MXPA01012653A - SUBSTITUTED PHENYLPROPIONIC ACID DERIVATIVES AS AGONISTS TO HUMAN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)a - Google Patents
SUBSTITUTED PHENYLPROPIONIC ACID DERIVATIVES AS AGONISTS TO HUMAN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)aInfo
- Publication number
- MXPA01012653A MXPA01012653A MXPA/A/2001/012653A MXPA01012653A MXPA01012653A MX PA01012653 A MXPA01012653 A MX PA01012653A MX PA01012653 A MXPA01012653 A MX PA01012653A MX PA01012653 A MXPA01012653 A MX PA01012653A
- Authority
- MX
- Mexico
- Prior art keywords
- group
- phenyl
- pharmaceutically acceptable
- derivatives
- methoxy
- Prior art date
Links
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical class OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 title claims description 11
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 title claims description 11
- 239000000556 agonist Substances 0.000 title description 5
- 150000004677 hydrates Chemical class 0.000 claims abstract description 28
- 239000011780 sodium chloride Substances 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 55
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 36
- -1 benzylthio group Chemical group 0.000 claims description 34
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 24
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000003921 oil Substances 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000001294 propane Substances 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 235000015107 ale Nutrition 0.000 claims 14
- XMIIGOLPHOKFCH-UHFFFAOYSA-N Phenylpropanoic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 7
- 235000019260 propionic acid Nutrition 0.000 claims 5
- 125000004429 atoms Chemical group 0.000 claims 3
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 2
- PJFGOJGZLXDMHN-UHFFFAOYSA-N 2-[[4-methoxy-3-[(4-phenoxyphenyl)methylcarbamoyl]phenyl]methyl]pentanoic acid Chemical compound CCCC(C(O)=O)CC1=CC=C(OC)C(C(=O)NCC=2C=CC(OC=3C=CC=CC=3)=CC=2)=C1 PJFGOJGZLXDMHN-UHFFFAOYSA-N 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 239000002307 peroxisome proliferator activated receptor agonist Substances 0.000 claims 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 abstract description 20
- 108010028924 PPAR alpha Proteins 0.000 abstract description 18
- 102000024367 PPAR alpha Human genes 0.000 abstract description 18
- 210000004369 Blood Anatomy 0.000 abstract description 11
- 239000008280 blood Substances 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 11
- 150000002632 lipids Chemical class 0.000 abstract description 11
- 229940107161 Cholesterol Drugs 0.000 abstract description 10
- 230000027455 binding Effects 0.000 abstract description 10
- 235000012000 cholesterol Nutrition 0.000 abstract description 7
- 102000005962 receptors Human genes 0.000 abstract description 5
- 108020003175 receptors Proteins 0.000 abstract description 5
- 239000003446 ligand Substances 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 230000003389 potentiating Effects 0.000 abstract description 3
- 230000001264 neutralization Effects 0.000 abstract description 2
- 239000003614 peroxisome proliferator Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- 238000004458 analytical method Methods 0.000 description 27
- 238000003756 stirring Methods 0.000 description 26
- 239000000203 mixture Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical class ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- 239000012267 brine Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 101700067048 CDC13 Proteins 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 235000014113 dietary fatty acids Nutrition 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 229940079593 drugs Drugs 0.000 description 9
- 239000000194 fatty acid Substances 0.000 description 9
- 150000004665 fatty acids Chemical class 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- 150000003626 triacylglycerols Chemical class 0.000 description 8
- 206010062060 Hyperlipidaemia Diseases 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 230000001603 reducing Effects 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 230000001225 therapeutic Effects 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- QPLDLSVMHZLSFG-UHFFFAOYSA-N copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 4
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 206010003210 Arteriosclerosis Diseases 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N Ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 210000004185 Liver Anatomy 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 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
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 230000037356 lipid metabolism Effects 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 230000003287 optical Effects 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 229940096700 plain lipid modifying drugs Fibrates Drugs 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- CUYUPLKTWHWPQY-UHFFFAOYSA-N 2-benzyl-1,3-oxazole Chemical compound C=1C=CC=CC=1CC1=NC=CO1 CUYUPLKTWHWPQY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 229940040692 Lithium Hydroxide Monohydrate Drugs 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 108060001084 Luciferase family Proteins 0.000 description 2
- 230000036740 Metabolism Effects 0.000 description 2
- 108010044210 PPAR-beta Proteins 0.000 description 2
- 210000002824 Peroxisome Anatomy 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M Sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 210000001789 adipocyte Anatomy 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000035786 metabolism Effects 0.000 description 2
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organs Anatomy 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reduced Effects 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 210000001519 tissues Anatomy 0.000 description 2
- 102000003995 transcription factors Human genes 0.000 description 2
- 108090000464 transcription factors Proteins 0.000 description 2
- WLOUCHKFBGGNEB-GXIKJMEPSA-N (5Z,9E,11Z,14Z,17Z)-8-hydroxyicosa-5,9,11,14,17-pentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C=C/C(O)C\C=C/CCCC(O)=O WLOUCHKFBGGNEB-GXIKJMEPSA-N 0.000 description 1
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- VHJLVAABSRFDPM-UHFFFAOYSA-N 1,4-dimercaptobutane-2,3-diol Chemical compound SCC(O)C(O)CS VHJLVAABSRFDPM-UHFFFAOYSA-N 0.000 description 1
- IATNZRYVIRYKDJ-UHFFFAOYSA-N 1-(chloromethyl)-4-phenoxybenzene Chemical compound C1=CC(CCl)=CC=C1OC1=CC=CC=C1 IATNZRYVIRYKDJ-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-Aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
- FLMKUNLIBWIRJQ-UHFFFAOYSA-N 2-methoxy-5-nitro-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound COC1=CC=C([N+]([O-])=O)C=C1C(=O)NCC1=CC=C(C(F)(F)F)C=C1 FLMKUNLIBWIRJQ-UHFFFAOYSA-N 0.000 description 1
- XXUNIGZDNWWYED-UHFFFAOYSA-N 2-methylbenzamide Chemical compound CC1=CC=CC=C1C(N)=O XXUNIGZDNWWYED-UHFFFAOYSA-N 0.000 description 1
- ZVAYUUUQOCPZCZ-UHFFFAOYSA-N 4-(diethoxyphosphorylmethyl)aniline Chemical compound CCOP(=O)(OCC)CC1=CC=C(N)C=C1 ZVAYUUUQOCPZCZ-UHFFFAOYSA-N 0.000 description 1
- HEJIYTVOUUVHRY-UHFFFAOYSA-N 4-benzyl-3-butanoyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N(C(=O)CCC)C1CC1=CC=CC=C1 HEJIYTVOUUVHRY-UHFFFAOYSA-N 0.000 description 1
- OWJMCUCRHSEHEX-ZVAWYAOSSA-N 5-[2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-carbonyl]butyl]-2-methoxybenzoic acid Chemical compound C([C@@H]1CC=2C=CC=CC=2)OC(=O)N1C(=O)C(CC)CC1=CC=C(OC)C(C(O)=O)=C1 OWJMCUCRHSEHEX-ZVAWYAOSSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N 5-flurouricil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- TTZPGMWNBQKNKX-UHFFFAOYSA-M 5-formyl-2-methoxybenzoate Chemical compound COC1=CC=C(C=O)C=C1C([O-])=O TTZPGMWNBQKNKX-UHFFFAOYSA-M 0.000 description 1
- NLUNAYAEIJYXRB-VYOQERLCSA-N 8(S)-HETE Chemical compound CCCCC\C=C/C\C=C/C=C/[C@@H](O)C\C=C/CCCC(O)=O NLUNAYAEIJYXRB-VYOQERLCSA-N 0.000 description 1
- 210000000593 Adipose Tissue, White Anatomy 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-N Arachidonic acid Chemical class CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 1
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N Benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N Benzylformate Chemical compound O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 229940001981 Carac Drugs 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N Carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000005751 Copper oxide Substances 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 229940088598 Enzyme Drugs 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 208000001130 Gallstone Diseases 0.000 description 1
- 206010019233 Headache Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000006575 Hypertriglyceridemia Diseases 0.000 description 1
- 101700072148 IAA2 Proteins 0.000 description 1
- 210000003734 Kidney Anatomy 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- VNYSSYRCGWBHLG-AMOLWHMGSA-N Leukotriene B4 Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC(O)=O VNYSSYRCGWBHLG-AMOLWHMGSA-N 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 229940040461 Lipase Drugs 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 229940017219 METHYL PROPIONATE Drugs 0.000 description 1
- MPCRDALPQLDDFX-UHFFFAOYSA-L Magnesium perchlorate Chemical compound [Mg+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O MPCRDALPQLDDFX-UHFFFAOYSA-L 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N N,N-dimethyl-2H-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-hydroxy-Succinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 108009000118 Nuclear Receptors Proteins 0.000 description 1
- ILUJQPXNXACGAN-UHFFFAOYSA-M O-methylsalicylate Chemical compound COC1=CC=CC=C1C([O-])=O ILUJQPXNXACGAN-UHFFFAOYSA-M 0.000 description 1
- CBRWKHMYFZHJPD-UHFFFAOYSA-M OCC=1C=CC(=C(C(=O)[O-])C=1)OC Chemical compound OCC=1C=CC(=C(C(=O)[O-])C=1)OC CBRWKHMYFZHJPD-UHFFFAOYSA-M 0.000 description 1
- 101710005767 POLR3C Proteins 0.000 description 1
- 101700059544 PTGR1 Proteins 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N Phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 206010038428 Renal disease Diseases 0.000 description 1
- 241000242739 Renilla Species 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N Sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 102000007451 Steroid Receptors Human genes 0.000 description 1
- 108010085012 Steroid Receptors Proteins 0.000 description 1
- 206010042602 Supraventricular extrasystoles Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 210000003462 Veins Anatomy 0.000 description 1
- PRDBLLIPPDOICK-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=C(C(F)(F)F)C=C1 PRDBLLIPPDOICK-UHFFFAOYSA-N 0.000 description 1
- BBWWIJXZFAJOBL-UHFFFAOYSA-K [O-]C(=O)C1=CC=CO1.[O-]C(=O)C1=CC=CO1.[O-]C(=O)C1=CC=CO1.CCCC[B+3]CCCC Chemical compound [O-]C(=O)C1=CC=CO1.[O-]C(=O)C1=CC=CO1.[O-]C(=O)C1=CC=CO1.CCCC[B+3]CCCC BBWWIJXZFAJOBL-UHFFFAOYSA-K 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical class [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229940053200 antiepileptics Fatty acid derivatives Drugs 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 201000001320 atherosclerosis Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- NIIJGWQZBUWENM-UHFFFAOYSA-N benzyl 5-(2-ethoxycarbonylbut-1-enyl)-2-methoxybenzoate Chemical compound CCOC(=O)C(CC)=CC1=CC=C(OC)C(C(=O)OCC=2C=CC=CC=2)=C1 NIIJGWQZBUWENM-UHFFFAOYSA-N 0.000 description 1
- WVXXIMFZZMTCHZ-UHFFFAOYSA-N benzyl 5-(acetyloxymethyl)-2-methoxybenzoate Chemical compound COC1=CC=C(COC(C)=O)C=C1C(=O)OCC1=CC=CC=C1 WVXXIMFZZMTCHZ-UHFFFAOYSA-N 0.000 description 1
- KDVSTVDDYSBDIK-HVNPKJTBSA-N benzyl 5-[2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-carbonyl]-1-hydroxybutyl]-2-methoxybenzoate Chemical compound C([C@@H]1CC=2C=CC=CC=2)OC(=O)N1C(=O)C(CC)C(O)C(C=1)=CC=C(OC)C=1C(=O)OCC1=CC=CC=C1 KDVSTVDDYSBDIK-HVNPKJTBSA-N 0.000 description 1
- VCFZBJOTEWVWPM-UHFFFAOYSA-N benzyl 5-formyl-2-methoxybenzoate Chemical compound COC1=CC=C(C=O)C=C1C(=O)OCC1=CC=CC=C1 VCFZBJOTEWVWPM-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000001925 catabolic Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 210000004027 cells Anatomy 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 229910000431 copper oxide Inorganic materials 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- 150000002066 eicosanoids Chemical class 0.000 description 1
- 230000002255 enzymatic Effects 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- BUSYVYQBCHAZDE-UHFFFAOYSA-N ethyl 2-ethylsulfanyl-3-[4-methoxy-3-[[4-(trifluoromethyl)phenyl]methylcarbamoyl]phenyl]propanoate Chemical compound CCOC(=O)C(SCC)CC1=CC=C(OC)C(C(=O)NCC=2C=CC(=CC=2)C(F)(F)F)=C1 BUSYVYQBCHAZDE-UHFFFAOYSA-N 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- 230000001605 fetal Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 150000004688 heptahydrates Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000010189 intracellular transport Effects 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 102000003835 leukotriene receptors Human genes 0.000 description 1
- 108090000146 leukotriene receptors Proteins 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 102000004882 lipase Human genes 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 108090001060 lipase Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-L lithium;dihydroxide Chemical compound [Li+].[OH-].[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-L 0.000 description 1
- 201000009673 liver disease Diseases 0.000 description 1
- 200000000011 liver disorder Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 media Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-M methanol;chloride Chemical compound [Cl-].OC FUKUFMFMCZIRNT-UHFFFAOYSA-M 0.000 description 1
- DUOQWTZZSYTGOS-UHFFFAOYSA-N methyl 3-[4-methoxy-3-[[4-(trifluoromethyl)phenyl]methylcarbamoyl]phenyl]-2,2-dimethylpropanoate Chemical compound COC(=O)C(C)(C)CC1=CC=C(OC)C(C(=O)NCC=2C=CC(=CC=2)C(F)(F)F)=C1 DUOQWTZZSYTGOS-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 210000002569 neurons Anatomy 0.000 description 1
- 101700075574 nhr-8 Proteins 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000004672 propanoic acids Chemical class 0.000 description 1
- 230000000069 prophylaxis Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 102000027730 retinoid hormone receptors Human genes 0.000 description 1
- 108091008001 retinoid hormone receptors Proteins 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 102000004217 thyroid hormone receptors Human genes 0.000 description 1
- 108090000721 thyroid hormone receptors Proteins 0.000 description 1
- 230000035916 transactivation Effects 0.000 description 1
- 230000002103 transcriptional Effects 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
Abstract
Novel substituted phenylpropionic acid derivatives capable of binding as a ligand to human peroxisome proliferator-activated receptora(PPARa) to thereby activate the receptor and thus showing a potent effect of lowering blood lipid (cholesterol and neutral lipid) levels. Substituted phenylpropionic acid derivatives represented by general formula (1), pharmaceutically acceptable salts thereof and hydrates of the same, and process for producing the same.
Description
^ \ 2id3
/ >
DERIVATIVES OF SUBSTITUTE PHENYLPROPANIC ACID
USEFUL AS RECEPTOR AGONISTS ACTIVATED WITH THE
PROLIFERATOR OF HUMAN PEROXPHAMY (PPARa)
FIELD OF THE INVENTION
[0001] The present invention relates to substitute f-e: propanoic acid derivatives, effective for therapy of the abnormality of the
lipid metabolism, useful as agonists of the peroxisome proliferator activated receptor of human (abbreviated as PPAR), in particular, as agonists for the isoform of human PPARa, its addition salts and its hydrates, methods for preparing them , and medicinal compositions containing these compounds.
BACKGROUND OF THE INVENTION
Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that belong to the superfamily of nuclear receptors, such as the steroid receptor, the retinoid receptor,
the thyroid receptor, etc. To date, they have
identified three isoforms (type a, type ß (od and type?) that present a different histological distribution in humans and in various animal species (Proc. Nati. Acád. Sci., 1992, 8_9, 4653). , PPARa is distributed in the liver, kidney, etc., with a high catabolic capacity with respect to fatty acids and in particular high expression in the liver is recognized, Endocrinology, 1995 137 354) which controls positively or negative the expressions of the relevant genes for the metabolism and the intracellular transport of the fatty acids (for example, the enzyme acetyl-Co.A synthetase, the protein of binding to fatty acids and the lipase for lipoproceins) and the genes for apol ipoproteíñas (AI, AI I, CIII) relevant to the metabolism of cholestero1 and neutral lipids. He
PPARβ is expressed ubiquitously in tissues or organs, including nerve cells. At present, the physiological importance of PPARβ is not yet understood. E PPAR? it is expressed in high form in adipocytes and is involved in the differentiation of adipocytes (J. Lipid Res., 1996, 3J7_, 907). In this way, each PPAR isoform plays a specific role in the
Particular organs and tissues In addition, it has been reiterated that mice with inhibited expression of PPARa have hypertriglyceridemia with aging and become obese because pr. mainly to the increase of white adipose tissue (J Biol. Chem., 1998, 273,
29577 hence the relevance between the activation of PPARa and the reduction of the action of lipids (cholesterol and triglycerides) in blood is strongly suggested. On the other hand, until now fibratc and statins have been widely used as therapeutic drugs for hyperlipidemia. However, fibrates have only a weak reducing effect on cholesterol, whereas statins have a weak reducing effect on lib = es fatty acids and triglycerides. In addition, with regard to fibrates, various adverse effects have been reported such as gastrointestinal damage, antema, headache, liver disorder, kidney disorder and gallstones. It is believed that the reason is due to the fact that fibrates have an extensive pharmacological function, hence the development of a therapeutic drug for hyperlipidemia is desired.
have a specific mechanism When considering the current situation of each of the conventional therapeutic drugs for hyperlipidemia, and the function on the lipid metabolism adjustment mechanisms and the relationship with the pathology of the hyperlipidemia of the transcription factor called
PPARa, which recently became clear, if a compound could be created that binds directly as a ligand of PPARa, in particular, PPARa of human and that can activate the PPARa of human, it is expected that the medicinal uses of it are as a compound that has the reducing effect of lipid: two (both cholesterol and triglycerides in blood due to a very specific mechanism.) For compounds that have an affinity for PPARa as ligands of PPARa, eicosanoids are reported in the HETE group (hydroxieicosatetranico acid) produced by oxidation with the cytochrome P-450, in particular 8-HETE, 8-HEPE, 'etc., in addition to LTB4 which is a metabolite of arachidonic acid (Proc. Nati Acad. Sci., 1997, 94, 312). However, these endogenous unsaturated fatty acid derivatives are
cycloalkyl or heneroaromatic ring, R- denotes an alkyl group, R4 indicates a hydrogen atom or an alkyl group, R6 indicates a hydrogen atom this could be connected to R9 to form a double bond, R7 indicates carboxyl group, a group acyl, an alkoxycarbonyl group which may have substituents, an alkyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, a group NHR8 or OR8, R8 denotes an acyl group which may have substituents or an alkoxycarbonyl group, R9 indicates a hydrogen atom, an alkyl group or an alkoxycarbonyl group, and R 10 inLdicates a hydrogen atom, an ammo group, an alkoxy group, an alkyl group, an aryloxy group or an aralkyloxy group. However, these compounds also have structure different from that of the compounds of the invention in the sense that the substituents on the benzene ring are of the disubstituted form at position 1 and position 4, nor is it disclosed that these compounds have the binding activity to PPARa of human or the activation function of transcription. As carboxylic acid derivatives with agonist effect on the leukotriene receptor,
Objectives that are solved by the invention The hyperlipidemia is a risk factor of atherosclerosis and, from a point of view of the prevention of arteriosclerosis disease, in particular, coronary artery sclerosis, the development is clinically desired of a therapeutic drug for miperl ipidemia that has effectiveness and a degree of safety.
BRIEF DESCRIPTION OF THE INVENTION
As a result of diligent studies focused on such a specific function on the lipid metabolism of human PPARa, directed to the erection of a structurally novel drug with efficacy and a high level of safety as a therapeutic drug for hyperlipidemia, the inventors have discovered that the novel substituted phenylpropanoic acid derivatives represented by the following general formula (1) have excellent binding activity to the human AERPP and transcriptional activation function and exhibit the lipid reducing effect, which leads to the
lower alkyl having 1 carbon atoms a group 2, 2 2-t ri f luoroet i lo, and this indicates a hydrogen atom in the case in which
R 'is an alkoxy group in Eerior having from 1 to 3 carbon atoms, a phenoxy group, a lower alkylthio group having 1 to 3 carbon atoms, a phenylthio group, a benzylthio group, and
• R denotes a lower alkoxy group having 1 to 3 carbon atoms, their salts and their hydrates
pharmaceutically acceptable. The salts of the 3 compounds represented
• by the general formula (1) in the invention are commonly used and metal salts, for example, alkali metal salts (eg salt), are mentioned.
of sodium, salt of LO pots, lithium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt etc.), aluminum salt, and other pharmaceutically acceptable salts. In addition, the compounds represented by the
General formula (1) in the invention sometimes include optical isomers based on the propandic acid portion. Such isomers and their mixtures are included in the field of the invention. The enantiomers can be prepared
ethecarbodi-imide, diethyl cyanofsulfate, phosphonic di-1-phenyl, carbonyldi-imidazole or the like
As the base, there may be mentioned, for example, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or an organic base such as pyridine or triethylamine. As the additive, there can be mentioned N-hydroxybenzotriazole, N-hydroxy succinimide, 4-dihydro-3-hydroxy-4-oxo-1, 2, 3-benzotriazine. The reaction can be carried out at a reaction temperature of
° C to 100 ° C, preferably 0 ° C to 50 ° C The reaction of the twenty-fourth procedure can be carried out under alkaline conditions. For alkaline conditions, lithium hydroxide or sodium hydroxide, a mixture of lithium hydroxide with hydrogen peroxide, or the like are used. The reaction can be carried out at a reaction temperature of -20 ° C to 100 ° C, preference 0 ° C to 50 ° C. As the administration form of the novel compounds of the invention, there may be mentioned for example, oral administration with tablet, capsule, granule, powder, inhaler, syrup or the like, or parenteral administration with
it was purified by chromatography on silica gel
(eluate n-hexane: ethyl acetate = 5: 1 v / v) to obtain 1.45g (74%) of ethyl (3-benzyloxycarbonyl-4-methoxyphenyl) -2- and ethyl acetate as an oil of yellow color Mass analysis m / z 368 (M +). Ethyl (3-benzyloxycarbonyl-4-methoxy phenyl) -2-ethylacrylate (4.00 g, 10.9 mmol) was dissolved in 200 ml of ethanol, 10% palladium on activated carbon (1.10 g) was added, and Hydrogenation was carried out at medium pressure for 3 hours at an initial pressure of 353 kE a. After completion of the reaction, the catalyst was filtered and the filtrate was concentrated to obtain 3.0 g (98%) of the title compound as an ac < color slightly yellow mass analysis m / z 280 (+ 1H-NMR (400MHz, CDC13) d 0.93 (3H, t, J =
7. 3 Hz), 1.18 (3H, t, J = 7.3 Hz), 1.52-1.59 (1H, m), 1.59-1.70 (1H, m), 2 55-2.61 (1H, m), 2.76 (1H, dd, J = 14.2, 6.4 Hz), 2 92 (1H, dd, J = 14.2, 6.4 Hz), 4.03-4.12 (2H, m), 4.06 (3H, s), 6.97 (1H, d, J = 8.8 Hz) , 7.38 (1H, dd, J = .8, 2.4 Hz), 8.00 (1H, d, J = 2.4 Hz).
ml 44.5 mmol) with stirring. Then, ethyl chlorocarbonate (1.86 ml, 19.5 mmol), dissolved in LO ml of dehydrated dichloromethane, was added dropwise. After stirring for 10 minutes at -10 ° C, 4 - (trifluoromethyl) -benzylamine (2.51 ml, 17.8 mmol), dissolved in 10 ml of dehydrated dichloromethane, was added dropwise. After stirring for 30 minutes at 10 ° C, the mixture was stirred for 7 hours at room temperature and then allowed to stand overnight, The reaction mixture was washed with aqueous citric acid solution, aqueous sodium bicarbonate solution and brine in sequence, then dried with anhydrous sodium sulfate and concentrated. The residue was recrystallized with a mixed solvent of n-hexane with ethyl acetate to obtain 7.I g (93%) of the intended compound as colorless crystals. Melting point: 77.5-79.5 ° C. Mass analysis S m / z 437 (M +). 1 H-NMR (400 MHz, CDC13) d 0.91 (3H, t, J =
7. 3 Hz), 1.18 (3H, t, J = 7.3 Hz), 1.51-1.69 (2H, m), 2.54-2.61 (1H, m), 2.75 (1H, dd, J = 13.7, 6.8 Hz), 2.92 (1H, dd, J = 1 l, 8.8 Hz), 3.92 (3H, s),
EXAMPLE 20 2-Ethyl-3- [4-methoxy-3- [N- [[4- (trifluoromethyl) phenyl] methyl] carbamoyl] phenyl] propane acid
2 | et i 1 - 3 - [4-methoxy-3 - [N - [[4- (tri-f-lumethyl-yl) -phenyl] -met-1-yl] -carbamoyl-1] phenyl] -propanoic acid ethyl ester (1.2 S g, 2.88 mmol, Example 7 ), 15 ml of ethanol and 1 ml of 1 mol / l aqueous solution of sodium hydroxide and, after stirring for 4 hours at 50 ° C, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, which was acidified with dilute hydrochloric acid. The precipitates produced were filtered, dried and then recrystallized with ethyl acetate to obtain 1.26 g (95: of the title compound as colorless prisms Melting point 144.5-146.5 ° C. Mass analysis m / z 409 (M +). Element analysis C2iH22F3N? 4 (409.40) Calculated: C, 61 1; H, 5.42; N, 3.42 Found: C, 6 48; H, 5.40; N, 3.41 XH-NMR (400 MHz, CDC13) d 0.96 (3H , t, J =
7. 3 Hz), 1.53-1.72 (2H, m), 2.59-2.66 (1H, m), 2.77
(1H, dd, J = 13.7, 6.8 H¿), 2.96 (1H, dd, J = 13.7, 8.3 Hz), 3.92 (3H, s), 4.73 (2H, d, J = 5.9 Hz),
acidified with dilute hydrochloric acid. Then, the precipitates were filtered and dried to obtain, in quantitative form, the title compound as milky white crystals. Mass analysis m / z 337 (M +
EXAMPLE 32 2-methoxy-3- [4-methoxy- - [N - [[4- (trifluoromethyl) phenyl] ethyl] carbamoi 1] ethyl phenylacrylate
Ethyl 2- (diethoxyphosphoryl) -2-methoxyacet ato (265 mg, 1.10 mmol) was dissolved in 3 ml of dehydrated tetrahydrofuran and potassium t-butoxide 123 mg, 1.10 mmol) was added with stirring and cooling with ice under an atmosphere. of argon, which was stirred for 30 minutes. Then, N- [[4- (trifluoromethyl) phenyl] met yl] -5-foxy-methyl-2-methoxybenzamide (33: mg 1.00 mmol) dissolved in ml of dehydrated tetrahydrofuran was added. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice water, which was extracted with ethyl acetate, washed with water and brine in sequence, then dried with anhydrous sodium sulfate and concentrated . The residue is
EXAMPLE REFERENCE 2 2-methoxy-5-nitro-N- [[4- (trifluoromethyl) phenyl] methyl] benzamide
The publicly known 2-methoxy-5-n-t-robenzoic acid (9.00 g, 45.7 mmoles) was dissolved [eg, De Paulis et al, J. Med. Chem., 1022 (1922)] in 450 ml of dichloromethane and, after adding triethylamine (8.11 ml, 58.4 mmoles) and ethyl chlorocarbonate (4.70 ml, 49.3 mmoles), the mixture was stirred for 45 minutes at room temperature. Then, 4-trifluoromethyl iloencylamina (9.59.54 mmol) was added dropwise, which was stirred for 30 minutes at room temperature. The reaction mixture was poured into water. The organic layer was separated, dried with anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate to obtain 12.58 g of the intended compound as a yellow powder. In addition, the filtrate was concentrated and recrystallized with ethyl acetate to obtain 2.13 g of the second crystals.
Total 14.6 g (91%). Analysis of more as m / z 354 (M +). 1 H-NMR (400 MHz, CDC13) d 4.09 (3H, s),
4. 75 (2H, d, J = 5.9 Hz, 7.11 (1H, d, J = 8.8 Hz),
7. 47 (2H, d, J = 7.8 Hz), 7.61 (2H, d, J = 7.8 Hz),
8. 05 (1H, brs), 8.36 (1H, dd, J = 8.8, 3.0 Hz),
9. 12 (1H, d, J = 3.0 Hz)
EXAMPLE 34 5-amino-2-methoxy-N- [[4- (trifluoromethyl) phenyl] methyl benzamide
I got zclarori 2-methoxy - 5 -nitro -N- [[4
(tri f luoromet i 1) -phenyl] met il] benzamide (14.6 g, 41.2 mmol) and 146 m of ethyl acetate and, after adding 10% on activated charcoal (2.6 g), the mixture was stirred for 5 hours at room temperature. The catalyst was filtered, washed with ethyl acetate, and the reaction mixture was co-concentrated. The residue was recrystallized with a mixed solvent of n-hexane with ethyl acetate to obtain 12.4 g (93% of the title compound as colorless crystals). Mass analysis m / z 324 (M + 1 H-NMR (400 MH CDC13) d 3.87 (3 H, s), 4.72 (2 H, d, J = 5.9 Hz), 6.80 (1 H, dd, J = 3.0 Hz), 6.83 (1H, d, J Hz), 7.46 (2H, d, J = 7.8 Hz), 7.59 (3H, m), and 43 (1H, brs!
EXAMPLE 35 Ethyl 2-bromo-3- [4-methoxy-3 [N- [[4- (trifluoromethyl) phenyl] ethyl] carbamoyl] phenyl] propanoate
-amino-2-methoxy -N- [[4
(trifluoromethyl) phenyl] methyl] benzamide (7.00 g, 21.6 mmoles 85 ml of acetone and 34 ml of methanol, which was cooled with ice) With stirring, 17.5 ml of 47% hydrobromic acid, sodium nitrite (1.65 g. g, 23.9 mmol) and 6.2 ml of water and the mixture was stirred for 10 minutes, then ethyl acrylate (13.4 ml, 128 mmol) and copper oxide (1) (416 mg, 2.91 mmol) were added at room temperature. After stirring for 30 minutes, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution, which was extracted with ethyl acetate.The extract was washed with brine, then dried with anhydrous magnesium sulfate and concentrated The residue was recrystallized with a mixed solvent of n-hexane with ethyl acetate to obtain 683 mg (71%) of the title compound as colorless crystals Mass analysis m / z 469 (M +). 1 H-NMR (400 MH z, CDC13) d 1.21-1.26 (6H,
m), 2.61-2.67 (2H, m), .96 (1H, dd, J = 14.2, 6.8 Hz), 3.18 (1H, dd, J = 4.2, 9.3 Hz), 3.53 (1H, dd,
J = 9.3, 6.8 Hz), 3.93 (3H, s), 4.10-4.19 (2H, m), 4.73 (2H, d, J = 5.9 Hz), 6.91 (1H, d, J = 8.3 Hz), 7.32 ( 1H, dd, J = 8.3, 2.4 Hz), 7.47 (2H, d, J = 7.8 Hz), 7.59 (2H, d, J = 7.8 Hz), 8.11 (1H, d, J = 2.4 Hz), 8.30 ( 1H, brs).
EXAMPLE 36 ethyl 2-ethylthio-3- [4-methoxy 3- [N- [[4- (trifluoromethyl) phenyl] methyl] carbamoyl] phenyl] propanoate
Bromo-3- [4-methoxy-3 - [N- [[4
(tri fluoromethyl) phenyl] me tyl] carbamoyl] phenyl] -propanoic acid ethyl ester (1.00 g, 2.05 mmol, example 37) and 56 ml of ethane 1 and, after adding sodium thioethoxide (268 mg, 2.55 mmol) with stirring, the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated, water was added, and the solution was extracted with ethyl acetate. The extract was washed with brine, then dried with anhydrous magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluate n-hexane: ethyl acetate = 2: 1 v / v) to obtain 3.4
s l
To the filtrate, the ual was washed with water and with brine, then it was echoed with anhydrous sodium sulfate and concentrated to obtain, in quantitative form, benzyl 5-formyl-2-methoxybenzoate. Mass analysis m / z 270 (M +) Melting point 5-59.5 ° C. Benzyl formate 1-2-methoxybenzoate (1.10 g, 4.07 min) and 30 ml of methanol were mixed and sodium borohydride (155 mg, 4.10 mmol) was added portionwise, stirring and cooling with ice. After stirring for 2 hours with cooling on ice, the reaction mixture was poured into water with ice and acidified with 1 mol / L hydrochloric acid, which was extracted with ethyl acetate. The extract was washed with water and with brine, then dried with anhydrous sodium sulfate and concentrated to obtain 1.11 g (99%) of benzyl 5-hydroxymethyl-1,2-methoxybenzoate (without further purification, this compound was used for the next reaction). Then, 5-hydroxymethyl-2-methoxybenzoate of benzyl and 100 ml of methylene chloride were mixed and, after adding pyridine (660 ml, 8.16 mmoles), anhydride or acetic acid (460 ml, 4.88 mmoles) and N, N - dimethylaminopyridine (25 mg, 0.205
mmoles) with stirring and cooling with ice, the mixture was stirred overnight. The reaction mixture was washed with 1 mol / L hydrochloric acid, aqueous sodium bicarbonate solution and brine, then dried with anhydrous sodium sulfate and concentrated to obtain 1.27 g (99%) of the title compound as an oil. colorless Mass analysis m / z 314 (M + XH-NMR (400 MHz, CDC13) d 2.08 (3H, s)
3. 91 (3H, s), 5.03 (2H, s), 5.35 (2H, s), 6.97 (1H, d, J = 3 Hz: 7.31-7 0 (6H, m), 7.83 (1H, d, J =
2. 4 Hz '
EXAMPLE 42 3- (3-benzyloxycarbonyl 4-methoxy phenyl-2,2-dimethyl-propanoate methyl)
Benzyl 5-acetoxymethyl-2-methoxybenzoate (630 mg, 2.00 mmol), methyl trimethyl-1-methylimethyl-ethoacetal (730 mg, 4.02 mmol) and 25 m of dehydrated methylene chloride were added and magnesium perchlorate was added. 45 mg, 0.202 mmol) under an argon atmosphere, which was stirred for 6 hours at room temperature. The reaction mixture was washed with water and
with brine, then dried with anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluate n-hexane: ethyl acetate = 8: 1 v / v) to obtain 131 mg. (18%) of the title compound as colorless crystals. Analysis of mass.s m / z 356 (M +). 1 H-NMR (400 MHI, CDCl 3) d 1.16 (6H, s),
2. 79 (2H 3.56 (3H, s) 3.88 (3H, 5.33 (2H,
(1H d, J = 8.8 Hz: 7.20 (1H, dd, J 2.4 Hz 7.30-7.47 (5H, m), 7.56 (1H, d, J =
2. 4 Hz)
EXAMPLE 43 3- (3-carboxy-4-methoxy phenyl) -2,2 -dimethyl methyl propionate
3- (3-Benzyloxycarbonyl-4-methoxy phenyl) -2,2-dimethyl-methyl-methoxide (310 mg, 0.870 mmol.) Was dissolved in ml of mixed solvent of ethanol with t and rahydrofuran at a ratio of 1. : 1, 10% palladium on activated charcoal (20 mg) was added, and hydrogenation was carried out at normal pressure for 5 hours. After completing the reaction, the catalyst was filtered and
dd, J = 8.3, 2.4 Hz), 7.47 (2H, d, J = 7.8 Hz), 7.59 (2H, d, J = 7.8 Hz), 7.99 (1H, d, J = 2.4 Hz), 8.29 (1H, brs).
EXAMPLE 45 3 - [4 -me toxy-3 - [N - [[4- (trifluoromethyl) phenyl] ethyl] carbamoyl] pheny1] -2,2-dimethylpropanoic acid
Using methyl 3 - [4-methoxy-3- [N- [[4- (trifluoromethyl) phenyl] methyl] carbamoyl] phenyl] -2,2-dimethyl propanoate (3 (i) 0 mg, 0.708 mmol; 47), ethanol (5 ml) and 10% aqueous solution of sodium hydroxide (2 ml) and carrying out the procedure similar to L example 22, 206 mg (90%) of the title compound were obtained as colorless crystals. Melting point 151.0-152.0 ° C Mass analysis m / z 409 (M + Analysis of the C2 iH22 F3N04 (4 0 9 .4 0 Calculated: C, 6 L .61; H, 5.42 N, 3.42 Found: C, 51.68; H, 5.45; N, 3.4; XH-NMR (400 MH¿, DMSO-d6) d 1.06 (6H, s),
2. 96 (2H, s), 3.88 (3HY S), 4.56 (2H, d, J = 6.4
Hz), 7.06 (1H, d, J = .8 Hz), 7.25 (1H, dd, J = 8.8, 2.4 Hz), 7.51-7.5! (2H, m), 7.70 (1H, d, J =
obtain 3.64 g (98%) of 1 title compound as a colorless oil. Analysis of masks m / z 247 (M "J
EXAMPLE 46 (+) -2-Ethyl-3- [4-jnetoxy-3- [N- [[4- (trifluoromethyl) phenyl] ethyl] carbamoyl] phenyl] propane acid
(S 4 -benzyl-3-butyryl-2-oxazolidinone (1.65 g, 6.68 mmol) was dissolved in 22 ml of dehydrated methylene chloride, which was cooled to -74 ° C under an argon atmosphere after adding triethylamine ( Mlll ml, 8.02 mmol), 1.0 mol / l solution of dibutylboron tri-furate in methylene chloride (7.35 ml, 7.35 mmol) was added dropwise in a lapse of 15 minutes, which was stirred for 30 mr. Then, after stirring for 50 minutes with cooling on ice, the mixture was cooled to -75 ° C. After this, 5-formyl-2-methoxybenzoate of benc Llo (1.81 g, 6.68 mmoles) dissolved in 56.5 ml of dehydrated methylene chloride in a laps D of 20 minutes.After stirring for 1.5 h at -75 ° C, the mixture was stirred for 2 hours c <by cooling on ice.
added a solution comprising: 30 ml of methanol, 16.7 ml of phosphate buffer solution and 7.3 ml of 30% aqueous hydrogen peroxide solution and the mixture was stirred for another 30 minutes at 0 ° C. The reaction mixture was poured into water, which was extracted with methylene chloride. The extract was washed with brine, then dried with anhydrous magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluate n-hexane: ethyl acetate = 3: 2 v / v) to obtain
1. 36 g (39%) of (4S) -3- [3- (3-benzyloxycarbonyl-4-methoxyphenyl) -2-ethyl-3-hydroxy-propioni 1] -4-benzyl-2-oxazole idinone. Analysis of plus s m / z 518 (M + l) +. Then, (4S) -3- [3- (3-benzyloxycarbonyl-4-methoxyphenyl) -2-ethyl-3-hydroxy-propionyl] -4-benzyl-2-oxazolidinone (1.35 g, 2.61 mmol) and ml of trifluoroacetic acid with ice cooling and triet i 1 silane (3.95 ml,
26. 1 mmol) in a laps) of 5 minutes. The mixture was stirred for 1 hour with cooling on ice, followed by stirring for 4 days at room temperature. The reaction mixture was concentrated and the residue was poured into aqueous hydroxide solution
sodium 0.5 mol / l, 3 or which was washed with ethyl acetate. The aqueous layer was acidified and extracted with methylene chloride. The extract was washed with brine, then dried with anhydrous magnesium sulfate and concentrated to obtain 1.34 g of (4S) -3- [3- (3-carboxy-4 -methoxy phenyl) -2- et lpropionyl] -4-benzyl-2-oxazole idinone crude as a yellow oil. This compound was used for the next reaction without p > Additional information. Crude (4S) -3- [3- (3-carboxy-4-methoxyphenyl) -2-ethylpropionyl] -4-benzyl-2-oxazolidinone (1.24 g), triethylamine (435 ml,
3. 13 mmol), ethyl chlorocarboxy (275 ml, 2.87 mmol), 4- (trifluoromethyl-1) benzylamine (686 mg, 3.92 mmol) and 33 ml of methylene chloride, and carrying out the procedure similar to example 7, gave 860 mg (E8%) of (4S) -3- [2-ethyl-3- [4-methoxy-3- [N - [[4- (trifluoromethyl) f-enyl] met-il] -carbamoi-1] phenyl] propioni 1] - 4 -benzyl-2-oxazole idinone as a colorless powder. Analysis of more, s m / z 568 (M +). 1 H-NMR (400 MHz, CDC13) d 0.98 (3H, t, J
7. 3 Hz), 1.58-1.65 (1H, m), 1.80-1.87 (1H, m), 2.71 (1H, dd, J = 13.2, 9.8 H z), 2.78 (1H, dd, J = 13.2,
6. 4 Hz), 3.00 (1H, dd, = 13.7, 8.3 Hz), 3.30 (1H,
dd, J = 13.7, 2.9 Hz), 3.92 (3H, s), 3.98-4.07 (3H, m), 4.61-4.67 (1H, m), 4.71 (2H, d, J = 5.9 Hz),
6. 90 (1H, d, J = 8.3 Hz), 7.20-7.37 (6H, m), 7.44
(2H, d, J = 7.8 Hz), l. l57 (2H, d, J = 7.8 Hz), 8.00
(1H, d, J = 2.5 Hz), 8.2 4 (1H, t, J = 5.9 Hz). (4S) -3- [2-Ethyl-3- [4-methoxy-3- [N- [[4- (trifluoromethyl) -phenyl] met yl] carbamoyl] phenyl] -propionyl] -4-benzyl was mixed - 2 -oxia zolidinone (860 mg, 1.51 mmol) with 8 ml of mixed solution of
tetrahydrofuran with water (4: 1 v / v), which was cooled with ice under an argon atmosphere. With
• stirring, 611 ml of 30% aqueous hydrogen peroxide solution was added within 2 minutes. This solution was added with 101 mg of
lithium hydroxide monohydrate dissolved in 2.7 ml of water in a period of 2 minutes. After stirring the mixture for 1 hr. with cooling on ice, sulfite of heptahydrate dissolved in 4 ml of water was added, and the mixture was stirred for 5 hours.
minutes at 0 ° C. The reaction mixture was poured into aqueous acid solution. hydrochloric acid at 5%, which was extracted with ethyl acetate. The extract was washed with brine, then dried with anhydrous magnesium sulfate and concentrated. The residue is
crystallized by adding ethyl acetate and n-hexane
to obtain 125 mg (20 of the title compound as colorless prisms) Melting point: 128.0-130.0 ° C Mass analysis m / z 409 (M +) Elemental analysis C2? H22F3N04 (409.40): Calculated: C, 6 tL. 61; H, 5.42; N, 3.42, Found: C, 61.48 H 5.40 N, 3.41 XH-NMR (400 MHz CDC13) d 0.96 (3H, t J = 7.3 Hz), 1.55-1.71 (2H, m 2.61-2.67 (1H, m), 2.77
1H, dd, J = 13.7, 6.4 Hz (1H, dd, J = 13.7
7. 8 Hz), 3.92 (3H, s), 4.73 (2H, d, J = 5.9 Hz), 6.90 (1H, d, J = 8.3 lic), 7.29 (1H, dd, J = 8.3, 2.4 Hz), 7.46 (2H, d, J = 8.3 Hz), 7.59 (2H, d, J = 8.3 Hz), 8.08 (1H, d, J = 2.4 Hz), 8.32 (1H, t, J = 5.9 Hz) Specific rotation [a ] D + 23 ° (C 0.4, MeOH)
Optical purity 88% e.e. (from analysis with HPLC using Chiral PAC AD).
EXAMPLES 47 and 48
Lps compounds listed in the
Table 6 in a limilar form to that indicated in example 1
57 4-CF3 rl-C4H9 OCH3 C2H5 465 M +) r 58 4 -OPh rl-C4H9 OCH3 C2H5 489 M +) 59 4-OCH2Ph p-C4H9 OCH3 C2H5 503 M +) 60 4-Ph n-C4H9 OCH3 C2H5 473 M + ) 61 2 -OPh C2H5 OCH3 C2H5 461 M +) 62 3 -OPh C2H5 OCH3 C2H5 461 +) 63 2 -OPh n-C3H7 OCH3 C2H5 475 MJ
64 3 -OPh n-C3H7 OCH3 C2H5 475 MJ
65 4-OPh (4-CH3) C2H5 OCH3 C2H5 475 M +) 66 4-OPh (3-CH3) C2H5 OCH3 C2H5 475 M +)
• 67 4-OPh (2-CH3) C2H5 OCH3 C2H5 475 M +) 68 4-OPh (4-Cl) C2H5 OCH3 C2H5 495 M +) 69 4-OPh (3-Cl) C2H5 OCH3 C2H5 495 M +) 70 4-OPh (4-F) C2H5 OCH3 C2H5 479 M +) 71 4-OPh (4-Br) C2H5 OCH3 C2H5 539 M +)
72 4-OPh (4-OCH3) C2H5 OCH3 C2H5 491 MJ
73 4-OPh (3-OCH3) C2H5 OCH3 C2H5 491 M +) 74 4-OPh (2-OCH3) C2H5 OCH3 C2H5 491 MJ
• 75 4-OPh (4-CH3) p-C3H7 OCH3 C2H5 489 M +) 76 4-OPh (3-CH3) n-C3H7 OCH3 C2H5 489 M +) 77 4-OPh (2-CH3) p-C3H7 OCH3 C2H5 489 M +) 78 4-OPh (3-Cl) n-C3H7 OCH3 C2H5 509 M +) 79 4-OPh (4-OCH3) n-C3H7 OCH3 C2H5 505 MJ
80 4-OPh (3-OCH 3) n-C 3 H 7 OCH 3 C 2 H 5 505 M +) 81 4-OPh (2-OCH 3) p-C 3 H 7 OCH 3 C 2 H 5 505 M +) 82 4-OPh (4-F) p-C 3 H 7 OCH 3 C 2 H 5 493 M +) 83 4-OPh (4-Br) rl-C3H7 OCH3 C2H5 553 M +) 84 4-OCF3 n-C3H7 OCH3 C2H5 467 M +)
• 85 4-CH3 n-C3H7 OCH3 C2H5 397 M +) 86 4-OCH3 n-C3H7 OCH3 C2H5 413 MJ
87 4-Ph (4-Cl) n-C3H7 OCH3 C2H5 493 M +) 88 4-Ph (4-CH3) r-C3H7 OCH3 C2H5 473 M +) 89 4-Ph (4-OCH3) n-C3H7 OCH3 C2H5 489 M +) 90 4-OCH2Ph (4-Cl) p-C3H7 OCH3 C2H5 523 M +) 91 4-OCH2Ph (4-CH3) n-C3H7 OCH3 C2H5 503 M +) 92 4-OPh (2-F) n-C3H7 OCH3 C2H5 493 M +) 93 4-OPh (2-OC2H5) p-C3H7 OCH3 C2H5 519 M +) 94 4-OPh (2-C2H5) p-C3H7 OCH3 C2H5 503 MJ
Example point fusion: Formula carac. Elemental analysis (%) CC) 107 4-OPh (4-CH3) C2H5 OCH3 126-127 C27H29N05 Cale. : C 72.46 H 6.53 N 3 13 Jan.: C 72.27 H 6.53 N 3 10
4-OPh (3-CH3) C2H5 OCH3 120-121 C27H29N05 Cale. : C 72.46 H 6.53 N 3 13 Jan.: C 72.47 H 6.48 N 3 10
109 4-OPh (2-CH3) C2H5 0CH3 142-143 C27H29N05 Cale. : C 72.46 H 6.53 N 3 13 Jan.: C 72.46 H 6.53 N 3 13
110 4-OPh (4-Cl) C2H5 0CH3 143-144 C26H26C1N05 Cale. : C 66.73 H 5.60 N 2 99 Jan. : C 66.52 H 5.64 N 2 97
111 4-OPh (3-Cl) C2H5 OCH3 131-132 C26H26C1N05 Cale. : C 66.73 H 5.60 N 2 99 Jan.: C 66.68 H 5.56 N 3 00
112 4-0Ph (4-F) C2H5 OCH3 137-139 C26H26FN05 Cale. : C 69.17 H 5.80 N 3 10 Jan.: C 69.09 H 5.85 N 3 12
113 4-OPh (4-Br) C2H5 OCH3 148-149 C26H26BrN05 Cale. : C 60.95 H 5.11 N 2.73 Jan .: C 61.02 H 5.09 N 2.78
114 4-OPh (4-OCH3) C2H5 0CH3 124-125 C2; H29N06 Cale. : C 69.96 H 6.31 N 3.02 Jan.: C 69.68 H 6.29 N 3.06
115 4-0Ph (3-0CH3) C2H5 OCH3 112-113 C27H29N06 Cale. : C 69.96 H 6.31 N 3.02 Jan.: C 69.75 H 6.25 N 3.04
116 -. 116 -0Ph (2-0CH3) C2H5 0CH3 124-125 C27H29NO6-l / 10 H20 Cale. C 69.69 H 6.33 N 3.01 Jan. C 69.53 H 6.32 N 2, 93
117 4-0Ph (4-CH3) n-C3H7 OCH3 139-141 C28H3jN05 Cale. C 72.86 H 6.77 N 3.03 Jan. C 72.63 H 6.78 N 3.10
118 4-OPh (3-CH3) n-C3H7 OCH3 102-103 C28H31NO5-l / 10 H20 Cale. C 72.58 H 6.79 N 3.02 Ene. C 72.41 H 6.82 N 3.02
119 4-OPh (2-CH3) p-C3H7 0CH3 114 C28H31N05 Cale. C 72.86 H 6.77 N 3.03 Jan. C 72.83 H 6.83 N 3.12
120 4-OPh (3-Cl) n-C3H7 OCH3 101-102 C27H28C1N05 Cale. C 67.28 H 5.86 N 2.91 Jan. C 67.23 H 5.80 N 2.90
121 4-OPh (4-OCH3) n-C3H7 OCH3 124-125 C28H31N06 Cale. C 70.42 H 6.54 N 2.93 Jan. C 70.36 H 6.57 N 2.99
122 4-OPh (3-OCH3) n-C3H7 OCH3 92-93 C28H31N06 Cale. C 70.42 H 6.54 N 2.93 Jan. C 70.13 H 6.64 N 2.87
123 4-OPh (2-OCH3) n-C3H7 0CH3 124-125 C28H31N06-1 / 10 H20 Cale. C 70.16 H 5.56 N 2.92 Jan. C 70.07 H 6.61 N 2.92
124 4-OPh (4-F) p-C3H7 0CH3 148-149 C27H28FN05 Cale. C 69.66 H 6.06 N 3.01 Jan. C 69.36 H 6.06 N 3.02
125 4-OPh (4-Br) rl-C3H7 0CH3 153-154 C27H28BrN05 Cale. C 61.60 H 5.36 N 2.66 Jan. C 61.57 H 5.31 N 2.70
126 4-OCF3 p-C3H7 OCH3 126-127 C22H24F3N05 Cale. C 60.13 H 5.51 N 3.19 Jan. C 59.86 H 5.50 N 3.16
7
(9.14 ml, 65.8 mmol) and pivaloyl chloride (8.07 ml, 65.6 mmol) with stirring and cooling with ice, which was then stirred for 1.5 hours at room temperature to synthesize the mixture acid anhydride derivative: o. On the other hand, in another vessel, potassium t-butoxide was mixed
(8.83 g, 78.7 mmol) and 88 ml of dehydrated tetrahydrofuran under an argon atmosphere was added by dripping (S) -4-benzyloxazole idin-2 -one (13.9 g, 78.7 mmol) dissolved in 70 ml of dehydrated tetrahydrofuran. . After completion of the dropwise addition, the mixture was stirred for 45 minutes. Then, the suspension of the previously synthesized mixed acid anhydride derivative was added dropwise, while filtering under an argon atmosphere. After completion of the dropwise addition, the reaction mixture was concentrated and then poured into water, which was extracted with ethyl acetate. The extract was washed with 5: hydrochloric acid: saturated sodium bicarbonate solution and brine in sequence, then dried with its anhydrous magnesium fate and concentrated. The residue was purified by chromatography on silica gel (eluate n-hexane: ethyl acetate 3: 2 v / v, then chloride
methanol: methanol = 15: 1 v / v) to obtain 15.2 g (41%) of the diastereomer mixture. To this mixture was added diisopropyl ether and ether, which was dissolved with heating, and then allowed to stand. The precipitated crystals were collected by filtration, washed with diisopropyl ether and then dried to obtain 5.62.
: of the compound intended as colorless crystals Mass analysis m / z 568 (M +)
EXAMPLE 161 Acid (S) - (+) -2-ethyl 1-3- [4-methoxy-3- [N - [[4- (tri fluoromethyl) phenyl] methyl] carbamoyl] phenyl] propane
It was dissolved [3 (2S), 4S] -3- [2-ethyl-3- [4-methoxy-3- [N - [[4- (trifluoromethyl) phenyl] met il] -carbamoyl] -f eni 1 ] propioni 1] -4-benz i loxazole idin-2-one (90.9 g, 0.160 m or is) in 802 ml of mixed solvent of tetrahydrofura not with water (4: 1 v / v), which was cooled with ice lowered an atmosphere of argon. With stirring, hydrogen peroxide was added dropwise to: 30% solution (63.7 ml, 0.630 mol) over a period of 5 minutes. After that,
Lithium hydroxide monohydrate (10.7 g, 0.256 mol) dissolved in 267 ml of water was added dropwise over a period of 5 minutes and the mixture was stirred for an additional 1 hour with cooling on ice to the reaction mixture was added, dripping, 64% scjdio bisulfite (102 g, 0.627 mol) dissolved in 401 ml of water The reaction mixture was concentrated, the residue was poured into ice with water, which was acidified by adding 5% hydrochloric acid, and then extracted with methylene chloride, the extract was washed with brine, then dried with anhydrous magnesium fate and concentrated.The residue was dissolved in ethyl acetate and n-hexane with heating and was left The irecipitated crystals were collected by filtration, dried, and a second quantity of crystals was obtained from the filtered solution, the first and the second crystals were combined, washed with mixed solvent of n-hexane with acetate. of ethyl (4: lv / v) in suspended state, and then dried to obtain 52.4 g (80%) of the intended compound as a colorless crystalline powder. Melting point: 128-130 ° C.
0
Mass analysis m / z 409 (M +) Elemental analysis C2? H22F3N04 (409.40 Calculated: C, 61.61; H, 5.42; N, 3.42 Found: C, 61.41; H, 5.44; N, 3.41 1H-NMR (400 MHz, CDC13) d 0.95 (3H, dd, J = 7.3, 7.3 Hz), 1.54-1.70 (2H, m), 2.58-2.65 (1H, m), 2.77 (1H, dd, J = 13.7, 6.3 Hz), 2.96 (1H, dd, J = 13.7, 8.3 Hz), 3.92 (3 H, s), 4.38 (1H, brs), 4.72
(2H, d, J = 5.9 Hz), 6.) 0 (1H, d, J = 8.3 Hz), 7.29
(1H, dd, J = 8.3, 2.4 Hz), 7.46 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J = 7 8 Hz), 8.07 (1H, d, J = 2.4 Hz), 8.34 (1H, t, J = 5.9 Hz). Specific rotation [a] 25 + 24 ° (C MeOH) Optical purity 99! e.e. (CHIRALI PAC AD 0.0046 x 0.25 m, eluate, n-hexane: i sopropanol: trifluoroacetic acid = 80: 20: 0.2, detection wavelength: 298 nm, column temperature: 30 ° C, flow velocity : 1.00 ml / min).
EXAMPLE 162 (R) -3- (1-valeroyl) -4-benzyloxazolidin-2 -one
An atmosphere of argon, potassium t-butoxide (2.47 g, 22.0 mmol) and 50 ml were mixed.
of dried tetrahydrofuran and added, dropwise, (R) -4-loxazole idin-2 -one (3.55 g, 20.0 mmol) in 30 ml of tetrahydrofuran dissolved with stirring and cooling with ice After stirring
minutes with cooling on ice, n-valeroyl chloride (2.60 ml,
21 mmol) dissolved in 20 ml of dehydrated tetrahydrofuran. After completing the addition by
After 10 drops, the mixture was stirred for 1 hour and aqueous solution was added to the reaction mixture.
• saturated with ammonium chloride, which was extracted with ethyl acetate. The extract was washed with water, saturated sodium bicarbonate solution and
Brine in sequence, then dried with anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on silica gel eluate n-hexane: ethyl acetate = 4: 1 v / v) to obtain 5.06 g (97%) of the intended compound as
a pale yellow oil. Mass analysis m / z 261 (M +).
EXAMPLE 163 benzyl 5-bromomethyl-2-methoxybenzoate
Benzyl 5-hydroxymethyl-2-methoxybenzoate was mixed (Patent Application No.
Hei 11-162235) 15.5 56.9 mmoles) and 300 ml of dehydrated ether were added dropwise, phosphorus tribromide (2.0 ml, 21.1 mmoles) with stirring and cooling with ice, which was stirred for an additional hour. To the reaction mixture, ice was added with water and the ether layer was separated. The ether layer was washed with water, saturated sodium bicarbonate solution and brine in sequence, then dried with anhydrous sodium sulfate and concentrated. The crystals obtained were recrystallized with di-isopropyl ether to obtain 12.7 g (66 g). %) of the compound intended as colorless prisms Analysis of mafeas m / z 334, 336 (M +!
EXAMPLE 164 [3 (2S), 4R] -3- [2-n-propi | 1-3- [4-methoxy-3- (benzyloxycarbonyl) phenyl] propionyl 1] -4-benzyloxazolidin-2 -one
Mixed (R) -3- (1-valeroyl) -4
benzyloxazole idin-2 -one (3.56 g, 13.6 mmol) and 70 ml of t et rahydrofurar.or dehydrated under an argon atmosphere, which was cooled to -78 ° C. With stirring, a 1 mol / L-solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (15.0 m 1, 15.0 mmol) was added dropwise. After completion of the dropwise addition, the mixture was stirred for 1 hour at -78 ° C and then a solution of benzyl bromometyl-2-methoxybenzoate (5.04 g, 15.0 mmol) in tetrahydrofuran (20) was added dropwise. ml). After completion of the dropwise addition, the mixture was stirred for 3 hours at -78 ° C, followed by stirring for 3 hours at a temperature between -35 and -40 ° C. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with water and brine in sequence, then dried with anhydrous sodium sulfate and concentrated. The residue was purified by cr < silica gel chromatography (eluate n-hexane: ethyl acetati = 4: 1 v / v) to obtain 6.11 g (87%) of 1 compound intended as a colorless oil. Mass analysis m / z 515 (M +).
EXAMPLE 16 5 [3 (2 S), 4 R] - 3 - [2-e t i l 3- [4-methoxy-3- (benzyloxycarbonyl) phenyl] propioni! 1] -4-benzyloxazolidin-2 -one
The title compound was obtained as a colorless oil in a similar manner to that of Example 5 Mass analysis m / z 501 (M +)
EXAMPLE 166 Acid [5 (2S, 4'R)] -2 methoxy-5 - [[2- (2-oxo-4-benzyloxazolidin-3-yl) carbonyl] pentyl] benzoic acid
•
[3 (2S), 4R] -3- [2-n-propyl-3- [4- 15-methoxy-3- (benzyloxycarbonyl) phenyl] propionyl] -4-benzylloxazole-2 was mixed. 20.9 g, 40.5 mmol), 2.00 g of 10% palladium on activated charcoal and 200 ml of ethyl acetate and the catalytic hydrogenation was carried out at an initial hydrogen pressure of
294 kPa. After completion of the reaction, the catalyst was filtered and washed with ethyl acetate. The reaction mixture and the washed material were combined and concentrated to obtain 17.2 g (100%) of the intended compound as an oil
gold incol.
Mass analysis m / z 425 (M +
EXAMPLE 167 Acid [5 (2S, 4'R)] - methoxy-5 - [[2- (2-oxo-4-benzyloxazolidin-3-yl) carbonyl] -butyl] -benzoic acid
The title compound was obtained as a colorless oil in a manner similar to that of Example 7. Mass analysis m / z 411 (M +)
EXAMPLE 168 [3 (2S), 4R] -3- [2-n-pro | pil-3- [4-methoxy-3- [N - [(4-phenoxy-phenyl) -methyl] -carbamoyl] -phenyl] -propionyl] - 4 benzyloxazole idin-2 -one
Bido [5 (2S, 4 'R)] -2-methoxy-5 was mixed
[[2- (2-oxo-4-benzyloxazolidin-3-yl) carbonyl] -pentyl] -benzoic acid (12.1 g, 28.4 mmol), triethylamine (10.0 mL, 71.7 mmol) and 200 mL of dichloromethane and added dropwise, ethyl chlorocarbonate (3.05 ml, 31.3 mmol) with stirring and cooling with ice, after stirring for 20 min at 0 ° C, 4-phenoxybenzyl hydrochloride was added portionwise (7.37
BIOLOGICAL ACTIVITY
EXAMPLE OF TEST 1
Transactivation test for the human peroxisome receptor activated with proliferator
PPARa) Cultured CHO cells were co-transfected in Dulbecco's modified Eagle medium containing 10% nonfat bovine fetal serum (FCS / DMEM), receptor plasmid expressing fused-protelin DNA-binding domain being the transcription of yeast with ligand-binding domain of PPARa of human type
(Biochemistry, 1993, 3_2, 15598) your reporter plasmid
(STRATAGENE Corp.), and Renilla luciferase plasmid
(Promega Corp.) as an internal reference standard with lipofectamine in serum-free state. After this, the test compound and (8S) -HETE were added as the control compound at 10% FCS / DMEM and both luciferase activities were measured after 24 hours, which were corrected with the internal reference standard . The results are shown in table 17.From these results it is demonstrated that the compounds of the invention have potent transcription activity for the activated receptor with
peroxisome proliferator a from human
EXAMPLE OF TRIAL 2
Unioi test to human peroxisome proliferator activated receptor (PPAR) a A plasmid expressing the 1 igand-PPARa binding domain protein from human ligated with the histidine tag (His hPPARa-LBD) was cultured by infection to cheri chi a col i
(JM-109) and the target protein was recovered and purified. 3 H] -5 - [(2,4-dioxot ia zol idin-5-yl) methyl] -2-methoxy-N - [[4- (trifluoromethyl) phenyl] -met i 1] benzamide (Amasham) was incubated. the test compound and
S) -HETE as the control computer for 45 minutes at room temperature at various concentrations together are the His-hPPARa-LBD protein in Tris 10 mmoles / 1 (pH 7.4) hydrochloride buffer solution containing 50 mmoles / 1 of potassium chloride and 10 mmoles / 1 of dithiothreitol. After the reaction, the amount of [3 H] -5 - [(2,4-dioxothiazole idin-5-yl) met il] -2-methoxy-N- [[4 - (trifluoromethyl) phenyl] met il was determined. ] benzamide using a ce flash counter in liquid, the results are shown in Table 17.
0.5% arabica, one day per day for four continuous days For the fed during the administration period, a modified diet rich in rucose (Oriental Yeast) was used.
After administering for 4 days, blood was collected from the vein of the tail and the n: Levels of triglyceride, total cholesterol and free fatty acids in blood were determined by the enzymatic method. The rate of reduction of triglycerides in the blood was calculated. blood, total cholesterol and free fatty acids, respectively, determining the proportion of a figure obtained by subtracting the average level of triglycerides in blood (or the average total cholesterol level) or the level of free fatty acids) from the dose group of the average triglyceride level < in blood (or the average total cholesterol level) or free fatty acid level) of the vehicle control group for the average level of blood triglycerides (or the average cholesterol level (total) or the level of fatty acids ibres) of the vehicle control group. The results are shown in table 18. As is evident from these results,
TABLE 1 9
Act Transcription volume Example EC50 (μmoles / 1) 174 0.024 178 0.094 179 0.0092
From these results, it is demonstrated that the compounds of the invention have a potent activity of tr: inscription for the receptor
to act on the prophylaxis of peroxisome
human
Results Starting from the results described above, the substituted phenylpropanoic acid derivative of the invention is a novel group of compounds having excellent binding activity.
to PPARa from human, transcription activity and
reductive action of blood lipids (cholesterol and lipids ne: other). With these compounds of the invention, starting from the fact cue they have activity
agonist on the PPARa of human, it can be said
that these are compounds, mentioned above, effective as drugs to reduce lipids,
in particular, drugs to reduce lipids for the liver, and drugs that suppress the advance of arteriosclerosis.
Claims (4)
- Derivatives of phenylatophanic acid are substituted by their pharmaceutically acceptable hydrates and hydrates according to claim 1, further characterized in that R1 is a benzyloxy group. 5. Derivatives of phenylpropanoic acid substituted its ales and pharmaceutically acceptable hydrates according to claim 1, further characterized in that R1 is a phenoxy group. 6. Derivatives of phenylapropanoic acid substituted for their ales and their pharmaceutically acceptable hydrates according to claim 1, further characterized in that R 2 is an ethyl group Derivatives of phenylapropanoic acid substituted its ales and its pharmaceutically acceptable hydrates in accordance with claim 1, further characterized in that R2 is a methoxy group. 8. Derivatives of substituted phenylpropanoic acid, their ales and their pharmaceutically acceptable hydrates according to claim 1, further characterized in that R2 is an n-propyl group
- Derivatives of the phenylpropanoic acid substituted their ales and their pharmaceutically acceptable hydrates according to claim 1 further characterized in that one of the compounds is 2-methoxy-3 - [4-methoxy-3 - [N- [[4- ( trifluoromethyl) phenyl] methyl] carbamoi 1] -phenyl] propanoic acid. 10. Derivatives of substituted phenylpropanoic acid, their oils and pharmaceutically acceptable hydrates according to claim 1, further characterized in that one of the compounds is 2-ethyl-3 - [4-methoxy-3 - [N- [[4- (trifluoromethyl) pheni]] met i 1] carbamoi 1] phenyl] -propanoic acid. 11. Derivatives of substituted phenylpropanoic acid, their pharmaceutically acceptable salts and hydrates according to claim 1, further characterized in that one of the compounds is 2-n-propyl-3 - [4-methoxy -3- [ N- [[4- (phenoxy) phenyl] methyl] carbamoyl] phenyl] -propanoic acid. 12. Derivatives of substituted phenylpropanoic acid, their ales and their pharmaceutically acceptable hydrates according to claim 1, further characterized in that lower having from 1 to 3 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group, a phenyl group which is unsubstituted or can have substituents, a phenoxy group which is unsubstituted or can have substituents or a benzyloxy group which is unsubstituted or may have substituents, R denotes a lower alkyl group having from 1 to 4 carbon atoms, a 2, 2, 2-trifluoromethyl group, a lower alkoxy group having from 1 to 3 carbon atoms, a phenoxy group, a lower alkylthio group having from 1 to 3 carton atoms, a phenylthio group or a benzylthio group, R3 denotes a hydrogen atom or a lower alkyl group having from 1 to 4 carbon atoms in the case of R2 when it is a lower alkyl group having from 1 to 4 carbon atoms or a group 2 J 2, 2 - t ri f luoroet i lo, and this indicates a hydrogen atom in the case in which R2 is a lower alkoxy group having 1 to 3 carbon atoms, a phenoxy group, a lower alkylthio group having 1 to 3 carbon atoms, a phenylthio group or a benzylthio group, and R 4 denotes a lower alkoxy group having 1 to3 carbon atoms, their pharmaceutically acceptable salts and hydrates, as ingredients wherein R1 denotes a lower alkyl group having from 1 to 4 carbon atoms, a lower alkoxy group having from 1 to 3 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group, a phenyl group which is unsubstituted or may have substituents, a phenoxy group which is unsubstituted or may have substituents or a benzyloxy group which is unsubstituted or may have substituents, R denotes a lower alkyl group having 3 | to 4 carbon atoms, a 2, 2, 2-trifluoroethyl group, a lower alkoxy group having from 1 to 3 carbon atoms, a phenoxy group, a lower alkylthio group having from 1 to 3 carbon atoms, phenylthio group or a benzylthio group, and R denotes a lower alkoxy group having from 1 to 3 carbon atoms 17.- A peroxisome proliferator activated receptor agonist of human (PPAR) a that contains at least one or more types of phenylpropanoic acid derivatives, their pharmaceutically acceptable salts and hydrates thereof according to claim 1, further sided because the steric configuration of the substituent on the propiodic acid portion in the case where R ~ is an hydrogen is the same as a 3- [N- [[4- (2-methoxyphenoxy) phenyl] methyl] carbamoi 1] -phenyl] propanoic acid. 24. Derivatives of phenylpropanoic acid substituted its ales and pharmaceutically acceptable hydrates according to claim 1, further characterized in that one of the compounds is 2-ethyl-3 - [4-methoxy -3- [N-] [[4- (3-methoxy phenoxy) pheni 1] met il] carbamoyl] phenyl] -propanoic acid. 25. Derivatives of substituted phenylpropanoic acid, their ales and their pharmaceutically acceptable hydrates according to claim 1 further characterized in that one of the compounds is 2-n-propy 1 - 3 - [4-methoxy] 3- [N - [[4- (3-methoxyphenoxy) phenyl] methyl] carbamoyl] -phenyl] propanoic acid. 26. Derivatives of substituted phenylpropanoic acid, their ales and their pharmaceutically acceptable hydrates according to claim 1, further characterized in that one of the compounds is 2-ethyl-3 - [4-methoxy-3 - [N- [ [4- (4-fluorophenoxy) pheni 1] methyl] carbamoyl] phenyl] -propanoic acid. 27.- Derivatives of substituted phenylpropanoic acid, its oils and its hydrates pharmaceutically acceptable according to claim 1., further characterized in that one of the compounds is: 2-n-propyl-3 - [4-methoxy -3- [N- [[4- (4-fluorophenoxy) phenyl] ] methyl] carbamoi 1] -phenyl] -propanoic acid. 28. Derivatives of phenylpropanoic acid substituted its ales and pharmaceutically acceptable hydrates according to claim 1 further characterized in that one of the compounds is (S) -2-et-il-3 - [4-methoxy] 3- [N - [[4- (trifluoromethyl) phenyl] met il] carbamoi 1] -phenyl] propanoic acid. 29. Derivatives of the substituted phenylpropanoic acid, their ales and their pharmaceutically acceptable hydrates according to claim 1 further characterized in that one of the compounds is (S) -2-et-3-yl- [4-methoxy] 3- [N- [(4-phenoxyphenyl) met il] carbamoi 1] phenyl] -propanoic. 30. Derivatives of substituted phenylpropanoic acid, their ales and their pharmaceutically acceptable hydrates according to claim 1, further characterized in that one of the compounds is (S) -2-et-3 - [4-methoxy] -3 - [N- [[4 - (2-methoxyphenoxy) phenyl] met i 1] carbamoi 1] phenyl] propanic. 31. Derivatives of phenylpropanoic acid substituted its ales and pharmaceutically acceptable hydrates according to claim 1, further characterized in that one of the compounds is (S) -2-et i 1-3 - [4-methoxy]
- 3- [N- [[
- 4- (4-fluorophenoxy phenyl] methyl] carbamoi 1] phenyl] propane., 32.- Derivatives of phenylpropanoic acid substituted its pharmaceutically acceptable salts and hydrates according to claim 1, further characterized in that one of the compounds is (S) -n-propyl-3 - [4-methoxy -3- [N- [(4-phenoxyphenyl) met yl] carbamoi 1] phenyl] -propanoic acid. of substituted phenylpropanoic acid, its acids and its hydrates pharmaceutically acceptible according to claim 1, further characterized in that one of the compounds e s. (S) -n-propyl-3 - [4-methoxy-3- [N- [[4- (2-methoxyphenoxy) phenyl] met yl] -carbamoyl] phenyl] propane acid. 34. - Derivatives of substituted phenylpropanoic acid, their pharmaceutically acceptable salts and hydrates in accordance with wherein R R 'R4 and Xp "are as described above by hydrophilizing the Xp" portion of these compounds
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11/162235 | 1999-06-09 | ||
JP2000157600 | 2000-05-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA01012653A true MXPA01012653A (en) | 2003-11-07 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6506797B1 (en) | Substituted phenylpropionic acid derivatives as agonists to human peroxisome proliferator-activated receptor (PPAR) α | |
CA2410647C (en) | Substituted phenylpropanoic acid derivatives | |
AU2006251768B2 (en) | Compounds, pharmaceutical compositions and methods for their use in treating metabolic disorders | |
CA2513092C (en) | Compounds for the treatment of metabolic disorders | |
CA2627363A1 (en) | Compounds for the treatment of insulin resistance syndrome and diabetes | |
US6706763B1 (en) | O-anisamide derivatives | |
US20030187068A1 (en) | Substituted phenylpropionic acid derivatives | |
JPWO2002044127A1 (en) | Substituted carboxylic acid derivatives | |
FR2842523A1 (en) | ACYLAMINOTHIAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION | |
US7241784B2 (en) | Carboxylic acid derivative and a pharmaceutical composition containing the derivative as active ingredient | |
US20040138213A1 (en) | Dihydronaphthalene derivative compounds and drugs containing these compounds as the active ingredient | |
EP1207157B1 (en) | Substituted benzylthiazolidine-2,4-dione derivatives | |
JPWO2002044130A1 (en) | Substituted carboxylic acid derivatives | |
MXPA01012653A (en) | SUBSTITUTED PHENYLPROPIONIC ACID DERIVATIVES AS AGONISTS TO HUMAN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)a | |
CA2487450C (en) | (2s)-2-ethylphenylpropanoic acid derivatives | |
JPWO2005009942A1 (en) | Optically active substituted phenylpropionic acid derivatives | |
JPWO2002044129A1 (en) | Substituted carboxylic acid derivatives | |
KR840001983B1 (en) | Process for preparing 1-(2-mercapto cycloalkyl) carbonyl -l-proline derivatives | |
CA2382582A1 (en) | Substituted benzylthiazolidine-2,4-dione derivatives |