がすべて単一の式で示されている。従って、本発明
は、これらの異性体及びこれら異性体の種々の割合での
混合物をすべて含むものである。Specific examples of suitable ester residues include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, benzyl, acetoxymethyl, 1- (acetoxy) ethyl, propionyloxymethyl, 1- ( Propionyloxy) ethyl, butyryloxymethyl, 1- (butyryloxy) ethyl, isobutyryloxymethyl, 1- (isobutyryloxy) ethyl, valeryloxymethyl, 1- (valeryloxy) ethyl, isovaleryloxymethyl , 1- (isovaleryloxy) ethyl, pivaloyloxymethyl, 1- (pivaloyloxy) ethyl, methoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) Ethyl, Po alkoxycarbonyloxy methyl,
1- (propoxycarbonyloxy) ethyl, isopropoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl, butoxycarbonyloxymethyl, 1- (butoxycarbonyloxy) ethyl, isobutoxycarbonyloxymethyl, 1- (isobutoxy Carbonyloxy) ethyl, t-butoxycarbonyloxymethyl, 1- (t-butoxycarbonyloxy)
Ethyl, cyclopentanecarbonyloxymethyl, 1-
(Cyclopentanecarbonyloxy) ethyl, cyclohexanecarbonyloxymethyl, 1- (cyclohexanecarbonyloxy) ethyl, cyclopentyloxycarbonyloxymethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, cyclohexyloxycarbonyloxymethyl, 1- (cyclohexyloxycarbonyl Oxy) ethyl, benzoyloxymethyl, 1- (benzoyloxy) ethyl, phenoxycarbonyloxymethyl, 1- (phenoxycarbonyloxy) ethyl,
(5-methyl-2-oxo-1,3-dioxolen-4
-Yl) methyl or 2-trimethylsilylethyl. The phenylpropionic acid derivative having the general formula (I) has various isomers. For example, there are optical isomers derived from the asymmetric carbon at the α-position of the carboxylic acid.
In the general formula (I), stereoisomers based on these asymmetric carbon atoms, and equivalent and unequal mixtures of these isomers are all represented by a single formula. Accordingly, the present invention includes all these isomers and mixtures of these isomers in various proportions.
【００２１】更に、前記一般式（Ｉ）を有するフェニル
プロピオン酸誘導体において、オキシム基部分に幾何異
性に基づくシス異性体及びトランス異性体が存在し得
る。前記一般式（Ｉ）においては、これらに基づく両異
性体及びこれらの等量及び非等量混合物がすべて単一の
式で示されている。従って、本発明は、これらの異性体
及びこれら異性体の種々の割合での混合物をすべて含む
ものである。Further, in the phenylpropionic acid derivative having the general formula (I), a cis isomer and a trans isomer based on geometrical isomerism in the oxime group may exist. In the general formula (I), both isomers based on these and equivalent and unequal mixtures thereof are represented by a single formula. Accordingly, the present invention includes all these isomers and mixtures of these isomers in various proportions.
【００２２】更に本発明は、前記一般式（Ｉ）を有する
フェニルプロピオン酸誘導体、その塩又はエステルが溶
剤和物（例えば水和物）を形成する場合には、これらも
すべて含むものである。Further, the present invention includes all the phenylpropionic acid derivatives having the above general formula (I), when the salts or esters thereof form solvates (for example, hydrates).
【００２３】更に本発明において、生体内において代謝
されて前記一般式（Ｉ）を有するフェニルプロピオン酸
誘導体、その塩又はエステルに変換される化合物（例え
ばアミド誘導体のような、いわゆるプロドラッグ）もす
べて含むものである。前記一般式（Ｉ）を有するフェニ
ルプロピオン酸誘導体において、好適には、（１）Ｘが
Ｎである化合物、（２）Ｒ1が水素原子、炭素数１乃至
６個の直鎖若しくは分岐鎖のアルコキシ基又はハロゲン
原子である化合物、（３）Ｒ1が水素原子である化合
物、（４）Ｒ2が炭素数１乃至６個の直鎖若しくは分岐
鎖のアルキル基又はハロゲン原子である化合物、であ
る。本発明の、前記一般式（Ｉ）を有するフェニルプロ
ピオン酸誘導体又はその薬理上許容される塩若しくはエ
ステルの具体例としては、次に例示する化合物を挙げる
ことができる。但し、本発明は下記の例示化合物に限定
されるものではない。Further, in the present invention, all compounds which are metabolized in vivo and converted into a phenylpropionic acid derivative having the above general formula (I), or a salt or ester thereof (for example, so-called prodrugs such as amide derivatives) are also included. Including. In the phenylpropionic acid derivative represented by the general formula (I), (1) a compound in which X is N, (2) a compound in which R 1 is a hydrogen atom, a linear or branched C 1 to C 6 (3) a compound in which R 1 is a hydrogen atom, (4) a compound in which R 2 is a linear or branched alkyl group having 1 to 6 carbon atoms or a halogen atom, is there. Specific examples of the phenylpropionic acid derivative having the general formula (I) or a pharmacologically acceptable salt or ester thereof of the present invention include the following compounds. However, the present invention is not limited to the following exemplified compounds.
【００２４】なお、以下の表１において、「Me」はメチ
ル基を、「Et」はエチル基を、「Pyr-2」は2-ピリジル
基を、「Ph」はフェニル基を、「t-Bu」はt-ブチル基
を、「MeO」はメトキシ基を、それぞれ示すIn the following Table 1, "Me" represents a methyl group, "Et" represents an ethyl group, "Pyr-2" represents a 2-pyridyl group, "Ph" represents a phenyl group, and "t- “Bu” indicates a t-butyl group, and “MeO” indicates a methoxy group.
【００２５】[0025]
【化３】 Embedded image
【００２６】[0026]
【表１】 [Table 1]
【００２７】[0027]
【発明の実施の形態】本発明の前記一般式（Ｉ）を有す
るフェニルプロピオン酸誘導体、その薬理上許容される
塩及びその薬理上許容されるエステルは、国際公開公報
WO97/37970（対応欧州特許出願公開公報EP916651A）に
記載の方法にしたがって製造することができる。本発明
の前記一般式（Ｉ）を有するフェニルプロピオン酸誘導
体、その薬理上許容される塩及びその薬理上許容される
エステルは、高脂血症、高血糖症、肥満症、耐糖能不全
（impaired glucose tolerance： IGT）状態、インスリ
ン抵抗性非耐糖能不全（insulin resistant non-IGT: N
GT）状態、高血圧症、骨粗鬆症、膵炎、悪液質、脂肪
肝、糖尿病合併症（例えば網膜症、腎症、白内障、冠動
脈疾患等）、動脈硬化症、白内障、妊娠糖尿病（gestat
ional diabetes mellitus: GDM）、インスリン抵抗性に
起因する疾病（例えば多嚢胞卵巣症候群（polycysticov
ary syndrome: PCOS）等）、炎症性疾患（例えば骨関節
炎、疼痛、発熱、炎症性腸炎等）、アクネ、日焼け、乾
癬、湿疹、アレルギー性疾患、喘息、ＧＩ潰瘍、心血管
性疾患（例えば虚血性心疾患等）、アテローム性動脈硬
化症及び虚血性疾患により惹起される細胞損傷（例えば
卒中により惹起される脳損傷等）、自己免疫疾患（例え
ば全身性エリテマトーデス、慢性関節リウマチ、若年性
関節リウマチ、シェーグレン症候群、全身性強皮症、混
合型結合組織病、皮膚筋炎、橋本病、原発性粘液水腫、
甲状腺中毒症、悪性貧血、潰瘍性大腸炎、自己免疫性萎
縮性胃炎、特発性Addison病、男性不妊症、Goodpasture
症候群、急性進行性糸球体腎炎、重症筋無力症、多発性
筋炎、尋常性天疱瘡、水疱性類天疱瘡、交感性眼炎、多
発性硬化症、自己免疫性溶血性貧血、特発性血小板減少
性紫斑病、心筋梗塞後症候群、リウマチ熱、ルポイド肝
炎、原発性胆汁性肝硬変症、ベーチェット病、CREST症
候群等）等の治療剤または予防剤、好適には高血糖症、
骨粗鬆症、膵炎またはリウマチ、特に高血糖症、膵炎ま
たはリウマチ、の治療剤または予防剤（特に治療剤）と
して有用である。BEST MODE FOR CARRYING OUT THE INVENTION The phenylpropionic acid derivative having the above general formula (I), its pharmacologically acceptable salt and its pharmacologically acceptable ester of the present invention are disclosed in International Publication No.
It can be produced according to the method described in WO97 / 37970 (corresponding European Patent Application Publication No. EP916651A). The phenylpropionic acid derivative having the above general formula (I), the pharmacologically acceptable salt thereof, and the pharmacologically acceptable ester thereof of the present invention may be used in the form of hyperlipidemia, hyperglycemia, obesity, impaired glucose tolerance. glucose tolerance: IGT status, insulin resistant non-IGT: N
GT) condition, hypertension, osteoporosis, pancreatitis, cachexia, fatty liver, diabetic complications (eg retinopathy, nephropathy, cataract, coronary artery disease, etc.), arteriosclerosis, cataract, gestational diabetes (gestat)
ional diabetes mellitus: GDM), diseases caused by insulin resistance (eg, polycystic ovary syndrome (polycysticov)
ary syndrome: PCOS), inflammatory diseases (eg, osteoarthritis, pain, fever, inflammatory enteritis, etc.), acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcers, cardiovascular diseases (eg, imaginary diseases) Blood disease caused by atherosclerosis and ischemic disease (eg, brain damage caused by stroke), autoimmune disease (eg, systemic lupus erythematosus, rheumatoid arthritis, rheumatoid arthritis) , Sjogren's syndrome, systemic scleroderma, mixed connective tissue disease, dermatomyositis, Hashimoto's disease, primary myxedema,
Thyrotoxicosis, pernicious anemia, ulcerative colitis, autoimmune atrophic gastritis, idiopathic Addison disease, male infertility, Goodpasture
Syndrome, acute progressive glomerulonephritis, myasthenia gravis, polymyositis, pemphigus vulgaris, pemphigus vulgaris, sympathetic ophthalmitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia Purpura, post-myocardial infarction syndrome, rheumatic fever, lupus hepatitis, primary biliary cirrhosis, Behcet's disease, CREST syndrome, etc.) or a prophylactic agent, preferably hyperglycemia,
It is useful as a therapeutic or preventive agent (particularly a therapeutic agent) for osteoporosis, pancreatitis or rheumatism, particularly hyperglycemia, pancreatitis or rheumatism.
【００２８】本発明の前記一般式（Ｉ）を有するフェニ
ルプロピオン酸誘導体、その薬理上許容される塩及びそ
のエステルは、種々の形態で投与される。その投与形態
としては特に限定はなく、各種製剤形態、患者の年齢、
性別その他の条件、疾患の程度等に応じて決定される。
例えば錠剤、丸剤、散剤、顆粒剤、シロップ剤、液剤、
懸濁剤、乳剤、顆粒剤およびカプセル剤の場合には経口
投与される。また注射剤の場合には単独であるいはぶど
う糖、アミノ酸等の通常の補液と混合して静脈内投与さ
れ、更には必要に応じて単独で筋肉内、皮内、皮下もし
くは腹腔内投与される。坐剤の場合には直腸内投与され
る。好適には経口投与である。The phenylpropionic acid derivative having the general formula (I), its pharmaceutically acceptable salt and its ester of the present invention are administered in various forms. There is no particular limitation on the administration form, various formulation forms, patient age,
It is determined according to gender and other conditions, degree of disease, and the like.
For example, tablets, pills, powders, granules, syrups, solutions,
Suspensions, emulsions, granules and capsules are administered orally. In the case of an injection, it is administered intravenously, alone or as a mixture with a normal replenisher such as glucose or amino acid, and, if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally. Preferably it is oral administration.
【００２９】これらの各種製剤は、常法に従って主薬に
賦形剤、結合剤、崩壊剤、潤沢剤、溶解剤、矯味矯臭、
コーティング剤等既知の医薬製剤分野において通常使用
しうる既知の補助剤を用いて製剤化することができる。These various preparations are prepared by adding excipients, binders, disintegrants, lubricants, solubilizers, flavors,
It can be formulated using known auxiliaries usually used in the field of known pharmaceutical preparations such as coating agents.
【００３０】錠剤の形態に成形するに際しては、担体と
してこの分野で従来公知のものを広く使用でき、例えば
乳糖、白糖、塩化ナトリウム、ぶどう糖、尿素、澱粉、
炭酸カルシウム、カオリン、結晶セルロース、ケイ酸等
の賦形剤、水、エタノール、プロパノール、単シロッ
プ、ぶどう糖液、澱粉液、ゼラチン溶液、カルボキシメ
チルセルロース、セラック、メチルセルロース、リン酸
カリウム、ポリビニルピロリドン糖の結合剤、乾燥澱
粉、アルギン酸ナトリウム、カンテン末、ラミナラン
末、炭酸水素ナトリウム、炭酸カルシウム、ポリオキシ
エチレンソルビタン脂肪酸エステル類、ラウリル硫酸ナ
トリウム、ステアリン酸モノグリセリド、澱粉、乳糖等
の崩壊剤、白糖、ステアリン、カカオバター、水素添加
油等の崩壊抑制剤、第４級アンモニウム塩基、ラウリル
硫酸ナトリウム等の吸収促進剤、グリセリン、澱粉等の
保湿剤、澱粉、乳糖、カオリン、ベントナイト、コロイ
ド状ケイ酸等の吸着剤、精製タルク、ステアリン酸塩、
硼酸末、ポリエチレングリコール等の滑沢剤等が例示で
きる。更に錠剤は必要に応じ通常の剤皮を施した錠剤、
例えば糖衣錠、ゼラチン被包錠、腸溶被錠、フィルムコ
ーティング錠あるいは二重錠、多層錠とすることができ
る。In the case of molding into tablets, carriers conventionally known in the art can be widely used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, and the like.
Binding of excipients such as calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone sugar Agent, dried starch, sodium alginate, agar powder, laminarane powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, disintegrators such as lactose, sucrose, stearin, cacao Disintegration inhibitors such as butter and hydrogenated oil; quaternary ammonium bases; absorption promoters such as sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid , Ltd. talc, stearates,
Lubricants such as boric acid powder and polyethylene glycol can be exemplified. Furthermore, tablets are tablets coated with normal skin as needed,
For example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets or multilayer tablets can be prepared.
【００３１】丸剤の形態に成形するに際しては、担体と
してこの分野で従来公知のものを広く使用でき、例えば
ぶどう糖、乳糖、澱粉、カカオ脂、硬化植物油、カオリ
ン、タルク等の賦形剤、アラビアゴム末、トラガント
末、ゼラチン、エタノール等の結合剤、ラミナランカン
テン等の崩壊剤等が例示できる。For molding into pills, carriers conventionally known in the art can be widely used, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, and the like. Examples thereof include rubber powder, tragacanth powder, binders such as gelatin and ethanol, and disintegrants such as laminaran agar.
【００３２】坐剤の形態に成形するに際しては、担体と
してこの分野で従来公知のものを広く使用でき、例えば
ポリエチレングリコール、カカオ脂、高級アルコール、
高級アルコールのエステル類、ゼラチン、半合成グリセ
ライド等を挙げることができる。In shaping into a suppository form, those conventionally known in the art can be widely used as carriers, such as polyethylene glycol, cocoa butter, higher alcohols and the like.
Esters of higher alcohols, gelatin, semi-synthetic glycerides and the like can be mentioned.
【００３３】注射剤として調製される場合には、液剤お
よび懸濁剤は殺菌され、且つ血液と等張であるのが好ま
しく、これら液剤、乳剤および懸濁剤の形態に成形する
に際しては、希釈剤としてこの分野において慣用されて
いるものを全て使用でき、例えば水、エチルアルコー
ル、プロピレングリコール、エトキシ化イソステアリル
アルコール、ポリオキシ化イソステアリルアルコール、
ポリオキシエチレンソルビタン脂肪酸エステル類等を挙
げることができる。なお、この場合、等張性の溶液を調
製するに十分な量の食塩、ぶどう糖、あるいはグリセリ
ンを医薬製剤中に含有せしめてもよく、また通常の溶解
補助剤、緩衝剤、無痛化剤等を添加してもよい。When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood. When formed into these solutions, emulsions and suspensions, they are diluted. All agents commonly used in this field can be used as the agent, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,
Examples thereof include polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and ordinary solubilizing agents, buffers, soothing agents, and the like may be used. It may be added.
【００３４】更に必要に応じて着色剤、保存剤、香料、
風味剤、甘味剤等や他の医薬品を含有せしめてもよい。If necessary, a coloring agent, a preservative, a fragrance,
Flavoring agents, sweeteners and the like and other pharmaceuticals may be included.
【００３５】上記医薬製剤中に含まれる有効成分化合物
の量は、特に限定されず広範囲に適宜選択されるが、通
常全組成物中１〜７０重量％、好ましくは１〜３０重量
％含まれる量とするのが適当である。The amount of the active ingredient compound contained in the above-mentioned pharmaceutical preparation is not particularly limited and may be appropriately selected in a wide range, but is usually from 1 to 70% by weight, preferably from 1 to 30% by weight in the total composition. Is appropriate.
【００３６】その投与量は、症状、年令、体重、投与方
法および剤型等によって異なるが、通常は成人に対して
１日、下限として０．００１ｍｇ（好ましくは０．０１
ｍｇ、更に好ましくは０．１ｍｇ）であり、上限として
２、０００ｍｇ（好ましくは２００ｍｇ、更に好ましく
は２０ｍｇ）を１回ないし数回投与することができる。The dose varies depending on symptoms, age, body weight, administration method and dosage form, but is usually 0.001 mg (preferably 0.01 mg) per day for an adult.
mg, more preferably 0.1 mg), and an upper limit of 2,000 mg (preferably 200 mg, more preferably 20 mg) can be administered once or several times.
【００３７】[0037]
【実施例】次に実施例、参考例、試験例および製剤例を
あげて本発明を更に詳細に説明するが、本発明はこれら
に限定されるものではない。EXAMPLES The present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples and Formulation Examples, but the present invention is not limited thereto.
【００３８】[0038]
【実施例１】2-(4-クロロフェノキシ)-3-[4-[2-[[1-[4-
(2-ピリジル)フェニル]エチリデン]アミノオキシ]エト
キシ]フェニル]プロピオン酸 エチルエステル（例示化
合物番号１） 下記参考例5(d)で製造した2-(4-クロロフェノキシ)-3-
(4-ヒドロキシフェニル)プロピオン酸 エチルエステル
(504 mg)をジメチルスルホキシド(2 ml)とトルエン(2 m
l)の混合溶媒に溶解し、水素化ナトリウム(55%, 85 mg)
を加えた。40℃で1時間攪拌した後、WO97/37970（EP916
651A）の参考例2の方法により製造した4'-(2-ピリジル)
アセトフェノンオキシム O-2-(メタンスルホニルオキ
シ)エチルエーテル(649 mg)のジメチルスルホキシド溶
液(2 ml)を滴下した。反応溶液を60℃で4時間攪拌した
後、酢酸エチル及び水を加えた。有機層を分離し、飽和
食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧
濃縮した。得られた粗製物を、さらにシリカゲルカラム
クロマトグラフィー（溶出溶液：ヘキサン/酢酸エチル
＝9/1）を用いて精製し、無色油状の目的化合物(504 m
g)を得た。1 H-NMR (270 MHz, CDCl3): δ ppm 1.19(3H, t, J=7.0Hz), 2.26 (3H, s), 3.17 (2H, d,
J=6.5Hz), 4.17 (2H,q, J=7.0Hz), 4.28 (2H, t, J=
5.0Hz), 4.54 (2H, t, J=5.0Hz), 4.69 (1H,t, J=6.5
Hz), 6.76 (2H, d, J=8.5Hz), 6.90 (2H, d, J=8.5H
z), 7.16-7.26(5H, m), 7.74-7.77 (4H, m), 8.00
(2H, d, J=8.5Hz), 8.70-8.71 (1H, m).Example 1 2- (4-chlorophenoxy) -3- [4- [2-[[1- [4-
(2-pyridyl) phenyl] ethylidene] aminooxy] eth
[Xix] phenyl] propionic acid ethyl ester (exemplification
Compound No. 1) 2- (4-chlorophenoxy) -3- produced in Reference Example 5 (d ) below
(4-Hydroxyphenyl) propionic acid ethyl ester
(504 mg) in dimethyl sulfoxide (2 ml) and toluene (2 m
l) in a mixed solvent of sodium hydride (55%, 85 mg)
Was added. After stirring at 40 ° C. for 1 hour, WO97 / 37970 (EP916)
651A) 4 '-(2-pyridyl) produced by the method of Reference Example 2
A solution of acetophenone oxime O-2- (methanesulfonyloxy) ethyl ether (649 mg) in dimethylsulfoxide (2 ml) was added dropwise. After stirring the reaction solution at 60 ° C. for 4 hours, ethyl acetate and water were added. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was further purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1) to give the target compound as a colorless oil (504 m
g) was obtained. 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 1.19 (3H, t, J = 7.0 Hz), 2.26 (3H, s), 3.17 (2H, d,
J = 6.5Hz), 4.17 (2H, q, J = 7.0Hz), 4.28 (2H, t, J =
5.0Hz), 4.54 (2H, t, J = 5.0Hz), 4.69 (1H, t, J = 6.5
Hz), 6.76 (2H, d, J = 8.5Hz), 6.90 (2H, d, J = 8.5H
z), 7.16-7.26 (5H, m), 7.74-7.77 (4H, m), 8.00
(2H, d, J = 8.5Hz), 8.70-8.71 (1H, m).
【００３９】[0039]
【実施例２】2-(4-クロロフェノキシ)-3-[4-[2-[[1-[4-
(2-ピリジル)フェニル]エチリデン]アミノオキシ]エト
キシ]フェニル]プロピオン酸（例示化合物番号２） 実施例1で製造した2-(4-クロロフェノキシ)-3-[4-[2-
[[1-[4-(2-ピリジル)フェニル]エチリデン]アミノオキ
シ]エトキシ]フェニル]プロピオン酸 エチルエステル
(500 mg)のエタノール溶液(8 ml)に、水酸化ナトリウム
水溶液(1N, 1.79ml)を加え、3時間、加熱還流を行っ
た。反応液を減圧濃縮した後、塩酸(1N)を加えて中和
し、酢酸エチルを加え、抽出を行った。酢酸エチル層を
分離し、飽和食塩水で洗浄後、無水硫酸マグネシウムで
乾燥し、減圧濃縮した。得られた粗製物を、さらにシリ
カゲルカラムクロマトグラフィー（溶出溶液：塩化メチ
レン/メタノール＝9/1）を用いて精製し、無色フォーム
状の目的化合物(169 mg)を得た。1 H-NMR (270 MHz, CDCl3): δ ppm 2.17 (3H, s), 2.99 (2H, brs), 4.13 (2H, brs),
4.45 (3H, brs), 6.55-7.16 (9H, m), 7.66 (4H, d,
J=8.5Hz), 7.89 (2H, d, J=8.5Hz), 8.63 (1H,d, J=
5.0Hz).Example 2 2- (4-chlorophenoxy) -3- [4- [2-[[1- [4-
(2-pyridyl) phenyl] ethylidene] aminooxy] eth
[Xy] phenyl] propionic acid (Exemplary Compound No. 2) 2- (4-chlorophenoxy) -3- [4- [2-
[[1- [4- (2-Pyridyl) phenyl] ethylidene] aminooxy] ethoxy] phenyl] propionic acid ethyl ester
A sodium hydroxide aqueous solution (1N, 1.79 ml) was added to an ethanol solution (8 ml) of (500 mg), and the mixture was heated under reflux for 3 hours. After the reaction solution was concentrated under reduced pressure, hydrochloric acid (1N) was added for neutralization, and ethyl acetate was added for extraction. The ethyl acetate layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was further purified by silica gel column chromatography (eluent: methylene chloride / methanol = 9/1) to obtain the target compound (169 mg) as a colorless foam. 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 2.17 (3H, s), 2.99 (2H, brs), 4.13 (2H, brs),
4.45 (3H, brs), 6.55-7.16 (9H, m), 7.66 (4H, d,
J = 8.5Hz), 7.89 (2H, d, J = 8.5Hz), 8.63 (1H, d, J =
5.0Hz).
【００４０】[0040]
【実施例３】3-[4-[2-[[1-(4'-フルオロ-4-ビフェニリ
ル)エチリデン]アミノオキシ]エトキシ]フェニル]-2-(4
-フルオロフェノキシ)プロピオン酸 エチルエステル
（例示化合物番号３） 参考例6(b)で製造した2-(4-フルオロフェノキシ)-3-(4-
ヒドロキシフェニル)プロピオン酸 エチルエステル(1.
8 g)、水素化ナトリウム(55%, 271 mg)及び参考例7(b)
で製造した2-[[1-(4'-フルオロ-4-ビフェニリル)エチリ
デン]アミノオキシ]エチル メタンスルホネート(2.14
g)を用いて、実施例1に準じて反応及び後処理を行うこ
とにより、白色紛体の目的化合物(1.45 g)を得た。 融点 103 - 105℃1 H-NMR (270 MHz, CDCl3): δ ppm 1.20 (3H, t, J=7.0Hz), 2.26 (3H, s), 3.16 (2H,
d, J=6.5Hz), 4.17 (2H,q, J=7.0Hz), 4.27 (2H, t,
J=4.5Hz), 4.54 (2H, t, J=4.5Hz), 4.66 (1H,t, J=
6.5Hz), 6.74-6.79 (2H, m), 6.88-6.94 (4H, m),
7.13 (2H, t, J=8.5Hz), 7.21 (2H, d, J=8.5Hz), 7.
52-7.59 (4H, m), 7.71 (2H, d, J=8.5Hz).Example 3 3- [4- [2-[[1- (4′-fluoro-4-biphenyli)
Le) ethylidene] aminooxy] ethoxy] phenyl] -2- (4
-Fluorophenoxy) propionic acid ethyl ester
(Exemplary Compound No. 3) 2- (4-fluorophenoxy) -3- (4-) produced in Reference Example 6 (b)
(Hydroxyphenyl) propionic acid ethyl ester (1.
8 g), sodium hydride (55%, 271 mg) and Reference Example 7 (b)
2-[[1- (4′-Fluoro-4-biphenylyl) ethylidene] aminooxy] ethyl methanesulfonate (2.14
Using g), the reaction and post-treatment were carried out according to Example 1, thereby obtaining the target compound as a white powder (1.45 g). Melting point 103-105 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 1.20 (3H, t, J = 7.0 Hz), 2.26 (3H, s), 3.16 (2H,
d, J = 6.5Hz), 4.17 (2H, q, J = 7.0Hz), 4.27 (2H, t,
J = 4.5Hz), 4.54 (2H, t, J = 4.5Hz), 4.66 (1H, t, J =
6.5Hz), 6.74-6.79 (2H, m), 6.88-6.94 (4H, m),
7.13 (2H, t, J = 8.5Hz), 7.21 (2H, d, J = 8.5Hz), 7.
52-7.59 (4H, m), 7.71 (2H, d, J = 8.5Hz).
【００４１】[0041]
【実施例４】3-[4-[2-[[1-(4'-フルオロ-4-ビフェニリ
ル)エチリデン]アミノオキシ]エトキシ]フェニル]-2-(4
-フルオロフェノキシ)プロピオン酸（例示化合物番号
４） 実施例3で製造した3-[4-[2-[[1-(4'-フルオロ-4-ビフェ
ニリル)エチリデン]アミノオキシ]エトキシ]フェニル]-
2-(4-フルオロフェノキシ)プロピオン酸 エチルエステ
ル(1.44 g)及び水酸化ナトリウム水溶液(1N, 5.0 ml)を
用いて、実施例2に準じて反応及び後処理を行うことに
より、無色結晶の目的化合物(1.13 g)を得た。 融点 109 - 110℃1 H-NMR (270 MHz, CDCl3): δ ppm 2.25 (3H, s), 3.18-3.21 (2H, m), 4.27 (2H, t, J=
5.0Hz), 4.54 (2H, t,J=5.0Hz), 4.72 (1H, t, J=5.5
Hz), 6.75-6.80 (2H, m), 6.88-6.89 (4H, m), 7.13
(2H, t, J=8.5Hz), 7.21 (2H, d, J=8.5Hz), 7.52-
7.58 (4H, m), 7.70 (2H, d, J=8.5Hz).Example 4 3- [4- [2-[[1- (4′-fluoro-4-biphenyli)
Le) ethylidene] aminooxy] ethoxy] phenyl] -2- (4
-Fluorophenoxy) propionic acid (exemplary compound number
4) 3- [4- [2-[[1- (4'-fluoro-4-biphenylyl) ethylidene] aminooxy] ethoxy] phenyl]-produced in Example 3
Using 2- (4-fluorophenoxy) propionic acid ethyl ester (1.44 g) and aqueous sodium hydroxide solution (1N, 5.0 ml), the reaction and post-treatment were carried out according to Example 2 to obtain colorless crystals. Compound (1.13 g) was obtained. Melting point 109-110 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 2.25 (3H, s), 3.18-3.21 (2H, m), 4.27 (2H, t, J =
5.0Hz), 4.54 (2H, t, J = 5.0Hz), 4.72 (1H, t, J = 5.5
Hz), 6.75-6.80 (2H, m), 6.88-6.89 (4H, m), 7.13
(2H, t, J = 8.5Hz), 7.21 (2H, d, J = 8.5Hz), 7.52-
7.58 (4H, m), 7.70 (2H, d, J = 8.5Hz).
【００４２】[0042]
【実施例５】(S)-3-[4-[2-[[1-(4-ビフェニリル)エチリ
デン]アミノオキシ]エトキシ]フェニル]-2-(4-メチルフ
ェノキシ)プロピオン酸 2-トリメチルシリルエチルエ
ステル（例示化合物番号５） WO97/37970（EP916651A）の参考例3(b)で製造した2-[[1
-(4-ビフェニリル)エチリデン]アミノオキシ]エタノー
ル(288 mg)、参考例1(e)で製造した(S)-3-(4-ヒドロキ
シフェニル)-2-(4-メチルフェノキシ)プロピオン酸 2-
トリメチルシリルエチルエステル(280 mg)及びトリフェ
ニルホスフィン(296 mg)のトルエン溶液(10 ml)に、ア
ゾジカルボン酸ジイソプロピルエステル(40%トルエン溶
液(0.61 ml))を0℃で滴下した。滴下終了後、室温にて1
6時間攪拌した。反応溶媒を減圧下留去し、シリカゲル
カラムクロマトグラフィー（溶出溶液：ヘキサン/酢酸
エチル＝9/1）を用いて精製し、無色油状の目的化合物
(270 mg)を得た。1 H-NMR (270 MHz, CDCl3): δ ppm 0.01 (9H, s), 0.92 (2H, t, J=8.5Hz), 2.24 (3H,
s), 2.26 (3H, s), 3.14-3.17 (2H, m), 4.10-4.23
(2H, m), 4.27 (2H, t, J=5.0Hz), 4.54 (2H, t, J=
5.0Hz), 4.66 (1H, t, J=6.5Hz), 6.73 (2H, d, J=8.
5Hz), 6.89 (2H, d, J=8.5Hz), 7.02 (2H, d, J=8.5H
z), 7.21 (2H, d, J=8.5Hz), 7.33-7.48 (3H, m),
7.58-7.62 (4H, m), 7.71 (2H, d, J=8.5Hz).Example 5 (S) -3- [4- [2-[[1- (4-Biphenylyl) ethyl]
Den] aminooxy] ethoxy] phenyl] -2- (4-methylf
Enoxy) propionic acid 2-trimethylsilylethyl ester
Stell (Exemplified Compound No. 5) 2-[[1] produced in Reference Example 3 (b) of WO97 / 37970 (EP916651A)
-(4-Biphenylyl) ethylidene] aminooxy] ethanol (288 mg), (S) -3- (4-hydroxyphenyl) -2- (4-methylphenoxy) propionic acid 2 prepared in Reference Example 1 (e) -
To a toluene solution (10 ml) of trimethylsilylethyl ester (280 mg) and triphenylphosphine (296 mg) was added dropwise, at 0 ° C, diisopropyl azodicarboxylate (40% toluene solution (0.61 ml)). After dropping, add 1 at room temperature.
Stirred for 6 hours. The reaction solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1) to give the target compound as a colorless oil.
(270 mg) was obtained. 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 0.01 (9H, s), 0.92 (2H, t, J = 8.5Hz), 2.24 (3H,
s), 2.26 (3H, s), 3.14-3.17 (2H, m), 4.10-4.23
(2H, m), 4.27 (2H, t, J = 5.0Hz), 4.54 (2H, t, J =
5.0Hz), 4.66 (1H, t, J = 6.5Hz), 6.73 (2H, d, J = 8.
5Hz), 6.89 (2H, d, J = 8.5Hz), 7.02 (2H, d, J = 8.5H)
z), 7.21 (2H, d, J = 8.5Hz), 7.33-7.48 (3H, m),
7.58-7.62 (4H, m), 7.71 (2H, d, J = 8.5Hz).
【００４３】[0043]
【実施例６】(S)-3-[4-[2-[[1-(4-ビフェニリル)エチリ
デン]アミノオキシ]エトキシ]フェニル]-2-(4-メチルフ
ェノキシ)プロピオン酸（例示化合物番号６） 実施例5で製造した(S)-3-[4-[2-[[1-(4-ビフェニリル)
エチリデン]アミノオキシ]エトキシ]フェニル]-2-(4-メ
チルフェノキシ)プロピオン酸 2-トリメチルシリルエ
チルエステル(270 mg)のテトラヒドロフラン溶液(5 ml)
に、テトラブチルアンモニウムフルオリドの1Mテトラヒ
ドロフラン溶液(1.1 ml)を加え、1.5時間室温にて攪拌
した。その後、反応溶媒を減圧下留去し、塩酸(1N)を加
えて中和した後、酢酸エチルを加え、抽出した。酢酸エ
チル層を分離し、飽和食塩水で洗浄後、無水硫酸マグネ
シウムで乾燥し、減圧濃縮した。生じた結晶をヘキサン
で濾取し、無色結晶の目的化合物(210 mg)を得た。 融点 128 - 130℃1 H-NMR (270 MHz, CDCl3): δ ppm 2.26 (6H, s), 3.21 (2H, d, J=6.5Hz), 4.27 (2H,
t, J=5.0Hz), 4.54 (2H,t, J=5.0Hz), 4.78 (1H, t,
J=6.5Hz), 6.75 (2H, d, J=8.5Hz), 6.89 (2H,d, J=
8.5Hz), 7.05 (2H, d, J=8.5Hz), 7.21 (2H, d, J=8.
5Hz), 7.31-7.48(3H, m), 7.58-7.62 (4H, m), 7.71
(2H, d, J=8.5Hz).Example 6 (S) -3- [4- [2-[[1- (4-biphenylyl) ethyl]
Den] aminooxy] ethoxy] phenyl] -2- (4-methylf
(Enoxy) propionic acid (Exemplified Compound No. 6) (S) -3- [4- [2-[[1- (4-biphenylyl)) prepared in Example 5
Ethylidene] aminooxy] ethoxy] phenyl] -2- (4-methylphenoxy) propionic acid 2-trimethylsilylethyl ester (270 mg) in tetrahydrofuran (5 ml)
Was added to a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.1 ml), and the mixture was stirred at room temperature for 1.5 hours. Thereafter, the reaction solvent was distilled off under reduced pressure, hydrochloric acid (1N) was added for neutralization, and ethyl acetate was added for extraction. The ethyl acetate layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crystals were collected by filtration with hexane to give the target compound (210 mg) as colorless crystals. Melting point 128-130 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 2.26 (6H, s), 3.21 (2H, d, J = 6.5 Hz), 4.27 (2H,
t, J = 5.0Hz), 4.54 (2H, t, J = 5.0Hz), 4.78 (1H, t,
J = 6.5Hz), 6.75 (2H, d, J = 8.5Hz), 6.89 (2H, d, J =
8.5Hz), 7.05 (2H, d, J = 8.5Hz), 7.21 (2H, d, J = 8.
5Hz), 7.31-7.48 (3H, m), 7.58-7.62 (4H, m), 7.71
(2H, d, J = 8.5Hz).
【００４４】[0044]
【実施例７】(S)-2-(4-メチルフェノキシ)-3-[4-[2-[[1
-[4-(2-ピリジル)フェニル]エチリデン]アミノオキシ]
エトキシ]フェニル]プロピオン酸 2-トリメチルシリル
エチルエステル（例示化合物番号７） WO97/37970（EP916651A）の参考例1(d)で製造した2-[[1
-[4-(2-ピリジル)フェニル]エチリデン]アミノオキシ]
エタノール(1.65 g)、参考例1(e)で製造した(S)-3-(4-
ヒドロキシフェニル)-2-(4-メチルフェノキシ)プロピオ
ン酸 2-トリメチルシリルエチルエステル(1.60 g)、ト
リフェニルホスフィン(1.69 g)及びアゾジカルボン酸ジ
イソプロピルエステル (40%トルエン溶液(3.47 ml))を
用いて、実施例5に準じて反応及び後処理を行うことに
より、無色油状の目的化合物(2.20 g)を得た。1 H-NMR (270 MHz, CDCl3): δ ppm 0.00 (9H, s), 0.91 (2H, t, J=8.5Hz), 2.24 (3H,
s), 2.26 (3H, s), 3.14-3.17 (2H, m), 4.09-4.23
(2H, m), 4.26 (2H, t, J=5.0Hz), 4.54 (2H, t, J=
5.0Hz), 4.64-4.68 (1H, m), 6.71 (2H, d, J=8.5H
z), 6.87 (2H, d, J=8.5Hz), 7.01 (2H, d, J=8.5H
z), 7.19-7.28 (3H, m), 7.73-7.79 (4H, m),8.00 (2
H, d, J=8.5Hz), 8.70 (1H, d, J=5.5Hz).Example 7 (S) -2- (4-methylphenoxy) -3- [4- [2-[[1
-[4- (2-Pyridyl) phenyl] ethylidene] aminooxy
[Ethoxy] phenyl] propionic acid 2-trimethylsilyl
Ethyl ester (Exemplified Compound No. 7) 2-[[1 produced in Reference Example 1 (d) of WO97 / 37970 (EP916651A)
-[4- (2-Pyridyl) phenyl] ethylidene] aminooxy
Ethanol (1.65 g), prepared in Reference Example 1 (e), (S) -3- (4-
Using (hydroxyphenyl) -2- (4-methylphenoxy) propionic acid 2-trimethylsilylethyl ester (1.60 g), triphenylphosphine (1.69 g) and diisopropyl azodicarboxylate (40% toluene solution (3.47 ml)) The target compound (2.20 g) was obtained as a colorless oil by carrying out the reaction and post-treatment according to Example 5. 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 0.00 (9H, s), 0.91 (2H, t, J = 8.5Hz), 2.24 (3H,
s), 2.26 (3H, s), 3.14-3.17 (2H, m), 4.09-4.23
(2H, m), 4.26 (2H, t, J = 5.0Hz), 4.54 (2H, t, J =
5.0Hz), 4.64-4.68 (1H, m), 6.71 (2H, d, J = 8.5H
z), 6.87 (2H, d, J = 8.5Hz), 7.01 (2H, d, J = 8.5H
z), 7.19-7.28 (3H, m), 7.73-7.79 (4H, m), 8.00 (2
H, d, J = 8.5Hz), 8.70 (1H, d, J = 5.5Hz).
【００４５】[0045]
【実施例８】(S)-2-(4-メチルフェノキシ)-3-[4-[2-[[1
-[4-(2-ピリジル)フェニル]エチリデン]アミノオキシ]
エトキシ]フェニル]プロピオン酸（例示化合物番号８） 実施例7で製造した(S)-2-(4-メチルフェノキシ)-3-[4-
[2-[[1-[4-(2-ピリジル)フェニル]エチリデン]アミノオ
キシ]エトキシ]フェニル]プロピオン酸 2-トリメチル
シリルエチルエステル(2.20 g)及びテトラブチルアンモ
ニウムフルオリドのテトラヒドロフラン溶液(1M, 9.00
ml)を用いて、実施例6に準じて反応及び後処理を行うこ
とにより、無色結晶の目的化合物(1.48 g)を得た。 融点 54 - 56℃1 H-NMR (270 MHz, CDCl3): δ ppm 2.25 (6H, s), 3.21 (2H, d, J=6.0Hz), 4.29 (2H,
t, J=4.5Hz), 4.55 (2H,t, J=4.5Hz), 4.78 (1H, t,
J=6.0Hz), 6.77 (2H, d, J=8.5Hz), 6.88 (2H,d, J=
8.5Hz), 7.03 (2H, d, J=8.5Hz), 7.21 (2H, d, J=8.
5Hz), 7.26-7.30(1H, m), 7.69-7.83 (4H, m), 7.89
(2H, d, J=8.5Hz), 8.72 (1H, d, J=5.0Hz).Example 8 (S) -2- (4-methylphenoxy) -3- [4- [2-[[1
-[4- (2-Pyridyl) phenyl] ethylidene] aminooxy
[Ethoxy] phenyl] propionic acid (Exemplified Compound No. 8) (S) -2- (4-methylphenoxy) -3- [4-
[2-[[1- [4- (2-Pyridyl) phenyl] ethylidene] aminooxy] ethoxy] phenyl] propionic acid 2-trimethylsilylethyl ester (2.20 g) and tetrabutylammonium fluoride in tetrahydrofuran (1M, 9.00
The resulting compound was subjected to the reaction and post-treatment according to Example 6 to obtain the target compound as colorless crystals (1.48 g). Melting point 54-56 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 2.25 (6H, s), 3.21 (2H, d, J = 6.0Hz), 4.29 (2H,
t, J = 4.5Hz), 4.55 (2H, t, J = 4.5Hz), 4.78 (1H, t,
J = 6.0Hz), 6.77 (2H, d, J = 8.5Hz), 6.88 (2H, d, J =
8.5Hz), 7.03 (2H, d, J = 8.5Hz), 7.21 (2H, d, J = 8.
5Hz), 7.26-7.30 (1H, m), 7.69-7.83 (4H, m), 7.89
(2H, d, J = 8.5Hz), 8.72 (1H, d, J = 5.0Hz).
【００４６】[0046]
【実施例９】(S)-3-[4-[2-[[1-(4-ビフェニリル)エチリ
デン]アミノオキシ]エトキシ]フェニル]-2-(4-t-ブチル
フェノキシ)プロピオン酸 2-トリメチルシリルエチル
エステル（例示化合物番号９） WO97/37970（EP916651A）の参考例3(b)の方法で製造し
た2-[[1-(4-ビフェニリル)エチリデン]アミノオキシ]エ
タノール(288 mg)、参考例2(e)で製造した(S)-2-(4-t-
ブチルフェノキシ)-3-(4-ヒドロキシフェニル)プロピオ
ン酸 2-トリメチルシリルエチルエステル(311 mg)、ト
リフェニルホスフィン(296 mg)及びアゾジカルボン酸ジ
イソプロピルエステル(40%トルエン溶液(0.61 ml))を用
いて、実施例5に準じて反応及び後処理を行うことによ
り、淡黄色油状の目的化合物(300 mg)を得た。1 H-NMR (270 MHz, CDCl3): δ ppm 0.00 (9H, s), 0.92 (2H, t, J=8.5Hz), 1.25 (9H,
s), 2.25 (3H, s), 3.14-3.17 (2H, m), 4.21-4.28
(4H, m), 4.53 (2H, t, J=4.5Hz), 4.67 (1H, dd, J=
6.0, 7.5Hz), 6.75 (2H, d, J=9.0Hz), 6.88 (2H, d,
J=8.5Hz), 7.19-7.24 (4H, m), 7.32-7.48 (3H, m),
7.57-7.62(4H, m), 7.71 (2H, d, J=8.5Hz).Example 9 (S) -3- [4- [2-[[1- (4-biphenylyl) ethyl]
Den] aminooxy] ethoxy] phenyl] -2- (4-t-butyl
Phenoxy) 2-trimethylsilylethyl propionate
Ester (Exemplified Compound No. 9) 2-[[1- (4-Biphenylyl) ethylidene] aminooxy] ethanol (288 mg) produced by the method of Reference Example 3 (b) of WO97 / 37970 (EP916651A), Reference Example 2 (S) -2- (4-t-) produced in (e)
(Butylphenoxy) -3- (4-hydroxyphenyl) propionic acid 2-trimethylsilylethyl ester (311 mg), triphenylphosphine (296 mg) and azodicarboxylic acid diisopropyl ester (40% toluene solution (0.61 ml)) The reaction and post-treatment were carried out according to Example 5 to obtain the desired compound (300 mg) as a pale yellow oil. 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 0.00 (9H, s), 0.92 (2H, t, J = 8.5Hz), 1.25 (9H,
s), 2.25 (3H, s), 3.14-3.17 (2H, m), 4.21-4.28
(4H, m), 4.53 (2H, t, J = 4.5Hz), 4.67 (1H, dd, J =
6.0, 7.5Hz), 6.75 (2H, d, J = 9.0Hz), 6.88 (2H, d,
J = 8.5Hz), 7.19-7.24 (4H, m), 7.32-7.48 (3H, m),
7.57-7.62 (4H, m), 7.71 (2H, d, J = 8.5Hz).
【００４７】[0047]
【実施例１０】(S)-3-[4-[2-[[1-(4-ビフェニリル)エチ
リデン]アミノオキシ]エトキシ]フェニル]-2-(4-t-ブチ
ルフェノキシ)プロピオン酸（例示化合物番号１０） 実施例9で製造した(S)-3-[4-[2-[[1-(4-ビフェニリル)
エチリデン]アミノオキシ]エトキシ]フェニル]-2-(4-t-
ブチルフェノキシ)プロピオン酸 2-トリメチルシリル
エチルエステル (300 mg)及びテトラブチルアンモニウ
ムフルオリドのテトラヒドロフラン溶液(1M, 1.20 ml)
を用いて、実施例6に準じて反応を行った。残渣をシリ
カゲルカラムクロマトグラフィー（溶出溶液：塩化メチ
ル/メタノール=24/1〜19/1）を用いて精製した後、イソ
プロピルエーテルとヘキサンを用いて濾取し、無色結晶
の目的化合物(170 mg)を得た。 融点 141 - 143℃1 H-NMR (270 MHz, CDCl3): δ ppm 1.27 (9H, s), 2.26 (3H, s), 3.21 (2H, d, J=6.5H
z), 4.27(2H, t, J=5.0Hz), 4.54 (2H, t, J=5.0Hz),
4.81 (1H, t, J=6.5Hz), 6.79 (2H, d, J=9.0Hz),
6.89 (2H, d, J=8.5Hz), 7.21 (2H, d, J=8.5Hz), 7.
27 (2H, d, J=9.0Hz), 7.33-7.48 (3H, m), 7.58-7.6
2 (4H, m), 7.72 (2H, d, J=8.5Hz).Example 10 (S) -3- [4- [2-[[1- (4-biphenylyl) ethyl
[Ridene] aminooxy] ethoxy] phenyl] -2- (4-t-butyl)
(Ruphenoxy) propionic acid (Exemplified Compound No. 10) (S) -3- [4- [2-[[1- (4-biphenylyl)) prepared in Example 9.
[Ethylidene] aminooxy] ethoxy] phenyl] -2- (4-t-
Butylphenoxy) propionic acid 2-trimethylsilylethyl ester (300 mg) and tetrabutylammonium fluoride in tetrahydrofuran (1M, 1.20 ml)
Was used to carry out a reaction according to Example 6. The residue was purified by silica gel column chromatography (eluent: methyl chloride / methanol = 24/1 to 19/1), and then filtered using isopropyl ether and hexane to give the target compound as colorless crystals (170 mg). I got 141-143 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 1.27 (9H, s), 2.26 (3H, s), 3.21 (2H, d, J = 6.5H
z), 4.27 (2H, t, J = 5.0Hz), 4.54 (2H, t, J = 5.0Hz),
4.81 (1H, t, J = 6.5Hz), 6.79 (2H, d, J = 9.0Hz),
6.89 (2H, d, J = 8.5Hz), 7.21 (2H, d, J = 8.5Hz), 7.
27 (2H, d, J = 9.0Hz), 7.33-7.48 (3H, m), 7.58-7.6
2 (4H, m), 7.72 (2H, d, J = 8.5Hz).
【００４８】[0048]
【実施例１１】(S)-2-(4-t-ブチルフェノキシ)-3-[4-[2
-[[1-[4-(2-ピリジル)フェニル]エチリデン]アミノオキ
シ]エトキシ]フェニル]プロピオン酸 2-トリメチルシ
リルエチルエステル（例示化合物番号１１） WO97/37970（EP916651A）の参考例1(d)の方法で製造し
た2-[[1-[4-(2-ピリジル)フェニル]エチリデン]アミノ
オキシ]エタノール(290 mg)、参考例2(e)で製造した(S)
-2-(4-t-ブチルフェノキシ)-3-(4-ヒドロキシフェニル)
プロピオン酸 2-トリメチルシリルエチルエステル(311
mg)、トリフェニルホスフィン(296 mg)及びアゾジカル
ボン酸ジイソプロピルエステル(40%トルエン溶液(0.61
ml))を用いて、実施例5に準じて反応及び後処理を行う
ことにより、無色油状の目的化合物(310 mg)を得た。1 H-NMR (270 MHz, CDCl3): δ ppm 0.00 (9H, s), 0.92 (2H, t, J=8.5Hz), 1.25 (9H,
s), 2.26 (3H, s), 3.13-3.17 (2H, m), 4.15-4.28
(4H, m), 4.54 (2H, t, J=4.5Hz), 4.64-4.69 (1H,
m), 6.75 (2H, d, J=9.0Hz), 6.88 (2H, d, J=8.5H
z), 7.19-7.26 (5H,m), 7.72-7.76 (4H, m), 8.00
(2H, d, J=8.5Hz), 8.69-8.71 (1H, m).Example 11 (S) -2- (4-t-butylphenoxy) -3- [4- [2
-[[1- [4- (2-Pyridyl) phenyl] ethylidene] aminooxy
[Ethoxy] phenyl] propionic acid 2-trimethylsi
Lylethyl ester (Exemplary compound No. 11) 2-[[1- [4- (2-Pyridyl) phenyl] ethylidene] aminooxy] ethanol produced by the method of Reference Example 1 (d) of WO97 / 37970 (EP916651A) 290 mg), prepared in Reference Example 2 (e) (S)
-2- (4-t-butylphenoxy) -3- (4-hydroxyphenyl)
Propionic acid 2-trimethylsilylethyl ester (311
mg), triphenylphosphine (296 mg) and azodicarboxylic acid diisopropyl ester (40% toluene solution (0.61 mg).
The resulting compound was subjected to the reaction and post-treatment according to Example 5 to obtain the target compound (310 mg) as a colorless oil. 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 0.00 (9H, s), 0.92 (2H, t, J = 8.5Hz), 1.25 (9H,
s), 2.26 (3H, s), 3.13-3.17 (2H, m), 4.15-4.28
(4H, m), 4.54 (2H, t, J = 4.5Hz), 4.64-4.69 (1H,
m), 6.75 (2H, d, J = 9.0Hz), 6.88 (2H, d, J = 8.5H
z), 7.19-7.26 (5H, m), 7.72-7.76 (4H, m), 8.00
(2H, d, J = 8.5Hz), 8.69-8.71 (1H, m).
【００４９】[0049]
【実施例１２】(S)-2-(4-t-ブチルフェノキシ)-3-[4-[2
-[[1-[4-(2-ピリジル)フェニル]エチリデン]アミノオキ
シ]エトキシ]フェニル]プロピオン酸（例示化合物番号
１２） 実施例11で製造した(S)-2-(4-t-ブチルフェノキシ)-3-
[4-[2-[[1-[4-(2-ピリジル)フェニル]エチリデン]アミ
ノオキシ]エトキシ]フェニル]プロピオン酸 2-トリメ
チルシリルエチルエステル(310 mg)及びテトラブチルア
ンモニウムフルオリドのテトラヒドロフラン溶液(1M,
1.7 ml)を用いて、実施例6に準じて反応を行った。残渣
をシリカゲルカラムクロマトグラフィー（溶出溶液：塩
化メチル/メタノール=24/1〜19/1）を用いて精製した
後、イソプロピルエーテルとヘキサンを用いて濾取し、
無色結晶の目的化合物(180 mg)を得た。 融点 148 - 150℃1 H-NMR (270 MHz, CDCl3): δ ppm 1.30 (9H, s), 2.31 (3H, s), 3.26 (2H, d, J=6.0H
z), 4.34 (2H, t, J=5.0Hz), 4.59 (2H, t, J=5.0H
z), 4.84 (1H, t, J=6.0Hz), 6.86 (2H, d, J=9.0H
z), 6.93 (2H, d, J=8.5Hz), 7.25-7.35 (5H, m),
7.74-7.88 (4H, m), 7.95 (2H, d, J=8.5Hz), 8.76
(1H, d, J=4.5Hz).Example 12 (S) -2- (4-t-butylphenoxy) -3- [4- [2
-[[1- [4- (2-Pyridyl) phenyl] ethylidene] aminooxy
[S] ethoxy] phenyl] propionic acid (exemplified compound number
12) (S) -2- (4-t-butylphenoxy) -3- produced in Example 11
[4- [2-[[1- [4- (2-pyridyl) phenyl] ethylidene] aminooxy] ethoxy] phenyl] propionic acid 2-trimethylsilylethyl ester (310 mg) and tetrabutylammonium fluoride in tetrahydrofuran ( 1M,
1.7 ml), and the reaction was carried out according to Example 6. The residue was purified by silica gel column chromatography (eluent: methyl chloride / methanol = 24/1 to 19/1), and then filtered using isopropyl ether and hexane.
The target compound (180 mg) was obtained as colorless crystals. Melting point 148-150 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 1.30 (9H, s), 2.31 (3H, s), 3.26 (2H, d, J = 6.0H
z), 4.34 (2H, t, J = 5.0Hz), 4.59 (2H, t, J = 5.0H
z), 4.84 (1H, t, J = 6.0Hz), 6.86 (2H, d, J = 9.0H
z), 6.93 (2H, d, J = 8.5Hz), 7.25-7.35 (5H, m),
7.74-7.88 (4H, m), 7.95 (2H, d, J = 8.5Hz), 8.76
(1H, d, J = 4.5Hz).
【００５０】[0050]
【実施例１３】(S)-3-[4-[2-[[1-(4-ビフェニリル)エチ
リデン]アミノオキシ]エトキシ]フェニル]-2-(4-フルオ
ロフェノキシ)プロピオン酸 2-トリメチルシリルエチ
ルエステル（例示化合物番号１３） WO97/37970（EP916651A）の参考例3(b)の方法で製造し
た2-[[1-(4-ビフェニリル)エチリデン]アミノオキシ]エ
タノール(83 mg)、参考例3(e)で製造した(S)-2-(4-フル
オロフェノキシ)-3-(4-ヒドロキシフェニル)プロピオン
酸 2-トリメチルシリルエチルエステル(100 mg)、トリ
フェニルホスフィン(86 mg)及びアゾジカルボン酸ジイ
ソプロピルエステル(40%トルエン溶液(0.14 ml))を用い
て、実施例5に準じて反応及び後処理を行うことによ
り、無色油状の目的化合物(88 mg)を得た。1 H-NMR (270 MHz, CDCl3): δ ppm 0.02 (9H, s), 0.92 (2H, dd, J=7.5, 9.5Hz), 2.26
(3H, s), 3.16 (2H, d,J=6.5Hz), 4.16-4.24 (2H,
m), 4.28 (2H, t, J=5.0Hz), 4.54 (2H, t, J=5.0H
z), 4.63 (1H, t, J=6.5Hz), 6.76 (2H, dd, J=4.0,
9.0Hz), 6.90 (2H,d, J=8.5Hz), 6.91 (2H, dd, J=8.
5, 9.0Hz), 7.21 (2H, d, J=8.5Hz), 7.36(1H, t, J=
7.0Hz), 7.45 (2H, dd, J=7.0, 8.5Hz), 7.60 (2H,
d, J=8.5Hz),7.61 (2H, d, J=8.5Hz), 7.73 (2H, d, J
=8.5Hz).Example 13 (S) -3- [4- [2-[[1- (4-biphenylyl) ethyl
[Ridene] aminooxy] ethoxy] phenyl] -2- (4-fluoro
Lofenoxy) propionic acid 2-trimethylsilylethyl
Glycol ester was prepared by the method of Reference Example 3 (Compound No. 13) WO97 / 37970 (EP916651A) (b) 2 - [[1- (4- biphenylyl) ethylidene] aminoxy] ethanol (83 mg), Example 3 (S) 2- (4-fluorophenoxy) -3- (4-hydroxyphenyl) propionic acid 2-trimethylsilylethyl ester (100 mg) produced in (e), triphenylphosphine (86 mg) and azodicarboxylic acid The reaction and post-treatment were carried out using diisopropyl ester (40% toluene solution (0.14 ml)) in the same manner as in Example 5 to obtain the target compound (88 mg) as a colorless oil. 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 0.02 (9H, s), 0.92 (2H, dd, J = 7.5, 9.5Hz), 2.26
(3H, s), 3.16 (2H, d, J = 6.5Hz), 4.16-4.24 (2H,
m), 4.28 (2H, t, J = 5.0Hz), 4.54 (2H, t, J = 5.0H
z), 4.63 (1H, t, J = 6.5Hz), 6.76 (2H, dd, J = 4.0,
9.0Hz), 6.90 (2H, d, J = 8.5Hz), 6.91 (2H, dd, J = 8.
5, 9.0Hz), 7.21 (2H, d, J = 8.5Hz), 7.36 (1H, t, J =
7.0Hz), 7.45 (2H, dd, J = 7.0, 8.5Hz), 7.60 (2H,
d, J = 8.5Hz), 7.61 (2H, d, J = 8.5Hz), 7.73 (2H, d, J
= 8.5Hz).
【００５１】[0051]
【実施例１４】(S)-3-[4-[2-[[1-(4-ビフェニリル)エチ
リデン]アミノオキシ]エトキシ]フェニル]-2-(4-フルオ
ロフェノキシ)プロピオン酸（例示化合物番号１４） 実施例13で製造した(S)-3-[4-[2-[[1-(4-ビフェニリル)
エチリデン]アミノオキシ]エトキシ]フェニル]-2-(4-フ
ルオロフェノキシ)プロピオン酸 2-トリメチルシリル
エチルエステル(938 mg)及びテトラブチルアンモニウム
フルオリドのテトラヒドロフラン溶液(1M, 3.8 ml)を用
いて、実施例6に準じて反応及び後処理を行うことによ
り、無色結晶の目的化合物(568 mg)を得た。 融点 106 - 107℃1 H-NMR (270 MHz, CDCl3): δ ppm 2.26 (3H, s), 3.20 (1H, d, J=5.0Hz), 3.21 (1H,
d, J=7.5Hz), 4.28 (2H,t, J=5.0Hz), 4.54 (2H, t,
J=5.0Hz), 4.73 (1H, dd, J=5.0, 7.5Hz), 6.79 (2H,
dd, J=4.0, 9.0Hz), 6.90 (2H, d, J=8.5Hz), 6.92
(2H, dd, J=8.0,9.0Hz), 7.22 (2H, d, J=8.5Hz), 7.
36 (1H, t, J=7.0Hz), 7.45 (2H, dd, J=7.0, 8.5Hz),
7.60 (2H, d, J=8.5Hz), 7.61 (2H, d, J=8.5Hz),
7.72 (2H,d, J=8.5Hz).Example 14 (S) -3- [4- [2-[[1- (4-Biphenylyl) ethyl
[Ridene] aminooxy] ethoxy] phenyl] -2- (4-fluoro
(Lophenoxy) propionic acid (Exemplified Compound No. 14) (S) -3- [4- [2-[[1- (4-biphenylyl)) prepared in Example 13
Examples were carried out using ethylidene [aminooxy] ethoxy] phenyl] -2- (4-fluorophenoxy) propionic acid 2-trimethylsilylethyl ester (938 mg) and tetrabutylammonium fluoride solution in tetrahydrofuran (1M, 3.8 ml). The target compound (568 mg) as colorless crystals was obtained by carrying out the reaction and post-treatment according to 6. Melting point 106-107 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 2.26 (3H, s), 3.20 (1H, d, J = 5.0 Hz), 3.21 (1H,
d, J = 7.5Hz), 4.28 (2H, t, J = 5.0Hz), 4.54 (2H, t,
J = 5.0Hz), 4.73 (1H, dd, J = 5.0, 7.5Hz), 6.79 (2H,
(dd, J = 4.0, 9.0Hz), 6.90 (2H, d, J = 8.5Hz), 6.92
(2H, dd, J = 8.0,9.0Hz), 7.22 (2H, d, J = 8.5Hz), 7.
36 (1H, t, J = 7.0Hz), 7.45 (2H, dd, J = 7.0, 8.5Hz),
7.60 (2H, d, J = 8.5Hz), 7.61 (2H, d, J = 8.5Hz),
7.72 (2H, d, J = 8.5Hz).
【００５２】[0052]
【実施例１５】(S)-2-(4-フルオロフェノキシ)-3-[4-[2
-[[1-(4'-メトキシ-4-ビフェニリル)エチリデン]アミノ
オキシ]エトキシ]フェニル]プロピオン酸 2-トリメチ
ルシリルエチルエステル（例示化合物番号１５） 参考例4(b)で製造した2-[1-(4'-メトキシ-4-ビフェニリ
ル)エチリデン]アミノオキシ]エタノール (325 mg)、参
考例3(e)で製造した(S)-2-(4-フルオロフェノキシ)-3-
(4-ヒドロキシフェニル)プロピオン酸 2-トリメチルシ
リルエチルエステル(286 mg)、トリフェニルホスフィン
(299 mg)及びアゾジカルボン酸ジイソプロピルエステル
(40%トルエン溶液(0.61 ml))を用いて、実施例5に準じ
て反応及び後処理を行うことにより、無色油状の目的化
合物(438 mg)を得た。1 H-NMR (270 MHz, CDCl3): δ ppm 0.01 (9H, s), 0.91 (2H, dd, J=7.5, 10.0Hz), 2.25
(3H, s), 3.15 (2H, d, J=6.5Hz), 3.85 (3H, s),
4.14-4.23 (2H, m), 4.26 (2H, t, J=5.0Hz),4.53 (2
H, t, J=5.0Hz), 4.62 (1H, t, J=6.5Hz), 6.75 (2H,
dd, J=4.5, 9.0Hz), 6.89 (2H, d, J=8.5Hz), 6.90
(2H, dd, J=8.5, 9.0Hz), 6.97 (2H, d,J=8.5Hz), 7.
20 (2H, d, J=8.5Hz), 7.53 (2H, d, J=8.5Hz), 7.54
(2H, d,J=8.5Hz), 7.68 (2H, d, J=8.5Hz).Example 15 (S) -2- (4-Fluorophenoxy) -3- [4- [2
-[[1- (4'-Methoxy-4-biphenylyl) ethylidene] amino
[Oxy] ethoxy] phenyl] propionic acid 2-trimethyi
Lucylylethyl ester (Exemplary Compound No. 15) 2- [1- (4′-methoxy-4-biphenylyl) ethylidene] aminooxy] ethanol (325 mg) produced in Reference Example 4 (b), Reference Example 3 (e (S) -2- (4-fluorophenoxy) -3-
(4-Hydroxyphenyl) propionic acid 2-trimethylsilylethyl ester (286 mg), triphenylphosphine
(299 mg) and azodicarboxylic acid diisopropyl ester
The reaction and post-treatment were carried out using (40% toluene solution (0.61 ml)) in the same manner as in Example 5 to obtain the target compound (438 mg) as a colorless oil. 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 0.01 (9H, s), 0.91 (2H, dd, J = 7.5, 10.0Hz), 2.25
(3H, s), 3.15 (2H, d, J = 6.5Hz), 3.85 (3H, s),
4.14-4.23 (2H, m), 4.26 (2H, t, J = 5.0Hz), 4.53 (2
H, t, J = 5.0Hz), 4.62 (1H, t, J = 6.5Hz), 6.75 (2H,
(dd, J = 4.5, 9.0Hz), 6.89 (2H, d, J = 8.5Hz), 6.90
(2H, dd, J = 8.5, 9.0Hz), 6.97 (2H, d, J = 8.5Hz), 7.
20 (2H, d, J = 8.5Hz), 7.53 (2H, d, J = 8.5Hz), 7.54
(2H, d, J = 8.5Hz), 7.68 (2H, d, J = 8.5Hz).
【００５３】[0053]
【実施例１６】(S)-2-(4-フルオロフェノキシ)-3-[4-[2
-[[1-(4'-メトキシ-4-ビフェニリル)エチリデン]アミノ
オキシ]エトキシ]フェニル]プロピオン酸（例示化合物
番号１６） 実施例15で製造した(S)-2-(4-フルオロフェノキシ)-3-
[4-[2-[[1-(4'-メトキシ-4-ビフェニリル)エチリデン]
アミノオキシ]エトキシ]フェニル]プロピオン酸2-トリ
メチルシリルエチルエステル(438 mg)及びテトラブチル
アンモニウムフルオリドのテトラヒドロフラン溶液(1M,
1.7 ml)を用いて、実施例6に準じて反応及び後処理を
行うことにより、無色結晶の目的化合物(243 mg)を得
た。 融点 118 - 120℃1 H-NMR (270 MHz, CDCl3): δ ppm 2.25 (3H, s), 3.20 (1H, d, J=7.0Hz), 3.21 (1H,
d, J=4.0Hz), 3.86 (3H,s), 4.27 (2H, t, J=5.0Hz),
4.53 (2H, t, J=5.0Hz), 4.73 (1H, dd, J=4.0, 7.0
Hz), 6.78 (2H, dd, J=4.0, 9.0Hz), 6.90 (2H, d, J
=8.5Hz), 6.92 (2H, dd, J=8.0, 9.0Hz), 6.98 (2H,
d, J=8.5Hz), 7.21 (2H, d, J=8.5Hz),7.54 (2H, d, J
=8.5Hz), 7.55 (2H, d, J=8.5Hz), 7.68 (2H, d, J=
8.5Hz).Example 16 (S) -2- (4-Fluorophenoxy) -3- [4- [2
-[[1- (4'-Methoxy-4-biphenylyl) ethylidene] amino
[Oxy] ethoxy] phenyl] propionic acid (exemplary compound
No. 16) (S) -2- (4-fluorophenoxy) -3- produced in Example 15
[4- [2-[[1- (4'-methoxy-4-biphenylyl) ethylidene]
Aminooxy] ethoxy] phenyl] propionic acid 2-trimethylsilylethyl ester (438 mg) and tetrabutylammonium fluoride in tetrahydrofuran (1M,
The reaction and post-treatment were carried out according to Example 6 using 1.7 ml) to give the target compound as colorless crystals (243 mg). Melting point 118-120 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 2.25 (3H, s), 3.20 (1H, d, J = 7.0Hz), 3.21 (1H,
d, J = 4.0Hz), 3.86 (3H, s), 4.27 (2H, t, J = 5.0Hz),
4.53 (2H, t, J = 5.0Hz), 4.73 (1H, dd, J = 4.0, 7.0
Hz), 6.78 (2H, dd, J = 4.0, 9.0Hz), 6.90 (2H, d, J
= 8.5Hz), 6.92 (2H, dd, J = 8.0, 9.0Hz), 6.98 (2H,
d, J = 8.5Hz), 7.21 (2H, d, J = 8.5Hz), 7.54 (2H, d, J
= 8.5Hz), 7.55 (2H, d, J = 8.5Hz), 7.68 (2H, d, J =
8.5Hz).
【００５４】[0054]
【実施例１７】(S)-2-(4-フルオロフェノキシ)-3-[4-[2
-[[1-[4-(2-ピリジル)フェニル]エチリデン]アミノオキ
シ]エトキシ]フェニル]プロピオン酸 2-トリメチルシ
リルエチルエステル（例示化合物番号１７） WO97/37970（EP916651A）の参考例1(d)の方法で製造し
た2-[[1-[4-(2-ピリジル)フェニル]エチリデン]アミノ
オキシ]エタノール(520 mg)、参考例3(e)で製造した(S)
-2-(4-フルオロフェノキシ)-3-(4-ヒドロキシフェニル)
プロピオン酸 2-トリメチルシリルエチルエステル(380
mg)、トリフェニルホスフィン(537 mg)及びアゾジカル
ボン酸ジイソプロピルエステル(40%トルエン溶液(0.94
ml))を用いて、実施例5に準じて反応及び後処理を行う
ことにより、無色油状の目的化合物(531 mg)を得た。1 H-NMR (270 MHz, CDCl3): δ ppm 0.01 (9H, s), 0.92 (2H, dd, J=7.5, 10.0Hz), 2.26
(3H, s), 3.15 (2H, d, J=6.5Hz), 4.15-4.23 (2H,
m), 4.28 (2H, t, J=5.0Hz), 4.54 (2H, t, J=5.0H
z), 4.63 (1H, t, J=6.5Hz), 6.76 (2H, dd, J=4.0,
9.0Hz), 6.90 (2H,d, J=8.5Hz), 6.91 (2H, dd, J=8.
5, 9.0Hz), 7.21 (2H, d, J=8.5Hz), 7.22-7.27 (1H,
m), 7.74-7.77 (4H, m), 8.00 (2H, d, J=8.5Hz),
8.71 (1H, d,J=5.0Hz).Example 17 (S) -2- (4-Fluorophenoxy) -3- [4- [2
-[[1- [4- (2-Pyridyl) phenyl] ethylidene] aminooxy
[Ethoxy] phenyl] propionic acid 2-trimethylsi
Lylethyl ester (Exemplified compound No. 17) 2-[[1- [4- (2-Pyridyl) phenyl] ethylidene] aminooxy] ethanol produced by the method of Reference Example 1 (d) of WO97 / 37970 (EP916651A) 520 mg), prepared in Reference Example 3 (e) (S)
-2- (4-fluorophenoxy) -3- (4-hydroxyphenyl)
Propionic acid 2-trimethylsilyl ethyl ester (380
mg), triphenylphosphine (537 mg) and azodicarboxylic acid diisopropyl ester (40% toluene solution (0.94 mg).
The reaction and after-treatment were carried out according to Example 5 using the compound (ml)) to obtain a colorless oily target compound (531 mg). 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 0.01 (9H, s), 0.92 (2H, dd, J = 7.5, 10.0Hz), 2.26
(3H, s), 3.15 (2H, d, J = 6.5Hz), 4.15-4.23 (2H,
m), 4.28 (2H, t, J = 5.0Hz), 4.54 (2H, t, J = 5.0H
z), 4.63 (1H, t, J = 6.5Hz), 6.76 (2H, dd, J = 4.0,
9.0Hz), 6.90 (2H, d, J = 8.5Hz), 6.91 (2H, dd, J = 8.
5, 9.0Hz), 7.21 (2H, d, J = 8.5Hz), 7.22-7.27 (1H,
m), 7.74-7.77 (4H, m), 8.00 (2H, d, J = 8.5Hz),
8.71 (1H, d, J = 5.0Hz).
【００５５】[0055]
【実施例１８】(S)-2-(4-フルオロフェノキシ)-3-[4-[2
-[[1-[4-(2-ピリジル)フェニル]エチリデン]アミノオキ
シ]エトキシ]フェニル]プロピオン酸（例示化合物番号
１８） 実施例17で製造した(S)-2-(4-フルオロフェノキシ)-3-
[4-[2-[[1-[4-(2-ピリジル)フェニル]エチリデン]アミ
ノオキシ]エトキシ]フェニル]プロピオン酸 2-トリメ
チルシリルエチルエステル(1.84 g)及びテトラブチルア
ンモニウムフルオリドのテトラヒドロフラン溶液(1M,
7.5 ml)を用いて、実施例6に準じて反応及び後処理を行
うことにより、無色結晶の目的化合物(1.16 g)を得た。 融点 88 - 90℃1 H-NMR (270 MHz, CDCl3): δ ppm 2.25 (3H, s), 3.20 (1H, d, J=7.0Hz), 3.21 (1H,
d, J=5.5Hz), 4.30 (2H,t, J=5.0Hz), 4.55 (2H, t,
J=5.0Hz), 4.72 (1H, dd, J=5.5, 7.0Hz), 6.81 (2H,
dd, J=4.5, 9.0Hz), 6.89 (2H, d, J=8.5Hz), 6.91
(2H, dd, J=8.5,9.0Hz), 7.22 (2H, d, J=8.5Hz), 7.
27-7.32 (1H, m), 7.69 (2H, d, J=8.5Hz), 7.72 (1
H, d, J=7.5Hz), 7.80 (1H, dd, J=2.0, 7.5Hz), 7.8
6 (2H, d,J=8.5Hz), 8.72 (1H, d, J=5.0Hz).Example 18 (S) -2- (4-fluorophenoxy) -3- [4- [2
-[[1- [4- (2-Pyridyl) phenyl] ethylidene] aminooxy
[S] ethoxy] phenyl] propionic acid (exemplified compound number
18) (S) -2- (4-fluorophenoxy) -3- produced in Example 17
[4- [2-[[1- [4- (2-Pyridyl) phenyl] ethylidene] aminooxy] ethoxy] phenyl] propionic acid 2-trimethylsilylethyl ester (1.84 g) and tetrabutylammonium fluoride in tetrahydrofuran ( 1M,
The reaction and post-treatment were carried out according to Example 6 using 7.5 ml) to obtain the target compound as colorless crystals (1.16 g). Melting point 88-90 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 2.25 (3H, s), 3.20 (1H, d, J = 7.0Hz), 3.21 (1H,
d, J = 5.5Hz), 4.30 (2H, t, J = 5.0Hz), 4.55 (2H, t,
J = 5.0Hz), 4.72 (1H, dd, J = 5.5, 7.0Hz), 6.81 (2H,
(dd, J = 4.5, 9.0Hz), 6.89 (2H, d, J = 8.5Hz), 6.91
(2H, dd, J = 8.5,9.0Hz), 7.22 (2H, d, J = 8.5Hz), 7.
27-7.32 (1H, m), 7.69 (2H, d, J = 8.5Hz), 7.72 (1
H, d, J = 7.5Hz), 7.80 (1H, dd, J = 2.0, 7.5Hz), 7.8
6 (2H, d, J = 8.5Hz), 8.72 (1H, d, J = 5.0Hz).
【００５６】[0056]
【参考例１】(S)-3-(4-ヒドロキシフェニル)-2-(4-メチ
ルフェノキシ)プロピオン酸 2-トリメチルシリルエチ
ルエステル (a) (S)-4-ベンジル-3-[(4-メチルフェノキシ)アセチ
ル]オキサゾリジン-2-オン 4-メチルフェノキシ酢酸(6.73 g)のジクロロメタン溶液
(70 ml)に塩化オキザリル(8.83 ml)とN,N-ジメチルホル
ムアミド(3滴)を室温で加え、1.5時間攪拌した。反応液
を減圧下濃縮した後、酸性ガスをトルエンによる共沸で
除去し、減圧下乾燥して、塩化4-メチルフェノキシアセ
チルを得た。Reference Example 1 (S) -3- (4-hydroxyphenyl) -2- (4-methyl
Rufenoxy) propionic acid 2-trimethylsilylethyl
Ester (a) (S) -4-benzyl-3-[(4-methylphenoxy) acetyl
[Oxazolidin-2-one] 4-methylphenoxyacetic acid (6.73 g) in dichloromethane
Oxalyl chloride (8.83 ml) and N, N-dimethylformamide (3 drops) were added to (70 ml) at room temperature, and the mixture was stirred for 1.5 hours. After the reaction solution was concentrated under reduced pressure, the acidic gas was removed by azeotropic distillation with toluene, and dried under reduced pressure to obtain 4-methylphenoxyacetyl chloride.
【００５７】(S)-4-ベンジル-2-オキサゾリジノン(7.08
g)のテトラヒドロフラン溶液(70 ml)に、n-ブチルリチ
ウムのヘキサン溶液(1.61N, 25.2 ml)を−78℃で滴下
し、滴下後同温で30分攪拌した。この溶液に、上記で得
た塩化4-メチルフェノキシアセチルのテトラヒドロフラ
ン溶液(70 ml)を−78℃で加え、0℃で1時間攪拌した。
反応液に酢酸エチルと水を加え、抽出した。酢酸エチル
層を塩酸(1N)、飽和炭酸水素ナトリウム水溶液及び飽和
食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧
濃縮した。これを、シリカゲルカラムクロマトグラフィ
ー（溶出溶液：ヘキサン/酢酸エチル＝3/1〜1/1）を用
いて精製し、無色油状の目的化合物(9.00 g)を得た。1 H-NMR (270 MHz, CDCl3): δ ppm 2.30(3H, s), 2.84 (1H, dd, J=9.5, 13.5Hz), 3.36
(1H, dd, J=3.0, 13.5Hz), 4.25-4.37 (2H, m), 4.68
-4.76 (1H, m), 5.22 (2H, s), 6.88 (2H, d,J=8.5H
z), 7.11 (2H, d, J=8.5Hz), 7.20-7.38 (5H, m). (b) (S)-4-ベンジル-3-[(2S,3R)-3-(4-ベンジルオキシ
フェニル)-3-ヒドロキシ-2-(4-メチルフェノキシ)プロ
ピオニル]オキサゾリジン-2-オン 参考例1(a)で製造した(S)-4-ベンジル-3-[(4-メチルフ
ェノキシ)アセチル]オキサゾリジン-2-オン(9.00 g)の
ジクロロメタン溶液(90 ml)に、0℃で、ジブチルボロン
トリフレートのジクロロメタン溶液(1M, 33.2 ml)とト
リエチルアミン(5.12 ml)を加え、同温で1時間攪拌し
た。反応液に、−78℃で、4-ベンジルオキシベンズアル
デヒド(6.46 g)のジクロロメタン溶液(6 ml)を滴下し
た。反応液をさらに0℃で2時間攪拌した。その後、反応
溶液に、飽和食塩水とメタノールの1/1の混合溶媒(20 m
l)と、過酸化水素水(31%)とメタノールの2/1混合溶媒(1
00 ml)を加え、1時間攪拌した。メタノールを減圧下留
去した。残留物を酢酸エチルで抽出し、塩酸(1N)、飽和
炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄後、無
水硫酸マグネシウムで乾燥し、減圧濃縮した。これを、
シリカゲルカラムクロマトグラフィー（溶出溶液：ヘキ
サン/酢酸エチル＝3/1〜1/1）を用いて精製し、フォー
ム状の目的化合物(9.80 g)を得た。1 H-NMR (270 MHz, CDCl3): δ ppm 2.28 (3H, s), 2.71 (1H, dd, J=9.0, 13.5Hz), 3.04
-3.10 (2H, m), 3.57 (1H, t, J=8.5Hz), 3.99 (1H,
dd, J=2.0, 8.5Hz), 4.22-4.28 (1H, m), 5.05-5.09
(3H, m), 6.18 (1H, d, J=6.0Hz), 6.89 (2H, d, J=
8.5Hz), 6.95 (2H, d, J=8.5Hz), 7.04-7.10 (4H,
m), 7.25-7.44 (10H, m). (c) (S)-4-ベンジル-3-[(2S,3R)-3-ヒドロキシ-3-(4-ヒ
ドロキシフェニル)-2-(4-メチルフェノキシ)プロピオニ
ル]オキサゾリジン-2-オン 参考例1(b)で製造した(S)-4-ベンジル-3-[(2S,3R)-3-(4
-ベンジルオキシフェニル)-3-ヒドロキシ-2-(4-メチル
フェノキシ)プロピオニル]オキサゾリジン-2-オン(9.80
g)のエタノール溶液(150 ml)に、パラジウム−炭素(5
%, 1.00 g)を加え、水素ガス雰囲気下、50℃で4時間攪
拌した。その後、触媒を濾過し、濾液を減圧濃縮した。
残留物に水を加え、酢酸エチルで抽出した。これを、無
水硫酸マグネシウムで乾燥し、フォーム状の目的化合物
(9.10 g)を得た。1 H-NMR (270 MHz, CDCl3): δ ppm 2.28(3H, s), 2.74 (1H, dd, J=9.0, 13.5Hz), 3.04-
3.10 (2H, m), 3.74 (1H, t, J=8.5Hz), 4.04 (1H, d
d, J=1.5, 8.5Hz), 4.28-4.34 (1H, m), 5.08,(1H,
t, J=5.5Hz), 5.15 ( 1H, s), 6.17 (1H, d, J=5.5H
z), 6.79 (2H, d,J=8.5Hz), 6.88 (2H, d, J=8.5Hz),
7.04-7.10 (4H, m), 7.25-7.38 (5H, m). (d) (S)-4-ベンジル-3-[(S)-3-(4-ヒドロキシフェニル)
-2-(4-メチルフェノキシ)プロピオニル]オキサゾリジン
-2-オン 参考例1(c)で製造した(S)-4-ベンジル-3-[(2S,3R)-3-ヒ
ドロキシ-3-(4-ヒドロキシフェニル)-2-(4-メチルフェ
ノキシ)プロピオニル]オキサゾリジン-2-オン(8.15 g)
のトリフルオロ酢酸溶液(90 ml)に、室温でトリエチル
シラン(24.0 ml)を加え、18時間攪拌し、その後、反応
液を減圧下、濃縮した。残留物に水を加え、酢酸エチル
で抽出し、飽和炭酸水素ナトリウム水溶液、塩酸(1N)及
び飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥
し、減圧濃縮した。得られた結晶をイソプロピルエーテ
ルとヘキサンの混合溶媒を用いて濾取し、無色結晶の目
的化合物(6.70 g)を得た。 m.p. 135 - 136℃1 H-NMR (270 MHz, CDCl3): δ ppm 2.26(3H, s), 2.77 (1H, dd, J=9.5, 13.5Hz), 3.08-
3.23 (3H, m), 4.01 (1H, t, J=8.5Hz), 4.15 (1H, d
d, J=2.0, 8.5Hz), 4.46-4.55 (1H, m), 4.80-4.88
(1H, m), 6.09 (1H, dd, J=6.0, 8.0Hz), 6.75 (2H,
d, J=8.5Hz), 6.80 (2H, d, J=8.5Hz), 7.05 (2H, d,
J=8.5Hz), 7.10-7.15 (2H, m), 7.21-7.33 (5H, m). (e) (S)-3-(4-ヒドロキシフェニル)-2-(4-メチルフェノ
キシ)プロピオン酸 2-トリメチルシリルエチルエステ
ル 参考例1(d)で製造した(S)-4-ベンジル-3-[(S)-3-(4-ヒ
ドロキシフェニル)-2-(4-メチルフェノキシ)プロピオニ
ル]オキサゾリジン-2-オン(6.50 g)のメタノール懸濁液
(80 ml)に、水酸化リチウム水溶液(1N, 37.7 ml)と過酸
化水素水(31%,4.14 ml)の混合溶液を滴下した。室温で1
時間攪拌した後、反応液にハイドロサルファイトナトリ
ウム(6.56 g)の水溶液(20 ml)を加え、1時間攪拌した
後、反応液を減圧濃縮した。残留物に水酸化ナトリウム
水溶液(1N)加えてアルカリ性にし、ジクロロメタンで洗
浄した後、塩酸を加えて酸性にした。酢酸エチルを加え
て攪拌した後、酢酸エチル層を分離し、無水硫酸マグネ
シウムで乾燥し、減圧濃縮した。得られた残留物をイソ
プロピルエーテルとヘキサンを用いて結晶化し、白色パ
ウダー状の(S)-3-(4-ヒドロキシフェニル)-2-(4-メチル
フェノキシ)プロピオン酸(3.38 g)を得た。(S) -4-benzyl-2-oxazolidinone (7.08
To a solution of g) in tetrahydrofuran (70 ml), a hexane solution of n-butyllithium (1.61 N, 25.2 ml) was added dropwise at -78 ° C, and the mixture was stirred at the same temperature for 30 minutes. To this solution was added the above-obtained solution of 4-methylphenoxyacetyl chloride in tetrahydrofuran (70 ml) at -78 ° C, and the mixture was stirred at 0 ° C for 1 hour.
Ethyl acetate and water were added to the reaction solution for extraction. The ethyl acetate layer was washed with hydrochloric acid (1N), a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This was purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1 to 1/1) to obtain the target compound (9.00 g) as a colorless oil. 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 2.30 (3H, s), 2.84 (1H, dd, J = 9.5, 13.5Hz), 3.36
(1H, dd, J = 3.0, 13.5Hz), 4.25-4.37 (2H, m), 4.68
-4.76 (1H, m), 5.22 (2H, s), 6.88 (2H, d, J = 8.5H
z), 7.11 (2H, d, J = 8.5Hz), 7.20-7.38 (5H, m). (b) (S) -4-benzyl-3-[(2S, 3R) -3- (4-benzyl Oxy
(Phenyl) -3-hydroxy-2- (4-methylphenoxy) pro
[Pionyl] oxazolidin-2-one (90 ml) of (S) -4-benzyl-3-[(4-methylphenoxy) acetyl] oxazolidin-2-one (9.00 g) prepared in Reference Example 1 (a) ) At 0 ° C was added with a dichloromethane solution of dibutyl boron triflate (1M, 33.2 ml) and triethylamine (5.12 ml), and the mixture was stirred at the same temperature for 1 hour. To the reaction solution was added dropwise a solution of 4-benzyloxybenzaldehyde (6.46 g) in dichloromethane (6 ml) at -78 ° C. The reaction was further stirred at 0 ° C. for 2 hours. Thereafter, the reaction solution was mixed with a 1/1 mixed solvent of saturated saline and methanol (20 m
l) and a 2/1 mixed solvent of hydrogen peroxide (31%) and methanol (1
00 ml) and stirred for 1 hour. The methanol was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with hydrochloric acid (1N), a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. this,
Purification was performed using silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1 to 1/1) to obtain a foamed target compound (9.80 g). 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 2.28 (3H, s), 2.71 (1H, dd, J = 9.0, 13.5Hz), 3.04
-3.10 (2H, m), 3.57 (1H, t, J = 8.5Hz), 3.99 (1H,
(dd, J = 2.0, 8.5Hz), 4.22-4.28 (1H, m), 5.05-5.09
(3H, m), 6.18 (1H, d, J = 6.0Hz), 6.89 (2H, d, J =
8.5Hz), 6.95 (2H, d, J = 8.5Hz), 7.04-7.10 (4H,
m), 7.25-7.44 (10H, m). (c) (S) -4-benzyl-3-[(2S, 3R) -3-hydroxy-3- (4-h
(Droxyphenyl) -2- (4-methylphenoxy) propioni
[Oxazolidin-2-one] (S) -4-benzyl-3-[(2S, 3R) -3- (4
-Benzyloxyphenyl) -3-hydroxy-2- (4-methylphenoxy) propionyl] oxazolidine-2-one (9.80
g) in ethanol solution (150 ml), palladium-carbon (5
%, 1.00 g) and stirred at 50 ° C. for 4 hours under a hydrogen gas atmosphere. Thereafter, the catalyst was filtered, and the filtrate was concentrated under reduced pressure.
Water was added to the residue and extracted with ethyl acetate. This is dried over anhydrous magnesium sulfate and the desired compound in the form of a foam is obtained.
(9.10 g) was obtained. 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 2.28 (3H, s), 2.74 (1H, dd, J = 9.0, 13.5Hz), 3.04-
3.10 (2H, m), 3.74 (1H, t, J = 8.5Hz), 4.04 (1H, d
d, J = 1.5, 8.5Hz), 4.28-4.34 (1H, m), 5.08, (1H,
t, J = 5.5Hz), 5.15 (1H, s), 6.17 (1H, d, J = 5.5H
z), 6.79 (2H, d, J = 8.5Hz), 6.88 (2H, d, J = 8.5Hz),
7.04-7.10 (4H, m), 7.25-7.38 (5H, m). (D) (S) -4-benzyl-3-[(S) -3- (4-hydroxyphenyl)
-2- (4-Methylphenoxy) propionyl] oxazolidine
Prepared in-2-one in Reference Example 1 (c) (S)-4-benzyl -3 - [(2S, 3R) -3- hydroxy-3- (4-hydroxyphenyl) -2- (4-methylphenoxy ) Propionyl] oxazolidin-2-one (8.15 g)
To a trifluoroacetic acid solution (90 ml) was added triethylsilane (24.0 ml) at room temperature, and the mixture was stirred for 18 hours. Thereafter, the reaction solution was concentrated under reduced pressure. Water was added to the residue, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, hydrochloric acid (1N) and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were collected by filtration using a mixed solvent of isopropyl ether and hexane to give the target compound (6.70 g) as colorless crystals. mp 135-136 ℃ 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 2.26 (3H, s), 2.77 (1H, dd, J = 9.5, 13.5Hz), 3.08-
3.23 (3H, m), 4.01 (1H, t, J = 8.5Hz), 4.15 (1H, d
d, J = 2.0, 8.5Hz), 4.46-4.55 (1H, m), 4.80-4.88
(1H, m), 6.09 (1H, dd, J = 6.0, 8.0Hz), 6.75 (2H,
d, J = 8.5Hz), 6.80 (2H, d, J = 8.5Hz), 7.05 (2H, d,
(J = 8.5Hz), 7.10-7.15 (2H, m), 7.21-7.33 (5H, m). (E) (S) -3- (4-hydroxyphenyl) -2- (4-methylpheno
Xy) 2-trimethylsilylethyl propionate
Prepared in Le Reference Example 1 (d) (S)-4-benzyl -3 - [(S) -3- ( 4- hydroxyphenyl) -2- (4-methylphenoxy) propionyl] oxazolidin-2-one ( 6.50 g) methanol suspension
A mixed solution of an aqueous solution of lithium hydroxide (1N, 37.7 ml) and aqueous hydrogen peroxide (31%, 4.14 ml) was added dropwise to (80 ml). 1 at room temperature
After stirring for an hour, an aqueous solution (20 ml) of sodium hydrosulfite (6.56 g) was added to the reaction solution, and after stirring for 1 hour, the reaction solution was concentrated under reduced pressure. The residue was alkalified by adding an aqueous sodium hydroxide solution (1N), washed with dichloromethane, and then acidified by adding hydrochloric acid. After adding ethyl acetate and stirring, the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized using isopropyl ether and hexane to obtain (S) -3- (4-hydroxyphenyl) -2- (4-methylphenoxy) propionic acid (3.38 g) as a white powder. .
【００５８】このカルボン酸(3.25 g)のジクロロメタン
懸濁液(40 ml)に、室温で塩化オキザリル(5.21 ml)とN,
N-ジメチルホルムアミド (5 drops)を加え、1時間攪拌
した。その後、反応液を減圧下、濃縮し、残った酸性ガ
スをトルエンを用いて共沸することにより除去し、過剰
な試薬を除去した。残留物のジクロロメタン溶液(40ml)
に、2-トリメチルシリルエタノール(8.55 ml)を加え、
室温で15時間攪拌した。この混合溶液に、トリエチルア
ミン(4.16 ml)と4-N,N-ジメチルアミノピリジン(146 m
g)を加え、室温で1時間攪拌した。反応液を減圧下、濃
縮し、残留物に水を加え、酢酸エチルで抽出した。酢酸
エチル層を飽和食塩水で洗浄後、無水硫酸マグネシウム
で乾燥し、減圧濃縮した。これを、シリカゲルカラムク
ロマトグラフィー（溶出溶液：ヘキサン/酢酸エチル＝6
/1〜4/1）を用いて精製し、無色結晶の目的化合物(3.43
g)を得た。 m.p. 94 - 95℃1 H-NMR (270 MHz, CDCl3): δ ppm 0.02 (9H, s), 0.92 (2H, t, J=8.5Hz), 2.25 (3H,
s), 3.13-3.19 (2H, m),4.10-4.28 (2H, m), 4.66 (1
H, dd, J=6.0, 7.0Hz), 4.77 (1H, s), 6.73(2H, d,
J=8.5Hz), 6.75 (2H, d, J=8.5Hz), 7.02 (2H, d, J=
8.5Hz), 7.16(2H, d, J=8.5Hz).To a suspension (40 ml) of this carboxylic acid (3.25 g) in dichloromethane was added oxalyl chloride (5.21 ml) and N, at room temperature.
N-Dimethylformamide (5 drops) was added and stirred for 1 hour. Thereafter, the reaction solution was concentrated under reduced pressure, and the remaining acidic gas was removed by azeotropic distillation with toluene to remove excess reagent. A solution of the residue in dichloromethane (40 ml)
Was added 2-trimethylsilylethanol (8.55 ml),
Stirred at room temperature for 15 hours. To this mixed solution, triethylamine (4.16 ml) and 4-N, N-dimethylaminopyridine (146 m
g) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate = 6).
/ 1 to 4/1) to give the target compound (3.43
g) was obtained. mp 94-95 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 0.02 (9H, s), 0.92 (2H, t, J = 8.5Hz), 2.25 (3H,
s), 3.13-3.19 (2H, m), 4.10-4.28 (2H, m), 4.66 (1
H, dd, J = 6.0, 7.0Hz), 4.77 (1H, s), 6.73 (2H, d,
J = 8.5Hz), 6.75 (2H, d, J = 8.5Hz), 7.02 (2H, d, J =
8.5Hz), 7.16 (2H, d, J = 8.5Hz).
【００５９】[0059]
【参考例２】(S)-2-(4-t-ブチルフェノキシ)-3-(4-ヒド
ロキシフェニル)プロピオン酸 2-トリメチルシリルエ
チルエステル (a) (S)-4-ベンジル-3-[(4-t-ブチルフェノキシ)アセチ
ル]オキサゾリジン-2-オン 4-t-ブチルフェノキシ酢酸(17.0 g)、塩化オキザリル(1
7.8 ml)、(S)-4-ベンジル-2-オキサゾリジノン(14.2 g)
及びn-ブチルリチウムのヘキサン溶液(1.61N,50.4 ml)
を用いて、参考例1(a)に準じて反応及び後処理を行うこ
とにより、無色結晶の目的化合物(28.3 g)を得た。 m.p. 107 - 108℃1 H-NMR (270 MHz, CDCl3): δ ppm 1.30(9H, s), 2.85 (1H, dd, J=9.5, 13.5Hz), 3.36
(1H, dd, J=3.0, 13.5Hz), 4.25-4.37 (2H, m), 4.68
-4.77 (1H, m), 5.22 (2H, s), 6.91 (2H, d,J=8.5H
z), 7.20-7.38 (7H, m). (b) (S)-4-ベンジル-3-[(2S,3R)-3-(4-ベンジルオキシ
フェニル)-2-(4-t-ブチルフェノキシ)-3-ヒドロキシプ
ロピオニル]オキサゾリジン-2-オン 参考例2(a)で製造した(S)-4-ベンジル-3-[(4-t-ブチル
フェノキシ)アセチル]オキサゾリジン-2-オン(28.2
g)、ジブチルボロントリフレートのジクロロメタン溶液
(1M, 92.1 ml)、トリエチルアミン(13.9 ml)及び4-ベン
ジルオキシベンズアルデヒド(17.9 g)を用いて、参考例
1(b)に準じて反応及び後処理を行うことにより、無色油
状の目的化合物(30.0 g)を得た。1 H-NMR (270 MHz, CDCl3): δ ppm 1.28(9H, s), 2.73 (1H, dd, J=9.0, 13.5Hz), 3.03-
3.12 (2H, m), 3.58 (1H, t, J=8.5Hz), 3.97 (1H, d
d, J=1.5, 8.5Hz), 4.23-4.29 (1H, m), 5.05(2H,
s), 5.08 (1H, t, J=5.5Hz), 6.19 (1H, d, J=5.5H
z), 6.92 (2H, d, J=8.5Hz), 6.95 (2H, d, J=8.5H
z), 7.06-7.08 (2H, m), 7.25-7.40 (12H, m). (c) (S)-4-ベンジル-3-[(2S,3R)-2-(4-t-ブチルフェノ
キシ)-3-ヒドロキシ-3-(4-ヒドロキシフェニル)プロピ
オニル]オキサゾリジン-2-オン 参考例2(b)で製造した(S)-4-ベンジル-3-[(2S,3R)-3-(4
-ベンジルオキシフェニル)-2-(4-t-ブチルフェノキシ)-
3-ヒドロキシプロピオニル]オキサゾリジン-2-オン (3
0.0 g)及びパラジウム−炭素(5%, 3.00 g)を用いて、参
考例1(c)に準じて反応及び後処理を行うことにより、フ
ォーム状の目的化合物(27.0 g)を得た。 1 H-NMR (270 MHz, CDCl3): δ ppm 2.05 (9H, s), 2.76 (1H, dd, J=9.0, 13.5Hz), 3.07
-3.13 (2H, m), 3.75 (1H, t, J=8.5Hz), 4.05 (1H,
dd, J=2.0, 8.5Hz), 4.29-4.34 (1H, m), 5.08, (1H,
t, J=5.5Hz), 5.32 (1H, s), 6.18 (1H, d, J=5.5H
z), 6.80 (2H, d,J=8.5Hz), 6.92 (2H, d, J=8.5Hz),
7.06-7.09 (2H, m), 7.25-7.36 (7H, m). (d) (S)-4-ベンジル-3-[(S)-2-(4-t-ブチルフェノキシ)
-3-(4-ヒドロキシフェニル)プロピオニル]オキサゾリジ
ン-2-オン 参考例2(c)で製造した(S)-4-ベンジル-3-[(2S,3R)-2-(4
-t-ブチルフェノキシ)-3-ヒドロキシ-3-(4-ヒドロキシ
フェニル)プロピオニル]オキサゾリジン-2-オン(25.3
g)及びトリエチルシラン(66 ml)を用いて、参考例1(d)
に準じて反応及び後処理を行うことにより、無色結晶の
目的化合物(18.2 g)を得た。 m.p. 160 - 161℃1 H-NMR (270 MHz, CDCl3): δ ppm 1.26 (9H, s), 2.79 (1H, dd, J=9.5, 13.5Hz), 3.08
-3.23 (3H, m), 4.03 (1H, t, J=8.5Hz), 4.17 (1H,
dd, J=2.5, 8.5Hz), 4.48-4.56 (1H, m), 4.77(1H, b
rs), 6.08 (1H, dd, J=5.5, 8.0Hz), 6.75 (2H, d, J
=8.5Hz), 6.83 (2H, d, J=8.5Hz), 7.11-7.14 (2H,
m), 7.22-7.32 (7H, m). (e) (S)-2-(4-t-ブチルフェノキシ)-3-(4-ヒドロキシフ
ェニル)プロピオン酸 2-トリメチルシリルエチルエス
テル 参考例2(d)で製造した(S)-4-ベンジル-3-[(S)-2-(4-t-
ブチルフェノキシ)-3-(4-ヒドロキシフェニル)プロピオ
ニル]オキサゾリジン-2-オン(24.3 g)、水酸化リチウム
水溶液(1N, 128 ml)及び過酸化水素水(31%, 14.1 ml)を
用いて、参考例1(e)に準じて反応及び後処理を行うこと
により、白色パウダー状の(S)-2-(4-t-ブチルフェノキ
シ)-3-(4-ヒドロキシフェニル)プロピオン酸(13.4 g)を
得た。[Reference Example 2](S) -2- (4-t-butylphenoxy) -3- (4-hydrido
Roxyphenyl) propionic acid 2-trimethylsilyl ester
Chill ester (a)(S) -4-benzyl-3-[(4-t-butylphenoxy) acetyl
[Oxazolidin-2-one] 4-t-butylphenoxyacetic acid (17.0 g), oxalyl chloride (1
7.8 ml), (S) -4-benzyl-2-oxazolidinone (14.2 g)
And n-butyllithium in hexane (1.61N, 50.4 ml)
To carry out the reaction and post-treatment according to Reference Example 1 (a).
As a result, the target compound (28.3 g) was obtained as colorless crystals. m.p. 107-108 ℃1 H-NMR (270 MHz, CDClThree): δ ppm 1.30 (9H, s), 2.85 (1H, dd, J = 9.5, 13.5Hz), 3.36
(1H, dd, J = 3.0, 13.5Hz), 4.25-4.37 (2H, m), 4.68
-4.77 (1H, m), 5.22 (2H, s), 6.91 (2H, d, J = 8.5H
z), 7.20-7.38 (7H, m). (b)(S) -4-benzyl-3-[(2S, 3R) -3- (4-benzyloxy
Phenyl) -2- (4-t-butylphenoxy) -3-hydroxyp
Lopionyl] oxazolidine-2-one (S) -4-benzyl-3-[(4-t-butyl) produced in Reference Example 2 (a)
Phenoxy) acetyl] oxazolidin-2-one (28.2
g), dibutyl boron triflate in dichloromethane solution
(1M, 92.1 ml), triethylamine (13.9 ml) and 4-ben
Reference Example Using Diloxybenzaldehyde (17.9 g)
By conducting the reaction and post-treatment according to 1 (b), a colorless oil
The desired compound (30.0 g) was obtained.1 H-NMR (270 MHz, CDClThree): δ ppm 1.28 (9H, s), 2.73 (1H, dd, J = 9.0, 13.5Hz), 3.03-
3.12 (2H, m), 3.58 (1H, t, J = 8.5Hz), 3.97 (1H, d
d, J = 1.5, 8.5Hz), 4.23-4.29 (1H, m), 5.05 (2H,
s), 5.08 (1H, t, J = 5.5Hz), 6.19 (1H, d, J = 5.5H
z), 6.92 (2H, d, J = 8.5Hz), 6.95 (2H, d, J = 8.5H
z), 7.06-7.08 (2H, m), 7.25-7.40 (12H, m). (c)(S) -4-benzyl-3-[(2S, 3R) -2- (4-t-butylpheno
(Xy) -3-hydroxy-3- (4-hydroxyphenyl) prop
Onyl] oxazolidine-2-one (S) -4-benzyl-3-[(2S, 3R) -3- (4) produced in Reference Example 2 (b)
-Benzyloxyphenyl) -2- (4-t-butylphenoxy)-
3-hydroxypropionyl] oxazolidine-2-one (3
0.0 g) and palladium-carbon (5%, 3.00 g).
By conducting the reaction and post-treatment according to Example 1 (c),
The desired compound (27.0 g) was obtained in the form of a foam. 1 H-NMR (270 MHz, CDClThree): δ ppm 2.05 (9H, s), 2.76 (1H, dd, J = 9.0, 13.5Hz), 3.07
-3.13 (2H, m), 3.75 (1H, t, J = 8.5Hz), 4.05 (1H,
dd, J = 2.0, 8.5Hz), 4.29-4.34 (1H, m), 5.08, (1H,
t, J = 5.5Hz), 5.32 (1H, s), 6.18 (1H, d, J = 5.5H
z), 6.80 (2H, d, J = 8.5Hz), 6.92 (2H, d, J = 8.5Hz),
7.06-7.09 (2H, m), 7.25-7.36 (7H, m). (D)(S) -4-benzyl-3-[(S) -2- (4-t-butylphenoxy)
-3- (4-Hydroxyphenyl) propionyl] oxazolidy
N-2-one (S) -4-benzyl-3-[(2S, 3R) -2- (4) produced in Reference Example 2 (c)
-t-butylphenoxy) -3-hydroxy-3- (4-hydroxy
Phenyl) propionyl] oxazolidine-2-one (25.3
g) and triethylsilane (66 ml) to obtain Reference Example 1 (d).
By performing the reaction and post-treatment in accordance with
The target compound (18.2 g) was obtained. m.p. 160-161 ℃1 H-NMR (270 MHz, CDClThree): δ ppm 1.26 (9H, s), 2.79 (1H, dd, J = 9.5, 13.5Hz), 3.08
-3.23 (3H, m), 4.03 (1H, t, J = 8.5Hz), 4.17 (1H,
dd, J = 2.5, 8.5Hz), 4.48-4.56 (1H, m), 4.77 (1H, b
rs), 6.08 (1H, dd, J = 5.5, 8.0Hz), 6.75 (2H, d, J
= 8.5Hz), 6.83 (2H, d, J = 8.5Hz), 7.11-7.14 (2H,
m), 7.22-7.32 (7H, m). (e)(S) -2- (4-t-butylphenoxy) -3- (4-hydroxyf
2-phenylmethylpropionate
Tell (S) -4-benzyl-3-[(S) -2- (4-t-) produced in Reference Example 2 (d)
(Butylphenoxy) -3- (4-hydroxyphenyl) propio
Nyl] oxazolidin-2-one (24.3 g), lithium hydroxide
Aqueous solution (1N, 128 ml) and aqueous hydrogen peroxide (31%, 14.1 ml)
And perform the reaction and post-treatment according to Reference Example 1 (e).
To give (S) -2- (4-t-butylphenoxy) as a white powder.
(C) -3- (4-hydroxyphenyl) propionic acid (13.4 g)
Obtained.
【００６０】このカルボン酸(13.3 g)、塩化オキザリル
(18.45 ml)及び2-トリメチルシリルエタノール(30.3 m
l)を用いて、参考例1(e)に準じて反応及び後処理を行う
ことにより、無色結晶の目的化合物(16.0 g)を得た。 m.p. 71 - 72℃1 H-NMR (270 MHz, CDCl3): δ ppm 0.06 (9H, s), 0.93 (2H, t, J=8.5Hz), 1.31 (9H,
s), 3.18-3.21 (2H, m),4.18-4.33 (2H, m), 4.69-4.
73 (2H, m), 6.79 (2H, d, J=8.5Hz), 6.80 (2H, d,
J=8.5Hz), 7.21 (2H, d, J=8.5Hz), 7.28 (2H, d, J=
8.5Hz).This carboxylic acid (13.3 g), oxalyl chloride
(18.45 ml) and 2-trimethylsilylethanol (30.3 m
The reaction and post-treatment were carried out according to Reference Example 1 (e) using l) to give the target compound (16.0 g) as colorless crystals. mp 71-72 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 0.06 (9H, s), 0.93 (2H, t, J = 8.5Hz), 1.31 (9H,
s), 3.18-3.21 (2H, m), 4.18-4.33 (2H, m), 4.69-4.
73 (2H, m), 6.79 (2H, d, J = 8.5Hz), 6.80 (2H, d,
J = 8.5Hz), 7.21 (2H, d, J = 8.5Hz), 7.28 (2H, d, J =
8.5Hz).
【００６１】[0061]
【参考例３】(S)-2-(4-フルオロフェノキシ)-3-(4-ヒド
ロキシフェニル)プロピオン酸 2-トリメチルシリルエ
チルエステル (a) (S)-4-ベンジル-3-[(4-フルオロフェノキシ)アセチ
ル]オキサゾリジン-2-オン 4-フルオロフェノキシ酢酸(1.70 g)、塩化オキザリル
(2.18 ml)、(S)-4-ベンジル-2-オキサゾリジノン(1.77
g)及びn-ブチルリチウムのヘキサン溶液(1.61N,7.14 m
l)を用いて、参考例1(a)に準じて反応及び後処理を行う
ことにより、無色結晶の目的化合物(2.76 g)を得た。 m.p. 113 - 115℃1 H-NMR (270 MHz, CDCl3): δ ppm 2.85 (1H, dd, J=9.5, 13.5Hz), 3.36 (1H, dd, J=3.
0, 13.5Hz), 4.26-4.38(2H, m), 4.68-4.77 (1H, m),
5.21 (2H, s), 6.90-7.04 (4H, m), 7.20-7.38 (5
H, m). (b) (S)-4-ベンジル-3-[(2S,3R)-3-(4-ベンジルオキシ
フェニル)-2-(4-フルオロフェノキシ)-3-ヒドロキシプ
ロピオニル]オキサゾリジン-2-オン 参考例3(a)で製造した(S)-4-ベンジル-3-[(4-フルオロ
フェノキシ)アセチル]オキサゾリジン-2-オン (1.96
g)、ジブチルボロントリフレートのジクロロメタン溶液
(1M, 7.14 ml)、トリエチルアミン(1.08 ml)及び4-ベン
ジルオキシベンズアルデヒド(1.39 g)を用いて、参考例
1(b)に準じて反応及び後処理を行うことにより、フォー
ム状の目的化合物(2.68 g)を得た。1 H-NMR (270 MHz, CDCl3): δ ppm 2.72 (1H, dd, J=9.0, 13.5Hz), 2.97-3.11 (1H, m),
3.05 (1H, dd, J=3.0,13.5Hz), 3.57 (1H, t, J=8.5H
z), 3.97 (1H, dd, J=2.0, 8.5Hz), 4.21-4.27 (1H,
m), 5.03-5.13 (1H, m), 5.05 (2H, s), 6.16 (1H,
d, J=5.5Hz), 6.85-7.06 (6H, m), 7.07-7.12 (2H,
m), 7.25-7.43 (10H, m). (c) (S)-4-ベンジル3-[(2S,3R)-2-(4-フルオロフェノキ
シ)-3-ヒドロキシ-3-(4- ヒドロキシフェニル)プロピオ
ニル]オキサゾリジン-2-オン 参考例3(b)で製造した(S)-4-ベンジル-3-[(2S,3R)-3-(4
-ベンジルオキシフェニル)-2-(4-フルオロフェノキシ)-
3-ヒドロキシプロピオニル]オキサゾリジン-2-オン(2.3
3 g)及びパラジウム−炭素(5%, 490 mg)を用いて、参考
例1(c)に準じて反応及び後処理を行うことにより、フォ
ーム状の目的化合物(1.94 g)を得た。 1 H-NMR (270 MHz, CDCl3): δ ppm 2.75 (1H, dd, J=9.0, 13.5Hz), 3.03-3.10 (1H, m),
3.07 (1H, dd, J=3.0,13.5Hz), 3.75 (1H, t, J=8.5H
z), 4.06 (1H, dd, J=2.0, 8.5Hz), 4.26-4.34 (1H,
m), 5.08, (1H, dd, J=4.5, 5.5Hz), 6.16 (1H, d, J
=5.5Hz), 6.81(2H, d, J=8.5Hz), 6.89-7.01 (4H,
m), 7.02-7.10 (2H, m), 7.24-7.30 (5H, m), 7.34
(2H, d, J=8.5Hz). (d) (S)-4-ベンジル-3-[(S)-2-(4-フルオロフェノキシ)
-3-(4-ヒドロキシフェニル)プロピオニル]オキサゾリジ
ン-2-オン 参考例3(c)で製造した(S)-4-ベンジル3-[(2S,3R)-2-(4-
フルオロフェノキシ)-3-ヒドロキシ-3-(4-ヒドロキシフ
ェニル)プロピオニル]オキサゾリジン-2-オン(1.89 g)
及びトリエチルシラン(5.4 ml)を用いて、参考例1(d)に
準じて反応及び後処理を行うことにより、無色結晶の目
的化合物(1.21 g)を得た。 m.p. 137 - 138℃1 H-NMR (270 MHz, CDCl3): δ ppm 2.77 (1H, dd, J=9.0, 13.5Hz), 3.08-3.20 (3H, m),
4.02 (1H, t, J=8.5Hz), 4.17 (1H, dd, J=2.5, 8.5H
z), 4.46-4.54 (1H, m), 4.82-4.92 (1H, m),6.06 (1
H, dd, J=6.0, 7.5Hz), 6.76 (2H, d, J=8.5Hz), 6.8
6 (2H, dd, J=4.5, 9.0Hz), 6.94 (2H, dd, J=8.0, 9.
0Hz), 7.09-7.12 (2H, m), 7.22 (2H,d, J=8.5Hz),
7.26-7.30 (5H, m). (e) (S)-2-(4-フルオロフェノキシ)-3-(4-ヒドロキシフ
ェニル)プロピオン酸 2-トリメチルシリルエチルエス
テル 参考例3(d)で製造した(S)-4-ベンジル-3-[(S)-2-(4-フ
ルオロフェノキシ)-3-(4-ヒドロキシフェニル)プロピオ
ニル]オキサゾリジン-2-オン(4.20 g)、水酸化リチウム
水溶液(1N, 24.1 ml)及び過酸化水素水(31%, 2.64 ml)
を用いて、参考例1(e)に準じて反応及び後処理を行うこ
とにより、白色パウダー状の(S)-2-(4-フルオロフェノ
キシ)-3-(4-ヒドロキシフェニル)プロピオン酸(2.31 g)
を得た。[Reference Example 3](S) -2- (4-fluorophenoxy) -3- (4-hydrido
Roxyphenyl) propionic acid 2-trimethylsilyl ester
Chill ester (a)(S) -4-benzyl-3-[(4-fluorophenoxy) acetyl
[Oxazolidin-2-one] 4-fluorophenoxyacetic acid (1.70 g), oxalyl chloride
(2.18 ml), (S) -4-benzyl-2-oxazolidinone (1.77
g) and n-butyllithium in hexane (1.61N, 7.14 m
Perform reaction and post-treatment according to Reference Example 1 (a) using l)
Thus, the target compound (2.76 g) was obtained as colorless crystals. m.p. 113-115 ℃1 H-NMR (270 MHz, CDClThree): δ ppm 2.85 (1H, dd, J = 9.5, 13.5Hz), 3.36 (1H, dd, J = 3.
0, 13.5Hz), 4.26-4.38 (2H, m), 4.68-4.77 (1H, m),
5.21 (2H, s), 6.90-7.04 (4H, m), 7.20-7.38 (5
H, m). (B)(S) -4-benzyl-3-[(2S, 3R) -3- (4-benzyloxy
Phenyl) -2- (4-fluorophenoxy) -3-hydroxyp
Lopionyl] oxazolidine-2-one (S) -4-benzyl-3-[(4-fluoro) produced in Reference Example 3 (a)
[Phenoxy) acetyl] oxazolidin-2-one (1.96
g), dibutyl boron triflate in dichloromethane solution
(1M, 7.14 ml), triethylamine (1.08 ml) and 4-ben
Reference Example Using Diloxybenzaldehyde (1.39 g)
By performing the reaction and post-treatment according to 1 (b),
Thus, the target compound (2.68 g) was obtained in the form of a rubber.1 H-NMR (270 MHz, CDClThree): δ ppm 2.72 (1H, dd, J = 9.0, 13.5Hz), 2.97-3.11 (1H, m),
3.05 (1H, dd, J = 3.0,13.5Hz), 3.57 (1H, t, J = 8.5H
z), 3.97 (1H, dd, J = 2.0, 8.5Hz), 4.21-4.27 (1H,
m), 5.03-5.13 (1H, m), 5.05 (2H, s), 6.16 (1H,
d, J = 5.5Hz), 6.85-7.06 (6H, m), 7.07-7.12 (2H,
m), 7.25-7.43 (10H, m). (c)(S) -4-benzyl 3-[(2S, 3R) -2- (4-fluorophenoxy
(S) -3-hydroxy-3- (4- (Hydroxyphenyl) propio
Nyl] oxazolidin-2-one (S) -4-benzyl-3-[(2S, 3R) -3- (4) produced in Reference Example 3 (b)
-Benzyloxyphenyl) -2- (4-fluorophenoxy)-
[3-hydroxypropionyl] oxazolidin-2-one (2.3
3 g) and palladium-carbon (5%, 490 mg)
By performing the reaction and post-treatment according to Example 1 (c),
The desired compound (1.94 g) was obtained in the form of a foam. 1 H-NMR (270 MHz, CDClThree): δ ppm 2.75 (1H, dd, J = 9.0, 13.5Hz), 3.03-3.10 (1H, m),
3.07 (1H, dd, J = 3.0,13.5Hz), 3.75 (1H, t, J = 8.5H
z), 4.06 (1H, dd, J = 2.0, 8.5Hz), 4.26-4.34 (1H,
m), 5.08, (1H, dd, J = 4.5, 5.5Hz), 6.16 (1H, d, J
= 5.5Hz), 6.81 (2H, d, J = 8.5Hz), 6.89-7.01 (4H,
m), 7.02-7.10 (2H, m), 7.24-7.30 (5H, m), 7.34
(2H, d, J = 8.5Hz). (D)(S) -4-benzyl-3-[(S) -2- (4-fluorophenoxy)
-3- (4-Hydroxyphenyl) propionyl] oxazolidy
N-2-one (S) -4-benzyl 3-[(2S, 3R) -2- (4-) produced in Reference Example 3 (c)
(Fluorophenoxy) -3-hydroxy-3- (4-hydroxyf
Enyl) propionyl] oxazolidin-2-one (1.89 g)
And Reference Example 1 (d) using
By conducting the reaction and post-treatment in accordance with
The target compound (1.21 g) was obtained. m.p. 137-138 ℃1 H-NMR (270 MHz, CDClThree): δ ppm 2.77 (1H, dd, J = 9.0, 13.5Hz), 3.08-3.20 (3H, m),
4.02 (1H, t, J = 8.5Hz), 4.17 (1H, dd, J = 2.5, 8.5H
z), 4.46-4.54 (1H, m), 4.82-4.92 (1H, m), 6.06 (1
H, dd, J = 6.0, 7.5Hz), 6.76 (2H, d, J = 8.5Hz), 6.8
6 (2H, dd, J = 4.5, 9.0Hz), 6.94 (2H, dd, J = 8.0, 9.
0Hz), 7.09-7.12 (2H, m), 7.22 (2H, d, J = 8.5Hz),
7.26-7.30 (5H, m). (E)(S) -2- (4-fluorophenoxy) -3- (4-hydroxyf
2-phenylmethylpropionate
Tell (S) -4-benzyl-3-[(S) -2- (4-phenyl) produced in Reference Example 3 (d)
(Ruolophenoxy) -3- (4-hydroxyphenyl) propio
Nyl] oxazolidin-2-one (4.20 g), lithium hydroxide
Aqueous solution (1N, 24.1 ml) and aqueous hydrogen peroxide (31%, 2.64 ml)
The reaction and post-treatment are performed according to Reference Example 1 (e) using
To form (S) -2- (4-fluoropheno
(Xy) -3- (4-hydroxyphenyl) propionic acid (2.31 g)
I got
【００６２】このカルボン酸(2.30 g)、塩化オキザリル
(1.80 ml)及び2-トリメチルシリルエタノール(15.96 m
l)を用いて、参考例1(e)に準じて反応及び後処理を行う
ことにより、無色結晶の目的化合物(1.81 g)を得た。 m.p. 99 - 100℃1 H-NMR (270 MHz, CDCl3): δ ppm 0.02 (9H, s), 0.93 (2H, dd, J=7.5, 10.0Hz), 3.15
(2H, d, J=6.5Hz), 4.16-4.24 (2H, m), 4.62 (1H,
t, J=6.5Hz), 4.82 (1H, brs), 6.74-6.79 (4H, m),
6.91 (2H, dd, J=8.5, 9.0Hz), 7.16 (2H, d, J=8.5H
z).This carboxylic acid (2.30 g), oxalyl chloride
(1.80 ml) and 2-trimethylsilylethanol (15.96 m
The reaction and post-treatment were carried out according to Reference Example 1 (e) using l) to give the target compound (1.81 g) as colorless crystals. mp 99-100 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 0.02 (9H, s), 0.93 (2H, dd, J = 7.5, 10.0Hz), 3.15
(2H, d, J = 6.5Hz), 4.16-4.24 (2H, m), 4.62 (1H,
t, J = 6.5Hz), 4.82 (1H, brs), 6.74-6.79 (4H, m),
6.91 (2H, dd, J = 8.5, 9.0Hz), 7.16 (2H, d, J = 8.5H
z).
【００６３】[0063]
【参考例４】2-[[1-(4'-メトキシ4-ビフェニリル)エチ
リデン]アミノオキシ]エタノール (a) 4'-(4-メトキシフェニル)アセトフェノン オキシ
ム 水酸化カリウム(2.9 g)のメタノール(40 ml)−水(8 ml)
の混合溶液に、塩酸ヒドロキシルアミン(3.07 g)を加
え、50℃で30分攪拌した後、4-(4-メトキシフェニル)-
アセトフェノン(5.0 g)を加えた。反応液を50℃で7時間
攪拌した後、水酸化カリウム(2.9 g)及び塩酸ヒドロキ
シルアミン(3.07 g)を加えた。さらに50℃で65時間攪拌
後、減圧濃縮し、酢酸エチルと水を加え、析出した結晶
を濾取し、水及び酢酸エチルで洗浄した。得られた結晶
をさらにイソプロピルエーテルで洗浄し、無色結晶の目
的化合物(4.05 g)を得た。 m.p. 82 - 84℃1 H-NMR (270 MHz, DMSO-d6): δ ppm 2.18 (3H, s), 3.80 (3H, s), 7.03 (2H, d, J=8.5H
z), 7.64 (4H, d, J=8.0Hz), 7.71 (2H, d, J=8.5H
z). (b) 2-[[1-(4'-メトキシ4-ビフェニリル)エチリデン]ア
ミノオキシ]エタノール 2-(2-ブロモエトキシ)テトラヒドロピラン(494 mg)及び
参考例4(a)で製造した4'-(4-メトキシフェニル)-アセト
フェノン オキシム(380 mg)のN,N-ジメチルアセトアミ
ド溶液（10 ml）に、炭酸カリウム(660 mg)を加え、80
℃で16時間攪拌した。反応後、反応液に酢酸エチルと水
の混合溶媒を加え、酢酸エチル層を分離し、無水硫酸マ
グネシウムで乾燥し、減圧濃縮した。これを、シリカゲ
ルカラムクロマトグラフィー（溶出溶液：ヘキサン/酢
酸エチル＝5/1）を用いて精製し、白色固体の4'-(4-メ
トキシフェニル)アセトフェノン オキシム O -2-[(テ
トラヒドロピラン-2-イル)オキシ]エチルエーテル (590
mg)を得た。[Reference Example 4] 2-[[1- (4'-methoxy-4-biphenylyl) ethyl
Ridene] aminooxy] ethanol (a) 4 '-(4-methoxyphenyl) acetophenone oxy
Beam methanol potassium hydroxide (2.9 g) (40 ml) - water (8 ml)
To the mixed solution of above, hydroxylamine hydrochloride (3.07 g) was added, and the mixture was stirred at 50 ° C. for 30 minutes.
Acetophenone (5.0 g) was added. After the reaction solution was stirred at 50 ° C. for 7 hours, potassium hydroxide (2.9 g) and hydroxylamine hydrochloride (3.07 g) were added. After stirring at 50 ° C. for 65 hours, the mixture was concentrated under reduced pressure, ethyl acetate and water were added, and the precipitated crystals were collected by filtration and washed with water and ethyl acetate. The obtained crystals were further washed with isopropyl ether to give the target compound (4.05 g) as colorless crystals. mp 82-84 ° C 1 H-NMR (270 MHz, DMSO-d 6 ): δ ppm 2.18 (3H, s), 3.80 (3H, s), 7.03 (2H, d, J = 8.5H
z), 7.64 (4H, d, J = 8.0Hz), 7.71 (2H, d, J = 8.5H
z). (b) 2-[[1- (4'-methoxy-4-biphenylyl) ethylidene] a
Minooxy] ethanol N, N-dimethylacetamide of 2- (2-bromoethoxy) tetrahydropyran (494 mg) and 4 ′-(4-methoxyphenyl) -acetophenone oxime (380 mg) produced in Reference Example 4 (a) To the solution (10 ml) was added potassium carbonate (660 mg),
Stirred at C for 16 hours. After the reaction, a mixed solvent of ethyl acetate and water was added to the reaction solution, the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This was purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1) to give 4 '-(4-methoxyphenyl) acetophenone oxime O-2-[(tetrahydropyran-2) as a white solid. -Yl) oxy] ethyl ether (590
mg).
【００６４】4'-(4-メトキシフェニル)アセトフェノン
オキシム O-2-[(テトラヒドロピラン-2-イル)オキ
シ]エチルエーテル(561 mg)のメタノール溶液(30 ml)に
p-トルエンスルホン酸一水和物(290 mg)を加え、室温で
2時間攪拌し、減圧濃縮した。残留物を酢酸エチルに溶
解し、飽和炭酸水素ナトリウム水溶液で洗浄後、硫酸マ
グネシウムで乾燥、減圧濃縮した。得られた結晶をイソ
プロピルエーテルで濾取し、無色結晶の目的化合物(390
mg)を得た。 m.p. 164 - 166℃1 H-NMR (270 MHz, CDCl3): δ ppm 2.30 (3H, s), 3.80 (3H, s), 3.94-3.98 (2H, m),
4.32-4.35 (2H, m), 6.99 (2H, d, J=8.5Hz), 7.55 (2
H, d, J=8.5Hz), 7.56 (2H, d, J=8.5Hz), 7.68(2H,
d, J=8.5Hz).A methanol solution (30 ml) of 4 '-(4-methoxyphenyl) acetophenone oxime O-2-[(tetrahydropyran-2-yl) oxy] ethyl ether (561 mg) was added.
Add p-toluenesulfonic acid monohydrate (290 mg) and add
The mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were collected by filtration with isopropyl ether to give the target compound (390) as colorless crystals.
mg). mp 164-166 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 2.30 (3H, s), 3.80 (3H, s), 3.94-3.98 (2H, m),
4.32-4.35 (2H, m), 6.99 (2H, d, J = 8.5Hz), 7.55 (2
H, d, J = 8.5Hz), 7.56 (2H, d, J = 8.5Hz), 7.68 (2H,
d, J = 8.5Hz).
【００６５】[0065]
【参考例５】2-(4-クロロフェノキシ)-3-(4-ヒドロキシ
フェニル)プロピオン酸 エチルエステル (a) 3-(4-ベンジルオキシフェニル)乳酸 エチルエステ
ル 3-(4-ヒドロキシフェニル)乳酸 エチルエステル(22.4
g)のN,N-ジメチルホルムアミド溶液(220 ml)に、臭化ベ
ンジル(21.9 g)と炭酸カルシウム(35.3 g)を加え、50℃
で2時間攪拌した後、反応液に酢酸エチルと水を加え
た。酢酸エチル層を分離し、硫酸マグネシウムで乾燥、
減圧濃縮した。これを、シリカゲルカラムクロマトグラ
フィー（溶出溶液：ヘキサン/酢酸エチル＝7/3）を用い
て精製し、淡黄色油状の目的化合物(31.0 g)を得た。 (b) 3-(4-ベンジルオキシフェニル)-2-メタンスルホニ
ルオキシプロピオン酸エチルエステル 参考例5(a)で製造した3-(4-ベンジルオキシフェニル)乳
酸 エチルエステル(3.32 g)の無水ジクロロメタン溶液
(30 ml)に、塩化メタンスルホニル(0.94 ml)を加え、さ
らに、トリエチルアミン(2.47 ml)を氷冷中、滴下し
た。反応液を室温で3時間攪拌後、減圧濃縮した。これ
に水を加え、酢酸エチルで抽出し、酢酸エチル層を無水
硫酸マグネシウムで乾燥、減圧濃縮した。残留物をヘキ
サンで結晶化し、無色結晶の目的化合物(3.60 g)を得
た。 m.p. 81 - 83℃1 H-NMR (270 MHz, CDCl3): δ ppm 1.27 (3H, t, J=7.0 Hz), 2.80 (3H, s), 3.02-3.29
(2H, m), 4.24 (2H, q,J=7.0 Hz), 5.05 (2H, s),
5.05-5.14 (1H, m), 6.93 (2H, d, J=8.5 Hz),7.17 (2
H, d, J=8.5 Hz), 7.28-7.45 (5H, m). (c) 3-(4-ベンジルオキシフェニル)-2-(4-クロロフェノ
キシ)プロピオン酸 エチルエステル 参考例5(b)で製造した3-(4-ベンジルオキシフェニル)-2
-メタンスルホニルオキシプロピオン酸 エチルエステ
ル(8.82 g)及び4-クロロフェノール(3.00 g)のN,N-ジメ
チルホルムアミド(110 ml)溶液に、炭酸カリウム(6.44
g)を加え、70℃で16時間攪拌した。反応液に酢酸エチル
と水を加え、酢酸エチル層を分離し、無水硫酸マグネシ
ウムで乾燥、減圧濃縮した。これを、シリカゲルカラム
クロマトグラフィー（溶出溶液：ヘキサン/酢酸エチル
＝9/1）を用いて精製し、無色結晶の目的化合物(5.99
g)を得た。 m.p. 63 - 64℃1 H-NMR (270 MHz, CDCl3): δ ppm 1.18 (3H, t, J=7.0 Hz), 3.17 (2H, d, J=6.5 Hz),
4.16 (2H, q, J=7.0 Hz), 4.69 (1H, t, J=6.5 Hz),
5.04 (2H, s), 6.75 (2H, d, J=9.0 Hz), 6.91(2H,
d, J=8.5 Hz), 7.13-7.23 (4H, m), 7.25-7.55 (5H,
m). (d) 2-(4-クロロフェノキシ)-3-(4-ヒドロキシフェニ
ル)プロピオン酸 エチルエステル 参考例5(c)で製造した3-(4-ベンジルオキシフェニル)-2
-(4-クロロフェノキシ)プロピオン酸 エチルエステル
(5.99 g)を臭化水素・酢酸溶液(25%, 60 ml)に溶解し、
室温で3時間攪拌した。その後、減圧濃縮し、エタノー
ル(70 ml)に溶解後、炭酸カリウム(4.68 g)を加え、室
温で4時間攪拌した。反応液を減圧濃縮し、酢酸エチル
と水を加えた。酢酸エチル層を分離し、無水硫酸マグネ
シウムで乾燥、減圧濃縮した。これを、シリカゲルカラ
ムクロマトグラフィー（溶出溶液：ヘキサン/酢酸エチ
ル＝9/1〜4/1）を用いて精製し、無色結晶の目的化合物
(3.85g)を得た。 m.p. 90 - 93℃1 H-NMR (270 MHz, CDCl3): δ ppm 1.19 (3H, t, J=7.0 Hz), 3.16 (2H, d, J=6.5 Hz),
4.17 (2H, q, J=7.0 Hz), 4.69 (1H, t, J=6.5 Hz),
4.95 (1H, brs), 6.76 (4H, d, J=8.5 Hz), 7.15 (2
H, d, J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz).[Reference Example 5] 2- (4-chlorophenoxy) -3- (4-hydroxy
(Phenyl) propionic acid ethyl ester (a) 3- (4-benzyloxyphenyl) lactic acid ethyl ester
Le 3- (4-hydroxyphenyl) lactate ethyl ester (22.4
g) in N, N-dimethylformamide solution (220 ml), benzyl bromide (21.9 g) and calcium carbonate (35.3 g) were added, and the mixture was heated at 50 ° C.
After stirring for 2 hours, ethyl acetate and water were added to the reaction solution. Separate the ethyl acetate layer, dry over magnesium sulfate,
It was concentrated under reduced pressure. This was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 7/3) to obtain the target compound (31.0 g) as a pale yellow oil. (b) 3- (4-benzyloxyphenyl) -2-methanesulfoni
Luxypropionic acid ethyl ester 3- (4-Benzyloxyphenyl) lactic acid ethyl ester (3.32 g) prepared in Reference Example 5 (a) in anhydrous dichloromethane
(30 ml), methanesulfonyl chloride (0.94 ml) was added, and triethylamine (2.47 ml) was added dropwise while cooling with ice. After the reaction solution was stirred at room temperature for 3 hours, it was concentrated under reduced pressure. Water was added thereto, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane to give the target compound as colorless crystals (3.60 g). mp 81-83 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 1.27 (3H, t, J = 7.0 Hz), 2.80 (3H, s), 3.02-3.29
(2H, m), 4.24 (2H, q, J = 7.0 Hz), 5.05 (2H, s),
5.05-5.14 (1H, m), 6.93 (2H, d, J = 8.5 Hz), 7.17 (2
(H, d, J = 8.5 Hz), 7.28-7.45 (5H, m). (C) 3- (4-benzyloxyphenyl) -2- (4-chloropheno
Xy) propionic acid ethyl ester 3- (4-benzyloxyphenyl) -2 produced in Reference Example 5 (b)
To a solution of ethyl methanesulfonyloxypropionate (8.82 g) and 4-chlorophenol (3.00 g) in N, N-dimethylformamide (110 ml) was added potassium carbonate (6.44 g).
g) was added and stirred at 70 ° C. for 16 hours. Ethyl acetate and water were added to the reaction solution, the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1) to give the target compound (5.99) as colorless crystals.
g) was obtained. mp 63-64 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 1.18 (3H, t, J = 7.0 Hz), 3.17 (2H, d, J = 6.5 Hz),
4.16 (2H, q, J = 7.0 Hz), 4.69 (1H, t, J = 6.5 Hz),
5.04 (2H, s), 6.75 (2H, d, J = 9.0 Hz), 6.91 (2H, s)
d, J = 8.5 Hz), 7.13-7.23 (4H, m), 7.25-7.55 (5H,
m). (d) 2- (4-chlorophenoxy) -3- (4-hydroxyphenyl)
E) Propionic acid ethyl ester 3- (4-benzyloxyphenyl) -2 produced in Reference Example 5 (c)
-(4-Chlorophenoxy) propionic acid ethyl ester
(5.99 g) in hydrogen bromide / acetic acid solution (25%, 60 ml),
Stirred at room temperature for 3 hours. Thereafter, the mixture was concentrated under reduced pressure, dissolved in ethanol (70 ml), added with potassium carbonate (4.68 g), and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This is purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1 to 4/1) to give the target compound as colorless crystals.
(3.85 g) was obtained. mp 90-93 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 1.19 (3H, t, J = 7.0 Hz), 3.16 (2H, d, J = 6.5 Hz),
4.17 (2H, q, J = 7.0 Hz), 4.69 (1H, t, J = 6.5 Hz),
4.95 (1H, brs), 6.76 (4H, d, J = 8.5 Hz), 7.15 (2
H, d, J = 8.5 Hz), 7.18 (2H, d, J = 8.5 Hz).
【００６６】[0066]
【参考例６】2-(4-フルオロフェノキシ)-3-(4-ヒドロキ
シフェニル)プロピオン酸 エチルエステル (a) 3-(4-ベンジルオキシフェニル)-2-(4-フルオロフェ
ノキシ)プロピオン酸エチルエステル 参考例5(a)で製造した3-(4-ベンジルオキシフェニル)乳
酸 エチルエステル(10.0 g)、4-フルオロフェノール
(4.15 g)及びトリフェニルホスフィン(10.6 g)のトルエ
ン溶液(10 ml)に、アゾジカルボン酸ジエチルエステル
(40%トルエン溶液、6.40 ml)のトルエン溶液(3.0 ml)
を、室温で滴下した。同温で2時間攪拌後、減圧濃縮し
た。残留物を、シリカゲルカラムクロマトグラフィー
（溶出溶液：ジクロロメタン/酢酸エチル＝3/2）を用い
て精製し、無色油状の目的化合物(7.00g)を得た。1 H-NMR (270 MHz, CDCl3):δppm 1.18 (3H, t, J=7.0 Hz), 3.16 (2H, d, J=6.5 Hz),
4.16 (2H, q, J=7.0 Hz), 4.66 (1H, t, J=6.5 Hz),
5.04 (2H, s), 6.72-6.80 (2H, m), 6.89-6.97(4H,
m), 7.21 (2H, d, J=8.5 Hz), 7.31-7.48 (5H, m). (b) 2-(4-フルオロフェノキシ)-3-(4-ヒドロキシフェニ
ル)プロピオン酸 エチルエステル 臭化水素・酢酸溶液(25%, 70 ml)に、参考例6(a)で製造
した3-(4-ベンジルオキシフェニル)-2-(4-フルオロフェ
ノキシ)プロピオン酸 エチルエステル(7.00g)を加え、
室温で3時間攪拌した。反応液を減圧濃縮し、エタノー
ル(70 ml)に溶解した後、炭酸カリウム(6.90 g)を加
え、室温で4時間攪拌した。反応液を減圧濃縮し、酢酸
エチルと水を加えた。酢酸エチル層を分離し、無水硫酸
マグネシウムで乾燥、減圧濃縮した。残留物を、シリカ
ゲルカラムクロマトグラフィー（溶出溶液：ヘキサン/
酢酸エチル＝9/1〜4/1）を用いて精製し、白色パウダー
状の目的化合物(2.75 g)を得た。 m.p. 80 - 81℃1 H-NMR (270 MHz, CDCl3):δppm 1.19 (3H, t, J=7.0 Hz), 3.15 (2H, d, J=6.5 Hz),
4.17 (2H, q, J=7.0 Hz), 4.65 (1H, t, J=6.5 Hz),
4.76 (1H, s), 6.71-6.80 (4H, m), 6.87-6.95(2H,
m), 7.16 (2H, d, J=8.5 Hz).[Reference Example 6] 2- (4-fluorophenoxy) -3- (4-hydroxy
(Ciphenyl) propionic acid ethyl ester (a) 3- (4-benzyloxyphenyl) -2- (4-fluorophenyl
Nonoxy) propionic acid ethyl ester 3- (4-benzyloxyphenyl) lactic acid ethyl ester (10.0 g) produced in Reference Example 5 (a), 4-fluorophenol
(4.15 g) and triphenylphosphine (10.6 g) in toluene solution (10 ml) were added to azodicarboxylic acid diethyl ester.
(40% toluene solution, 6.40 ml) toluene solution (3.0 ml)
Was added dropwise at room temperature. After stirring at the same temperature for 2 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 3/2) to give the target compound as a colorless oil (7.00 g). 1 H-NMR (270 MHz, CDCl 3 ): δppm 1.18 (3H, t, J = 7.0 Hz), 3.16 (2H, d, J = 6.5 Hz),
4.16 (2H, q, J = 7.0 Hz), 4.66 (1H, t, J = 6.5 Hz),
5.04 (2H, s), 6.72-6.80 (2H, m), 6.89-6.97 (4H,
m), 7.21 (2H, d, J = 8.5 Hz), 7.31-7.48 (5H, m). (b) 2- (4-Fluorophenoxy) -3- (4-hydroxyphenyl
3) Propionic acid ethyl ester Hydrogen bromide / acetic acid solution (25%, 70 ml), 3- (4-benzyloxyphenyl) -2- (4-fluorophenoxy) propionic acid produced in Reference Example 6 (a) Ethyl ester (7.00 g) was added,
Stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethanol (70 ml), added with potassium carbonate (6.90 g), and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane /
Purification using ethyl acetate = 9/1 to 4/1) gave the target compound (2.75 g) as a white powder. mp 80-81 ° C 1 H-NMR (270 MHz, CDCl 3 ): δppm 1.19 (3H, t, J = 7.0 Hz), 3.15 (2H, d, J = 6.5 Hz),
4.17 (2H, q, J = 7.0 Hz), 4.65 (1H, t, J = 6.5 Hz),
4.76 (1H, s), 6.71-6.80 (4H, m), 6.87-6.95 (2H,
m), 7.16 (2H, d, J = 8.5 Hz).
【００６７】[0067]
【参考例７】2-[[1-(4'-フルオロ-4-ビフェニリル)エチ
リデン]アミノオキシ]エチル メタンスルホネート (a) 2-[[1-(4'-フルオロ-4-ビフェニリル)エチリデン]
アミノオキシ]エタノール2-(2-ブロモエトキシ)テトラ
ヒドロピラン(6.84 g)、4'-(4-フルオロフェニル)アセ
トフェノン オキシム(5.00 g)、炭酸カリウム(6.02 g)
及び触媒量のp-トルエンスルホン酸一水和物を用いて、
WO97/37970（EP916651A）の参考例1(c)と参考例1(d)に
準じて反応及び後処理を行い、白色結晶の目的化合物
(3.84 g)を得た。 m.p. 131 - 133℃1 H-NMR (270 MHz, CDCl3):δppm 2.30 (3H, s), 3.96 (2H, t, J=4.5Hz), 4.34 (2H,
t, J=4.5Hz), 7.14 (2H,t, J=8.5Hz), 7.53-7.59 (4
H, m), 7.69 (2H, d, J=8.5Hz). (b) 2-[[1-(4'-フルオロ-4-ビフェニリル)エチリデン]
アミノオキシ]エチル メタンスルホネート 塩化メタンスルホニル(1.15ml)と参考例7(a)で製造した
2-[[1-(4'-フルオロ-4-ビフェニリル)エチリデン]アミ
ノオキシ]エタノール(3.70 g)のジクロロメタン溶液(40
ml)に、トリエチルアミン(2.83 ml)を0℃で滴下し、室
温で2時間攪拌した。反応液を減圧濃縮し、酢酸エチル
と水を加えた。酢酸エチル層を分離し、飽和食塩水で洗
浄後、無水硫酸マグネシウムで乾燥、減圧濃縮した。得
られた結晶をヘキサンとイソプロピルエーテルを用いて
濾取し、無色結晶の目的化合物(4.70 g)を得た。 m.p. 103 - 106℃1 H-NMR (270 MHz, CDCl3):δppm 2.29 (3H, s), 3.04 (3H, s), 4.46 (2H, t, J=4.5H
z), 4.56 (2H, t, J=4.5Hz), 7.14 (2H, t, J=8.5H
z), 7.54-7.59 (4H, m), 7.72 (2H, d, J=8.5Hz).[Reference Example 7] 2-[[1- (4'-fluoro-4-biphenylyl) ethyl
Ridene] aminooxy] ethyl methanesulfonate (a) 2-[[1- (4'-fluoro-4-biphenylyl) ethylidene]
Aminooxy] ethanol 2- (2-bromoethoxy) tetrahydropyran (6.84 g), 4 '-(4-fluorophenyl) acetophenone oxime (5.00 g), potassium carbonate (6.02 g)
And a catalytic amount of p-toluenesulfonic acid monohydrate,
The reaction and post-treatment were carried out according to Reference Examples 1 (c) and 1 (d) of WO97 / 37970 (EP916651A), and the target compound was white crystals.
(3.84 g) was obtained. mp 131-133 ° C 1 H-NMR (270 MHz, CDCl 3 ): δppm 2.30 (3H, s), 3.96 (2H, t, J = 4.5Hz), 4.34 (2H,
t, J = 4.5Hz), 7.14 (2H, t, J = 8.5Hz), 7.53-7.59 (4
H, m), 7.69 (2H, d, J = 8.5Hz). (B) 2-[[1- (4'-Fluoro-4-biphenylyl) ethylidene]
Aminooxy ] ethyl methanesulfonate Manufactured with methanesulfonyl chloride (1.15 ml) and Reference Example 7 (a)
2-[[1- (4′-Fluoro-4-biphenylyl) ethylidene] aminooxy] ethanol (3.70 g) in dichloromethane solution (40
ml), triethylamine (2.83 ml) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added. The ethyl acetate layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were collected by filtration using hexane and isopropyl ether to give the target compound (4.70 g) as colorless crystals. mp 103-106 ° C 1 H-NMR (270 MHz, CDCl 3 ): δ ppm 2.29 (3H, s), 3.04 (3H, s), 4.46 (2H, t, J = 4.5H
z), 4.56 (2H, t, J = 4.5Hz), 7.14 (2H, t, J = 8.5H
z), 7.54-7.59 (4H, m), 7.72 (2H, d, J = 8.5Hz).
【００６８】[0068]
【試験例】[Test example]
【００６９】[0069]
【試験例１】血糖降下作用 体重４０ｇ以上で高血糖状態を示す雄性ＫＫマウスに、
各化合物０．０１％（約１０ｍｇ／ｋｇ／ｄａｙ）の割
合で粉末飼料Ｆ−２（船橋農場）に混ぜて３日間投与し
た。別に、粉末飼料のみを与えたマウスを対照群とし
た。次いで無麻酔下で尾静脈より採血し、遠心分離によ
り得られた血漿中の血糖値をグルコローダーＦ（Ａ＆Ｔ
社製）にて測定した。Test Example 1 Hypoglycemic Action Male KK mice showing a hyperglycemic state with a body weight of 40 g or more were
Each compound was mixed with powder feed F-2 (Funabashi Farm) at a ratio of 0.01% (about 10 mg / kg / day) and administered for 3 days. Separately, mice that received only powdered feed were used as a control group. Subsequently, blood was collected from the tail vein under anesthesia, and the blood glucose level in the plasma obtained by centrifugation was measured using a glucoloader F (A & T).
Manufactured by the company).
【００７０】血糖降下率は次の式より求めた。The blood glucose lowering rate was determined by the following equation.
【００７１】血糖降下率（％）＝［（対照群血糖値−化
合物投与群血糖値）／対照群血糖値］× 100 得られた結果を表２に示す。Blood glucose lowering rate (%) = [(control group blood glucose level−compound administration group blood glucose level) / control group blood glucose level] × 100 The results are shown in Table 2.
【００７２】[0072]
【表２】 ──────────────────────────────── 試験化合物 血糖降下率（％） ──────────────────────────────── 実施例２の化合物 ６０ 実施例４の化合物 ５５ 実施例６の化合物 ６３ 実施例８の化合物 ６２ 実施例１０の化合物 ５９ 実施例１２の化合物 ５６ 実施例１４の化合物 ６４ 実施例１６の化合物 ５７ 実施例１８の化合物 ５７ ──────────────────────────────── 表２から、本発明の化合物は優れた血糖降下作用を示す
ことがわかる。[Table 2] ──────────────────────────────── Test compound Hypoglycemic rate (%) ──────化合物 Compound of Example 2 60 Compound of Example 4 55 Compound of Example 6 63 Compound of Example 8 Compound of Example 10 59 Compound of Example 12 56 Compound of Example 14 64 Compound of Example 16 57 Compound of Example 18 ──────────── Table 2 shows that the compounds of the present invention exhibit excellent hypoglycemic action.
【００７３】[0073]
【試験例２】血中トリグリセリド降下作用 肥満糖尿db/dbマウスに、各化合物０．０００３％（約
０．４５ｍｇ／ｋｇ／ｄａｙ）の割合で粉末飼料Ｆ−２
（船橋農場）に混ぜて一週間投与した。別に、粉末飼料
のみを与えたマウスを対照群とした。次いで無麻酔下で
尾静脈より採血し、遠心分離により得られた血漿中のト
リグリセリド値をトリグリセライドE−テストワコー
（和光純薬工業株式会社製）にて測定した。Test Example 2 Blood triglyceride-lowering effect Obese diabetic db / db mice were powdered at a ratio of 0.0003% (approximately 0.45 mg / kg / day) to compound F-2.
(Funabashi Farm) and administered for one week. Separately, mice that received only powdered feed were used as a control group. Next, blood was collected from the tail vein under anesthesia, and the triglyceride level in the plasma obtained by centrifugation was measured using Triglyceride E-Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.).
【００７４】血中トリグリセリド降下率は次の式より求
めた。The blood triglyceride drop rate was determined by the following equation.
【００７５】血中トリグリセリド降下率（％）＝［（対
照群血中トリグリセリド値−化合物投与群血中トリグリ
セリド値）／対照群血中トリグリセリド値］×100 得られた結果を表３に示す。Blood triglyceride lowering rate (%) = [(control group blood triglyceride value−compound administration group blood triglyceride value) / control group blood triglyceride value] × 100 The results are shown in Table 3.
【００７６】[0076]
【表３】 ──────────────────────────────── 試験化合物 血中トリグリセリド降下率（％） ──────────────────────────────── 実施例４の化合物 ４６ 実施例１２の化合物 ６２ 実施例１４の化合物 ７７ 実施例１８の化合物 ７０ ──────────────────────────────── 表３から、本発明の化合物は優れた血中トリグリセリド
降下作用を示すことがわかる。[Table 3] ──────────────────────────────── Test compound Blood triglyceride lowering rate (%) ────化合物 Compound of Example 4 46 Compound of Example 12 62 Compound of Example 14 77 Compound of Example 18 Compound 70 か ら Table 3 shows that the compounds of the present invention have excellent blood triglyceride lowering activity. It can be seen that
【００７７】[0077]
（１）カプセル剤 実施例４の化合物 １０ ｍｇ ラクトース １１０ ｍｇ コーン・スターチ ５８ ｍｇステアリン酸マグネシウム ２ ｍｇ 合計 １８０ ｍｇ 上記で示される各成分の粉末を良く混合し、６０メッシ
ュの篩（メッシュの基準はＴｙｌｅｒ基準による）を通
す。得られる粉末１８０ｍｇをはかり分け、ゼラチンカ
プセル（Ｎｏ．３）に充填し、カプセル剤を調製する。 （２）錠剤 実施例１２の化合物 １０ ｍｇ ラクトース ８５ ｍｇ コーン・スターチ ３４ ｍｇ 微結晶セルロース ２０ ｍｇステアリン酸マグネシウム １ ｍｇ 合計 １５０ ｍｇ 上記で示される各成分の粉末を良く混合し、各１５０ｍ
ｇ重量の錠剤に圧縮成型する。必要ならば、これらの錠
剤は糖またはフィルムで被覆してもよい。 （３）顆粒剤 実施例１８の化合物 １０ ｍｇ ラクトース ８３９ ｍｇ コーン・スターチ １５０ ｍｇヒドロキシプロピルセルロース １ ｍｇ 合計 １０００ ｍｇ 上記で示される各成分の粉末を良く混合し、純水で湿ら
し、バスケット式顆粒化機で顆粒化し、乾燥して顆粒剤
を得る。(1) Capsules Compound of Example 4 10 mg Lactose 110 mg Corn starch 58 mg Magnesium stearate 2 mg Total 180 mg Powder of each component shown above is mixed well, and the mixture is sieved to 60 mesh (mesh standard: (According to Tyler standard). 180 mg of the obtained powder is weighed and filled into a gelatin capsule (No. 3) to prepare a capsule. (2) Tablets Compound of Example 12 10 mg Lactose 85 mg Corn starch 34 mg Microcrystalline cellulose 20 mg Magnesium stearate 1 mg Total 150 mg Powder of each component shown above was mixed well, and 150 m each
Compress to weigh tablets. If necessary, these tablets may be coated with sugar or a film. (3) Granules Compound of Example 18 10 mg Lactose 839 mg Corn starch 150 mg Hydroxypropylcellulose 1 mg Total 1000 mg Powder of each component shown above is mixed well, moistened with pure water, and basket type granules Granulate and dry to obtain granules.
【００７８】[0078]
【発明の効果】本発明のフェニルプロピオン酸誘導体、
その薬理上許容される塩又はその薬理上許容されるエス
テルは、高脂血症、高血糖症、耐糖能不全状態、インス
リン抵抗性非耐糖能不全状態、高血圧症、骨粗鬆症、膵
炎、糖尿病合併症、動脈硬化症、白内障、妊娠糖尿病、
多嚢胞卵巣症候群、炎症性疾患、乾癬、喘息、動脈硬化
症、自己免疫疾患等の治療剤及び／又は予防剤として有
用である。The phenylpropionic acid derivative of the present invention,
The pharmacologically acceptable salt or the pharmacologically acceptable ester is hyperlipidemia, hyperglycemia, impaired glucose tolerance, insulin-resistant nonglucose intolerance, hypertension, osteoporosis, pancreatitis, diabetic complications , Arteriosclerosis, cataract, gestational diabetes,
It is useful as a therapeutic and / or prophylactic agent for polycystic ovary syndrome, inflammatory diseases, psoriasis, asthma, arteriosclerosis, autoimmune diseases and the like.
【００７９】また、本発明のフェニルプロピオン酸誘導
体その薬理上許容される塩又はその薬理上許容されるエ
ステルは、優れた血中トリグリセリド降下作用を示す。The phenylpropionic acid derivative of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof exhibits an excellent blood triglyceride lowering action.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｐ 3/06 Ａ６１Ｐ 3/06 9/10 9/10 １０１ １０１ 17/00 17/00 19/10 19/10 27/06 27/06 29/00 １０１ 29/00 １０１ 37/00 37/00 37/08 37/08 Ｃ０７Ｄ 213/53 Ｃ０７Ｄ 213/53 213/61 213/61 213/65 213/65 Ｃ０７Ｆ 7/08 Ｃ０７Ｆ 7/08 Ｋ (72)発明者 藤田 岳 東京都品川区広町１丁目２番58号 三共株 式会社内 (72)発明者 藤原 俊彦 東京都品川区広町１丁目２番58号 三共株 式会社内 Ｆターム(参考） 4C055 AA01 BA02 BA30 BB15 CA01 CA02 CA39 CA42 DA01 4C086 AA01 AA03 BC17 MA04 MA35 MA37 MA52 NA14 ZA33 ZA36 ZA45 ZA70 ZA89 ZA96 ZB13 ZB15 ZC33 ZC35 4C206 AA01 AA03 DA21 HA08 KA01 MA04 MA55 MA57 MA72 NA14 ZA36 ZA45 ZA70 ZA89 ZA96 ZB07 ZB13 ZB15 ZC33 ZC35 4H006 AA01 AB20 4H049 VN01 VP01 VQ02 VQ19 VR24 VU06 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification symbol FI Theme coat ゛ (Reference) A61P 3/06 A61P 3/06 9/10 9/10 101 101 17/00 17/00 19/10 19/19 / 10 27/06 27/06 29/00 101 29/00 101 37/00 37/00 37/08 37/08 C07D 213/53 C07D 213/53 213/61 213/61 213/65 213/65 C07F 7 / 08 C07F 7/08 K (72) Inventor Takeshi Fujita 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Toshihiko Fujiwara 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo F-term in stock company (reference) 4C055 AA01 BA02 BA30 BB15 CA01 CA02 CA39 CA42 DA01 4C086 AA01 AA03 BC17 MA04 MA35 MA37 MA52 NA14 ZA33 ZA36 ZA45 ZA70 ZA89 ZA96 ZB13 ZB15 ZC33 ZC35 4C206 AA01 MA12 MA ZA45 ZA70 ZA89 ZA96 ZB07 ZB13 ZB15 ZC33 ZC35 4H006 AA01 AB 20 4H049 VN01 VP01 VQ02 VQ19 VR24 VU06
Claims (8)
数１乃至６個の直鎖若しくは分岐鎖のアルキル基、炭素
数１乃至６個の直鎖若しくは分岐鎖のアルコキシ基又は
ハロゲン原子を示し、Ｒ2は炭素数１乃至６個の直鎖若
しくは分岐鎖のアルキル基、炭素数１乃至６個の直鎖若
しくは分岐鎖のアルコキシ基又はハロゲン原子を示
す。）で表わされる化合物又はその薬理上許容される塩
若しくはエステル。1. A compound represented by the following general formula (I): (Wherein X represents CH or N, R 1 is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, or A compound represented by a halogen atom, and R 2 represents a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, or a halogen atom. Or a pharmacologically acceptable salt or ester thereof.
子、炭素数１乃至６個の直鎖若しくは分岐鎖のアルコキ
シ基又はハロゲン原子である化合物。3. The compound according to claim 1, wherein R 1 is a hydrogen atom, a linear or branched alkoxy group having 1 to 6 carbon atoms or a halogen atom.
である化合物。4. The compound according to claim 1, wherein R 1 is a hydrogen atom.
乃至６個の直鎖若しくは分岐鎖のアルキル基又はハロゲ
ン原子である化合物。5. The method according to claim 1, wherein R 2 has 1 carbon atom.
A compound having from 6 to 6 linear or branched alkyl groups or halogen atoms.
容される塩。6. A pharmacologically acceptable salt of the compound according to claim 1.
容されるエステル。7. A pharmacologically acceptable ester of the compound according to claim 1.
(2-ピリジル)フェニル]エチリデン]アミノオキシ]エト
キシ]フェニル]プロピオン酸、3-[4-[2-[[1-(4'-フルオ
ロ-4-ビフェニリル)エチリデン]アミノオキシ]エトキ
シ]フェニル]-2-(4-フルオロフェノキシ)プロピオン
酸、(S)-2-(4-メチルフェノキシ)-3-[4-[2-[[1-(4-ビフ
ェニリル)エチリデン]アミノオキシ]エトキシ]フェニ
ル]プロピオン酸、(S)-3-[4-[2-[[1-[4-(2-ピリジル)フ
ェニル]エチリデン]アミノオキシ]エトキシ]フェニル]-
2-(4-メチルフェノキシ)プロピオン酸、(S)-3-[4-[2-
[[1-(4-ビフェニリル)エチリデン]アミノオキシ]エトキ
シ]フェニル]-2-(4-t-ブチルフェノキシ)プロピオン
酸、(S)-2-(4-t-ブチルフェノキシ)-3-[4-[2-[[1-[4-(2
-ピリジル)フェニル]エチリデン]アミノオキシ]エトキ
シ]フェニル]プロピオン酸、(S)-3-[4-[2-[[1-(4-ビフ
ェニリル)エチリデン]アミノオキシ]エトキシ]フェニ
ル]-2-(4-フルオロフェノキシ)プロピオン酸、(S)-2-(4
-フルオロフェノキシ)-3-[4-[2-[[1-(4'-メトキシ-4-ビ
フェニリル)エチリデン]アミノオキシ]エトキシ]フェニ
ル]プロピオン酸、若しくは、(S)-2-(4-フルオロフェノ
キシ)-3-[4-[2-[[1-[4-(2-ピリジル)フェニル]エチリデ
ン]アミノオキシ]エトキシ]フェニル]プロピオン酸、又
はその薬理上許容される塩若しくはエステル。(8) 2- (4-chlorophenoxy) -3- [4- [2-[[1- [4-
(2-pyridyl) phenyl] ethylidene] aminooxy] ethoxy] phenyl] propionic acid, 3- [4- [2-[[1- (4′-fluoro-4-biphenylyl) ethylidene] aminooxy] ethoxy] phenyl] 2- (4-fluorophenoxy) propionic acid, (S) -2- (4-methylphenoxy) -3- [4- [2-[[1- (4-biphenylyl) ethylidene] aminooxy] ethoxy] phenyl ] Propionic acid, (S) -3- [4- [2-[[1- [4- (2-pyridyl) phenyl] ethylidene] aminooxy] ethoxy] phenyl]-
2- (4-methylphenoxy) propionic acid, (S) -3- [4- [2-
[[1- (4-Biphenylyl) ethylidene] aminooxy] ethoxy] phenyl] -2- (4-t-butylphenoxy) propionic acid, (S) -2- (4-t-butylphenoxy) -3- [ 4- [2-[[1- [4- (2
-Pyridyl) phenyl] ethylidene] aminooxy] ethoxy] phenyl] propionic acid, (S) -3- [4- [2-[[1- (4-biphenylyl) ethylidene] aminooxy] ethoxy] phenyl] -2- (4-Fluorophenoxy) propionic acid, (S) -2- (4
-Fluorophenoxy) -3- [4- [2-[[1- (4'-methoxy-4-biphenylyl) ethylidene] aminooxy] ethoxy] phenyl] propionic acid or (S) -2- (4- Fluorophenoxy) -3- [4- [2-[[1- [4- (2-pyridyl) phenyl] ethylidene] aminooxy] ethoxy] phenyl] propionic acid, or a pharmaceutically acceptable salt or ester thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001285989A JP2002167371A (en) | 2000-09-21 | 2001-09-20 | Phenylpropionic acid derivative |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000286495 | 2000-09-21 | ||
| JP2000-286495 | 2000-09-21 | ||
| JP2001285989A JP2002167371A (en) | 2000-09-21 | 2001-09-20 | Phenylpropionic acid derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2002167371A true JP2002167371A (en) | 2002-06-11 |
Family
ID=26600387
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2001285989A Pending JP2002167371A (en) | 2000-09-21 | 2001-09-20 | Phenylpropionic acid derivative |
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| Country | Link |
|---|---|
| JP (1) | JP2002167371A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007503468A (en) * | 2003-05-19 | 2007-02-22 | アイアールエム・リミテッド・ライアビリティ・カンパニー | Immunosuppressive compounds and compositions |
-
2001
- 2001-09-20 JP JP2001285989A patent/JP2002167371A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007503468A (en) * | 2003-05-19 | 2007-02-22 | アイアールエム・リミテッド・ライアビリティ・カンパニー | Immunosuppressive compounds and compositions |
| JP2011012069A (en) * | 2003-05-19 | 2011-01-20 | Irm Llc | Immunosuppressant compound and composition |
| US7939519B2 (en) | 2003-05-19 | 2011-05-10 | Novartis Ag | Immunosuppresant compounds and compositions |
| JP4700616B2 (en) * | 2003-05-19 | 2011-06-15 | アイアールエム・リミテッド・ライアビリティ・カンパニー | Immunosuppressive compounds and compositions |
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