DE3028776A1 - Hypolipaemic 1,3-di:phenoxy-propanone derivs. - prepd. by oxidn. of hydroxy-propoxy cpds. with di:methyl sulphoxide - Google Patents
Hypolipaemic 1,3-di:phenoxy-propanone derivs. - prepd. by oxidn. of hydroxy-propoxy cpds. with di:methyl sulphoxideInfo
- Publication number
- DE3028776A1 DE3028776A1 DE19803028776 DE3028776A DE3028776A1 DE 3028776 A1 DE3028776 A1 DE 3028776A1 DE 19803028776 DE19803028776 DE 19803028776 DE 3028776 A DE3028776 A DE 3028776A DE 3028776 A1 DE3028776 A1 DE 3028776A1
- Authority
- DE
- Germany
- Prior art keywords
- phenoxy
- hypolipaemic
- compounds
- general formula
- ch2ch
- 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.)
- Withdrawn
Links
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 title claims description 15
- 230000000055 hyoplipidemic effect Effects 0.000 title abstract description 6
- -1 hydroxy-propoxy Chemical group 0.000 title description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 4
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 9
- GJXXDQBMNMSDNT-UHFFFAOYSA-N 1,3-diphenoxypropan-2-one Chemical class C=1C=CC=CC=1OCC(=O)COC1=CC=CC=C1 GJXXDQBMNMSDNT-UHFFFAOYSA-N 0.000 claims description 8
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 201000005577 familial hyperlipidemia Diseases 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 abstract description 10
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 abstract description 7
- 238000012360 testing method Methods 0.000 abstract description 7
- 229960001214 clofibrate Drugs 0.000 abstract description 4
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 abstract description 3
- 241000700159 Rattus Species 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- 239000008280 blood Substances 0.000 abstract description 2
- 210000004369 blood Anatomy 0.000 abstract description 2
- 150000001768 cations Chemical class 0.000 abstract 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000002329 infrared spectrum Methods 0.000 description 5
- 238000004949 mass spectrometry Methods 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 150000003626 triacylglycerols Chemical class 0.000 description 5
- 229920002261 Corn starch Chemical class 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000008120 corn starch Chemical class 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001718 carbodiimides Chemical class 0.000 description 3
- 239000001913 cellulose Chemical class 0.000 description 3
- 229920002678 cellulose Chemical class 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- MTXILUWIDDZWSG-UHFFFAOYSA-N CC(CC(C=C1)=CC=C1OCC(COC1=CC=C(C(C)(C)C)C=C1)O)C(OC)=O Chemical compound CC(CC(C=C1)=CC=C1OCC(COC1=CC=C(C(C)(C)C)C=C1)O)C(OC)=O MTXILUWIDDZWSG-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 235000002595 Solanum tuberosum Nutrition 0.000 description 2
- 244000061456 Solanum tuberosum Species 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical class O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Chemical class 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229940126601 medicinal product Drugs 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 229920001592 potato starch Chemical class 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000005720 sucrose Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HHRACYLRBOUBKM-UHFFFAOYSA-N 2-[(4-tert-butylphenoxy)methyl]oxirane Chemical compound C1=CC(C(C)(C)C)=CC=C1OCC1OC1 HHRACYLRBOUBKM-UHFFFAOYSA-N 0.000 description 1
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical class 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 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 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 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Chemical class 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- SMEGJBVQLJJKKX-HOTMZDKISA-N [(2R,3S,4S,5R,6R)-5-acetyloxy-3,4,6-trihydroxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@@H]1[C@H]([C@@H]([C@H]([C@@H](O1)O)OC(=O)C)O)O SMEGJBVQLJJKKX-HOTMZDKISA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- TXCGAZHTZHNUAI-UHFFFAOYSA-N clofibric acid Chemical compound OC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 TXCGAZHTZHNUAI-UHFFFAOYSA-N 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000594 mannitol Chemical class 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- WRKKBDIQKYNZTJ-UHFFFAOYSA-N methyl 3-(4-hydroxyphenyl)-2-methylpropanoate Chemical compound COC(=O)C(C)CC1=CC=C(O)C=C1 WRKKBDIQKYNZTJ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical compound O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- DWYLYERNXXVPBH-UHFFFAOYSA-N propyl 3-[4-[3-(4-fluorophenoxy)-2-hydroxypropoxy]phenyl]-2-methylprop-2-enoate Chemical compound C(CC)OC(=O)C(=CC1=CC=C(OCC(COC2=CC=C(C=C2)F)O)C=C1)C DWYLYERNXXVPBH-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
- C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Titel: Neue , 1,3-Diphenoxypropan-2-on-DerivateTitle: New, 1,3-Diphenoxypropan-2-One Derivatives
sowie Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel Beschreibung Neue 1,3-Diphenoxypropan-2-on-Derivate sowie Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel. as well as processes for their production and medicaments containing them description New 1,3-diphenoxypropan-2-one derivatives and processes for their preparation and Medicinal products containing them.
Wie aus der DE-OS 27 35 856 hervorgeht, besitzen 1,3-Diphenoxypropan-2-on-Derivate, die an einem der Phenoxyreste Chlor, Brom oder eine Isopropyl- bzw. tert. Butylgruppe tragen und am anderen Phenoxyrest eine Carboxyl- bzw.As can be seen from DE-OS 27 35 856, have 1,3-diphenoxypropan-2-one derivatives, those on one of the phenoxy radicals chlorine, bromine or an isopropyl or tert. Butyl group wear and on the other phenoxy radical a carboxyl or
2-Carboxyvinyl- oder 2-Carboxyethylgruppe enthalten, bei guter Verträglichkeit eine ausgeprägte lipidsenkende Wirkung.Contain 2-carboxyvinyl or 2-carboxyethyl groups, with good tolerance a pronounced lipid-lowering effect.
Es wurde nun überraschenderweise festgestellt, daß 1,3-Diphenoxypropan-2-on-Derivate der im Patentanspruch 1 angegebenen Formel (1) eine gegenüber 2-(4'-Chlorphenoxy)-2-methylpropionsäure-ethylester (CLOFIBRAT) deutlich überlegene, hypolipämische Wirkung besitzen. Diese Verbindungen verringern bei sehr guter Verträglichkeit insbesondere den Triglyceridspiegel und bzw. oder den Cholesterinspiegel des Blutes. Gegenüber den ähnlich aufgebauten Stoffen der DE-OS 27 35 856 unterscheiden sich die neuen 1,3-Diphenoxypropan-2-on-Derivate durch den Einbau einer Isopropylengruppe bzw. der Isopropenylengruppe zwischen dem Benzolring der einen Phenoxygruppe und der Carboxyl- oder Estergruppe, wodurch überraschenderweise Vorteile bei ihrer therapeutischen Anwendung erreicht werden.It has now surprisingly been found that 1,3-diphenoxypropan-2-one derivatives the formula (1) given in claim 1 is an ethyl ester of 2- (4'-chlorophenoxy) -2-methylpropionic acid (CLOFIBRAT) have clearly superior, hypolipemic effects. These connections reduce the triglyceride level and in particular with very good tolerability or or the cholesterol level in the blood. Compared to the similarly structured substances DE-OS 27 35 856 differ from the new 1,3-diphenoxypropan-2-one derivatives by incorporating an isopropylene group or the isopropenylene group between the Benzene ring of a phenoxy group and the carboxyl or ester group, surprisingly Advantages can be achieved in their therapeutic application.
Die Herstellung dieser neuen, hypolipämisch wirkenden Verbindungen kann in an sich bekannter Weise erfolgen, wobei man erfindungsgemäß die in Anspruch 2 angegebenen Verfahren anwendet Ausgehend von Verbindungen der allgemeinen Formel (2) in der R1 R2 und A die in Anspruch 1 beschriebene Bedeutung besitzen, lassen sich die erfindungsgemäßen Verbindungen nach Formel 1 durch eine selektive Oxidation mit Dimethylsulfoxid erhalten. Für eine gezielte Oxidation ist von wesentlicher Bedeutung das Einhalten bestimmter Reaktionskriterien, wie sie in den Beispielen näher beschrieben werden.These new, hypolipemic compounds can be prepared in a manner known per se, using the method specified in claim 2 according to the invention. Starting from compounds of the general formula (2) in which R1, R2 and A have the meaning described in claim 1, the compounds according to the invention according to formula 1 can be obtained by selective oxidation with dimethyl sulfoxide. For a targeted oxidation it is of essential importance that certain reaction criteria are met, as described in more detail in the examples.
Die Herstellung der verschiedenen Salze nach Formel (1) kann in der Weise erfolgen, daß man die Säuren in wäßrigalkoholischem Milieu mit Basen der Alkali- bzw. Erdalkalireihe, mit Aluminiümbasen, ferner mit Ammoniak oder anderen therapeutisch verwendbaren Aminen nach bekannten Verfahren reagieren läßt. The preparation of the various salts according to formula (1) can be in the Way done that the acids in an aqueous alcoholic medium with bases of the alkali or alkaline earth series, with aluminum bases, furthermore with ammonia or others therapeutically usable amines can react by known methods.
Verbindungen der allgemeinen Formel (2) lassen sich nach Verfahren herstellen, wie sie bereits in der DE-PS 24 60 689 beschrieben sind. Compounds of the general formula (2) can be prepared by processes produce as they are already described in DE-PS 24 60 689.
So lassen sich Verbindungen der allgemeinen Formel (3) - in der R ein Fluor- oder Chloratom sein kann bzw. eine tert.Compounds of the general formula (3) - in which R can be a fluorine or chlorine atom or a tert.
Butylgruppe darstellt, mit Verbindungen der allgemeinen Formel (4) umsetzen in der A die in Anspruch 1 angegebene Bedeutung besitzt und R eine Alkylgruppe mit bis zu 3 Kohlenstoffatomen darstellt, die gerade oder verzweigt, gesättigt oder ungesättigt sein kann und gegebenenfalls endständig eine Methoxygruppe trägt.Represents butyl group, react with compounds of the general formula (4) in which A has the meaning given in claim 1 and R is an alkyl group with up to 3 carbon atoms which can be straight or branched, saturated or unsaturated and optionally bears a methoxy group at the end.
Für die therapeutische Anwendung als hypolipämische Arzneimittel werden die neuen Verbindungen der allgemeinen Formel (1) und ihre Salze bevorzugt oral verabreicht. Gewöhnlich beträgt die orale Tagesdosis bei Erwachsenen 0.1 bis 5 g vorzugsweise 0.3 bis 2 g.Can be used for therapeutic use as a hypolipemic drug the new compounds of the general formula (1) and their salts preferably orally administered. Usually the oral daily dose in adults is 0.1 to 5 g preferably 0.3 to 2 g.
Die Wirkstoffe können zur oralen Verabreichung in üblicher Weise galenisch verarbeitet werden. Als pharmazeutische Trägerstoffe eignen sich gängige Hilfsstoffe wie Lactose, Saccharose, Mannit, Kartoffel- oder Maisstärke, Cellulosederivate oder Gelatine, gegebenenfalls unter Zusatz von Gleitmitteln, wie z.B. Magnesium-oder Calciumstearat, sowie Polyethylenglykole. The active ingredients can be administered orally in a customary manner be processed galenically. Common pharmaceutical carriers are suitable Auxiliaries such as lactose, sucrose, mannitol, potato or corn starch, cellulose derivatives or gelatin, optionally with the addition of lubricants, such as magnesium or Calcium stearate, as well as polyethylene glycols.
Bevorzugte Verabreichungsformen sind Steckkapseln aus Hartgelatine sowie geschlossene Weichgelatinekapseln. In Steckkapseln kann gegebenenfalls der reine Wirkstoff evtl. mit einem geringen Zusatz an Gleitmitteln enthalten sein. Bei entsprechenden physikaliscnen Eigenschaften des Wirkstoffes wird eine Verarbeitung zu Granulaten bevorzugt, wobei als Hilfsstoffe Kartoffel- oder Maisstärke, mikronisierte Cellulose, Cellulosederivate, Gelatine oder auch hochdisperse Kieselsäuren mitverwendet werden. Ölige Wirkstoffe werden in reiner Form bevorzugt in Weichgelatinekapseln konfektioniert. Preferred forms of administration are hard gelatine capsules and closed soft gelatin capsules. In push-fit capsules, the pure active ingredient possibly with a small addition of lubricants. If the active substance has the appropriate physical properties, processing to granules preferred, with potato or corn starch, micronized as auxiliaries Cellulose, cellulose derivatives, gelatin or highly dispersed silicas are also used will. Oily active ingredients are preferred in their pure form in soft gelatin capsules assembled.
Gegebenenfalls wird der reine Wirkstoff in geeigneten Flüssigkeiten gelöst oder suspendiert, so z. B. in flüssigen Polyethylengiykolen oder Pflanzenölen.If necessary, the pure active ingredient is in suitable liquids dissolved or suspended, e.g. B. in liquid polyethylene glycols or vegetable oils.
Im folgenden wird die Erfindung anhand von Ausführungsbeispielen näher erläutert. In the following the invention is illustrated by means of embodiments explained in more detail.
Beispiel 1 3-[4'-(2-Methoxycarbonylpropyl)-phenoxy]-1-(4'-tert.butylphenoxy)-propan-2-on a) Herstellung des Ausgangsproduktes 3-[4'-(2-Methoxycarbonylpropyl)-phenoxy]-1-(4'-tert.butylphenoxy)-propan-2-ol 42.8 g (0.2 Mol) 3-(4'-Hydroxyphenyl)-2-methylpropionsäure-methylester ) und 2.64 g (0.048 Mol) Natriummethylat werden in 300 ml Methanol gelöst und nach Zugabe von 41.2 g (0.2 Mol) 3-(4'-tert.-Butylphenoxy)-1,2-epoxypropan 16 Stdn. unter Rückfluß erhitzt.Example 1 3- [4 '- (2-Methoxycarbonylpropyl) -phenoxy] -1- (4'-tert-butylphenoxy) -propan-2-one a) Preparation of the starting product 3- [4 '- (2-methoxycarbonylpropyl) -phenoxy] -1- (4'-tert-butylphenoxy) -propan-2-ol 42.8 g (0.2 mol) 3- (4'-hydroxyphenyl) -2-methylpropionic acid methyl ester) and 2.64 g (0.048 mol) of sodium methylate are dissolved in 300 ml of methanol and, after the addition of 41.2 g (0.2 mol) of 3- (4'-tert-butylphenoxy) -1,2-epoxypropane for 16 hours under reflux heated.
Anschließend wird das Lösungsmittel i.Vak. entfernt, der Rückstand in Ether aufgenommen und nach mehrmaligem Ausschütteln mit 1 N Natronlauge mit Wasser neutral gewaschen. Nach dem Trocknen über Natriumsulfat wird das Lösungsmittel i.Vak. entfernt und das ölige Rohprodukt an Kieselgel mit Chloroform säulenchromato-20 graphisch gereinigt. Farblose, hochviskose Flüssigkeit; nD = 1.5307; Ausbeute : 56.6 g (71 %).Then the solvent is in vacuo. removed the residue taken up in ether and shaken out several times with 1 N sodium hydroxide solution with water washed neutral. After drying over sodium sulfate, the solvent is in vacuo. removed and the oily crude product on silica gel with chloroform column chromatography-20 graphically cleaned. Colorless, highly viscous liquid; nD = 1.5307; Yield: 56.6 g (71%).
C24H3205 (400.5) 2) Mol.-Gew. : 400 (massenspektrometrisch bestimmt) ) IR-Spektrum (Film) : #(O-H) : 3450 cm-1 #(C=O) : 1725 cm-1 ¹H-NMR-Spektrum (CDCl3)3) : 1.0 bis 1.4 m und 1.3 s (12) CH3C und (CH3)3C 2.7 m (4) CH2CH und OH 3.6 s (3) NOCH, 4.1 m (5) CH2CHCH2 6.6 bis 7.4 m (8) Aromat.C24H3205 (400.5) 2) Mol. Wt. : 400 (determined by mass spectrometry) ) IR spectrum (film): # (O-H): 3450 cm-1 # (C = O): 1725 cm-1 1 H-NMR spectrum (CDCl3) 3) : 1.0 to 1.4 m and 1.3 s (12) CH3C and (CH3) 3C 2.7 m (4) CH2CH and OH 3.6 s (3) STILL, 4.1 m (5) CH2CHCH2 6.6 to 7.4 m (8) Aromat.
hergestellt durch Hydrierung von 4'-Hydroxy-α-methylzimtsäuremethylester nach bekannten Verfahren 2) bestimmt mittels Elektronenstoß-Ionisation (70 eV) 3) aufgenommen bei 60 MHz die chemischen Verschiebungen sind in ppm gegen TMS (#= 0.0) angegeben, die relativen Intensitäten sind in Klammern beigefügt. produced by hydrogenation of methyl 4'-hydroxy-α-methylcinnamate according to known methods 2) determined by electron impact ionization (70 eV) 3) recorded at 60 MHz the chemical shifts are in ppm against TMS (# = 0.0) indicated, the relative intensities are given in brackets.
s'= Singulett; d = Dublett; t = Triplett; m = Multiplett b) Erfindungsgemäße licrstellung von 3-[4'-(2-Methoxycarbonylpropyl)-phenoxy]-1-(4'-tert.butylphenoxy)-propan-2-on 14.5 ml (0.2 Mol) wasserfreies Dimethylsulfoxid in 120 ml trockenem Dichlormethan werden unter starkem Rühren bei - 70°C langsam mit 20 ml (0.14 Mol) Trifluoressigsäureanhydrid in 30 ml trockenem Dichlormethan versetzt. Die dabei entstandene Suspension wird noch 10 Min. gerührt und anschließend langsam mit 40.0 g (0.1 Mol) 3-[4'-(2-Methoxycarbonylpropyl)-phenoxy]-1-(4'-tert.butylphenoxy)-propan-2-ol in 40 ml trockenem Dichlormethan versetzt, so daß die Reaktionstemperatur nicht über - 50"C ansteigt. Nach 30 Min. werden 25 ml Triethylamin vorsichtig zugefügt und das Reaktionsgemisch durch Entfernen des Kältebades allmählich auf Raumtemperatur gebracht. Die klare Reaktionslösung wird mit Wasser versetzt und die abgeschiedene organische Phase mit 1 N Salzsäure, dann mit 1 M Kaliumcarbonatlösung und schließlich mit Wasser gewaschen. Nach dem Trocknen über Natriumsulfat wird das Lösungsmittel i.Vak. entfernt und der Rückstand an Kieselgel nit Chloroform säulenchromatographisch gereinigt. Farblose Kristalle vom Schmp. 45 bis 47°C (Diisopropylether/Petrolether); Ausbeute: 15.0 g (38 %). s' = singlet; d = doublet; t = triplet; m = multiplet b) Preparation according to the invention of 3- [4 '- (2-methoxycarbonylpropyl) -phenoxy] -1- (4'-tert-butylphenoxy) -propan-2-one 14.5 ml (0.2 mol) of anhydrous dimethyl sulfoxide in 120 ml of dry dichloromethane are slowly mixed with 20 ml (0.14 mol) of trifluoroacetic anhydride at -70 ° C. with vigorous stirring added in 30 ml of dry dichloromethane. The resulting suspension is Stirred for a further 10 minutes and then slowly added with 40.0 g (0.1 mol) 3- [4 '- (2-methoxycarbonylpropyl) phenoxy] -1- (4'-tert-butylphenoxy) propan-2-ol added in 40 ml of dry dichloromethane, so that the reaction temperature does not rises above −50 ° C. After 30 minutes, 25 ml of triethylamine are carefully added and the reaction mixture gradually to room temperature by removing the cold bath brought. The clear reaction solution is mixed with water and the deposited organic phase with 1 N hydrochloric acid, then with 1 M potassium carbonate solution and finally washed with water. After drying over sodium sulfate, the solvent becomes i.Vac. removed and the residue on silica gel with chloroform by column chromatography cleaned. Colorless crystals with a melting point of 45 to 47 ° C. (diisopropyl ether / petroleum ether); Yield: 15.0 g (38%).
24 30 5 (398.5) Mol.- Gew. 398 (massenspektrometrisch bestimmt) IR-Spektrum (KBr) : # (C=O) : 1730 cm-1 1H-NfR-Spektrum (CCl4) : 0.9 bis 1.2 m (3) CH3CH, 1.3 s (9) (CH3)3C, 2.3 bis 3.1 m (3) CH2CH, 3.5 s (3) OCH3, 4.6 s (2) OCH2, 4.7 s (2) OCH2, 6.5 bis 7.4 m (8) Aromat.24 30 5 (398.5) mol. Wt. 398 (determined by mass spectrometry) IR spectrum (KBr): # (C = O): 1730 cm-1 1H-NfR spectrum (CCl4): 0.9 to 1.2 m (3) CH3CH, 1.3 s (9) (CH3) 3C, 2.3 to 3.1 m (3) CH2CH, 3.5 s (3) OCH3, 4.6 s (2) OCH2, 4.7 s (2) OCH2, 6.5 to 7.4 m (8) aromatic.
Beispiel 2 3-[4'-(2-Propoxycarbonyl-1-propenyl)-phenoxy]-1-(4'-fluorphenoxy)-propan-2-on 38.8 g (0.1 Mol) 3-[4'-(2-Propoxycarbonyl-1-propenyl)-phenoxy] 1-(4'-fluorphenoxy)-propan-2-ol werden in 180 ml absolutem Ether gelöst und mit 14 ml (0.2 Mol) Dimethylsulfoxid, 3.2 ml Pyridin und 45.0 g (0.22 Mol) Dicyclohexylcarbodiimid versetzt.Example 2 3- [4 '- (2-Propoxycarbonyl-1-propenyl) -phenoxy] -1- (4'-fluorophenoxy) -propan-2-one 38.8 g (0.1 mole) 3- [4 '- (2-propoxycarbonyl-1-propenyl) -phenoxy] 1- (4'-fluorophenoxy) -propan-2-ol are dissolved in 180 ml of absolute ether and 14 ml (0.2 mol) of dimethyl sulfoxide, 3.2 ml of pyridine and 45.0 g (0.22 mol) of dicyclohexylcarbodiimide were added.
Nach Abkühlung auf ca. 0°C werden 2.1 ml Trifluoressigsäure vorsichtig unter Rühren zugefügt und das Reaktionsgemisch durch Entfernen des Kältebades allmählich auf Raumtemperatur gebracht. Man rührt solange weiter (ca. 20 Stunden) bis dünnschichtchromatographisch keine Ausgangsverbindung mehr nachzuweisen ist. Zur Beseitigung von überschüssigem Carbodiimid wird das Reaktionsgemisch portionsweise mit einer konzentrierten Lösung von 20.0 g Oxalsäure in Methanol versetzt und 20 Min.After cooling to approx. 0 ° C., 2.1 ml of trifluoroacetic acid are carefully added added with stirring and the reaction mixture gradually by removing the cold bath brought to room temperature. Stirring is continued (approx. 20 hours) until thin-layer chromatography no more starting compound can be detected. To remove excess Carbodiimide is added to the reaction mixture in portions with a concentrated solution of 20.0 g of oxalic acid in methanol and 20 min.
gerührt. Nach Abtrennung des entstandenen Dicyclohexylharnstoff-Niederschlags wird die etherische Lösung mit einer Natriumhydrogencarbonatlösung und dann mit Wasser gewaschen. Nach dem Tocknen über Natriumsulfat wird das Lösungsmittel i.Vak.touched. After the dicyclohexylurea precipitate formed has been separated off the ethereal solution with a sodium hydrogen carbonate solution and then with Water washed. After drying over sodium sulfate, the solvent is in vacuo.
entfern: und der Rückstand an Kieselgel mit Ether/Petrolether (1/1) säulenchromatographisch gereinigt. Farblose Kristalle vom Schmp. 64.5 bis 65.50C (Diisopropylether); Ausbeute: 15.4 g (40 ).remove: and the residue on silica gel with ether / petroleum ether (1/1) Purified by column chromatography. Colorless crystals from m.p. 64.5 to 65.50C (Diisopropyl ether); Yield: 15.4 g (40).
C22123F05 (386.4) Mol.-Gew. 386 (massenspektrometrisch bestimmt) IR-Spektrum (KBr) : #(C=O) : 1730 cm-1 (Keton) -1 1710 cm (Ester) -1 Q(C=C) : 1630 cm ¹H-NMR-Spektrum (CDCl3) : 1.0 t (3) CH3CH2 1.3 bis 2.0 m (2) Cll3CL12, 2.l d (3) CH3C=, 4.2 t (9) CH2CH20, 4.8 s (2) CH20, 4.9 s (2) CH20 6.6 bis 7.8 m (9) Aromat. und CH= Beispiel 3 3-{4-[2-(2-Propinoxycarbonyl)-propyl]-phenoxy}-1-(4'-chlorphenoxy)-propan-2-on 40.8 g (0.1 Mol) 3-{4-[2-(2-Propinoxycarbonyl)-propyl]-phenoxy}-1-(4'-chlorphenoxy)-propan-2-ol werden in 220 ml absolutem Ether gelöst und mit 17 ml (0.24 Mo) Dimethylsulfoxid, 7.5 ml Pyridin und 38.0 g (0.19-Mol) Dicyclohexylcarbodiimid versetzt. Nach Abkühlung auf ca. 0°C werden vorsichtig unter Rühren 2.5 ml Trifluoressigsäure zugefügt und das Reaktionsgemisch durch Entfernen des Kältebades allmählich auf Raumtemperatur gebracht.C22123F05 (386.4) mol wt. 386 (determined by mass spectrometry) IR spectrum (KBr): # (C = O): 1730 cm -1 (ketone) -1 1710 cm (ester) -1 Q (C = C): 1630 cm 1 H-NMR spectrum (CDCl3): 1.0 t (3) CH3CH2 1.3 to 2.0 m (2) Cll3CL12, 2.l d (3) CH3C =, 4.2 t (9) CH2CH20, 4.8 s (2) CH20, 4.9 s (2) CH20 6.6 to 7.8 m (9) aromatic. and CH = example 3 3- {4- [2- (2-propynoxycarbonyl) propyl] phenoxy} -1- (4'-chlorophenoxy) propan-2-one 40.8 g (0.1 mole) 3- {4- [2- (2-propynoxycarbonyl) propyl] phenoxy} -1- (4'-chlorophenoxy) propan-2-ol are dissolved in 220 ml of absolute ether and treated with 17 ml (0.24 Mo) of dimethyl sulfoxide, 7.5 ml of pyridine and 38.0 g (0.19 mol) of dicyclohexylcarbodiimide were added. After cooling down 2.5 ml of trifluoroacetic acid are carefully added to about 0 ° C. with stirring and the reaction mixture gradually to room temperature by removing the cold bath brought.
Nach 20 Stunden Rühren bei Raumtemperatur und anschließendem einstündigem Erhitzen unter Rückfluß ist dünnschichtchromatographisch kein Ausgangsprodukt mehr nachzuweisen. Zur Beseitigung von überschüssigem Carbodiimid wird das abgekühlte Reaktionsgemisch portionsweise mit einer konzentrierten Lösung von 18.0 g Oxalsäure in Methanol versetzt und 20 Min. gerührt.After stirring at room temperature for 20 hours and then for one hour Heating under reflux is no longer a starting product according to thin-layer chromatography to prove. The carbodiimide is cooled to remove excess carbodiimide Reaction mixture in portions with a concentrated solution of 18.0 g of oxalic acid added in methanol and stirred for 20 min.
Nach Abtrennung des entstandenen Dicyclohexylharnstoff-Niederschlags wird die etherische Lösung mit einer Natriumhydrogencarbonat?ösung - und dann mit Wasser gewaschen. Nach dem Trocknen über Natriumsulfat wird das Lösungsmittel iÄTak. entfernt und der Rückstand an Kieselgel mit Chloroform säulenchromatographisch gereinigt. Das Lösungsmittel wird i.Vak. entfernt und der Rückstand aus Ether bei - 25°C kristallisiert. Farblose Kristalle vom Schmp. 31 bis 33°C (Ether); Ausbeute: 12.9 g (32 7).After the dicyclohexylurea precipitate formed has been separated off the ethereal solution with a sodium hydrogen carbonate solution - and then with Water washed. After drying over sodium sulfate, the solvent is iÄTak. removed and the residue purified by column chromatography on silica gel with chloroform. The solvent is in vacuo. removed and the residue crystallized from ether at -25 ° C. Colorless crystals with a melting point of 31 to 33 ° C (ether); Yield: 12.9 g (32 7).
C22H21ClO5 (400.8) Mol.-Gew.: 400 (massenspektrometrisch bestimmt) IR-Spektrum (CHCl3): #(#CH) : 3300 cm-1 #(C=O) : 1735 cm-1 ¹H-NMR-Spektrum (CDCl3) : 0.9 bis 1.4 m (3) CR3, 2.4 t (1) =-CH, 2.5 bis 3.1 m (3) C112CH, 4.6 d (2) CH2C=-, 4.8 s (2) OCH2, 4.9 s (2) NOCH, 6.6 bis 7.4 m (8) Aromat In analoger Weise zu den Beispielen 1 bis 3 wurden weitere Verbindungen der allgemeinen Formel (1) hergestellt und in nachfolgender Tabelle 1 mit physikaliscilen Kennzahlen aufgeführt. Aus Gründen der Vollständigkeit werden in folgender Tabelle die in den Beispielen beschriebenen Verbindungen nochmals angegeben.C22H21ClO5 (400.8) Mol.wt .: 400 (determined by mass spectrometry) IR spectrum (CHCl3): # (# CH): 3300 cm-1 # (C = O): 1735 cm-1 1 H-NMR spectrum (CDCl3) : 0.9 to 1.4 m (3) CR3, 2.4 t (1) = -CH, 2.5 to 3.1 m (3) C112CH, 4.6 d (2) CH2C = -, 4.8 s (2) OCH2, 4.9 s (2) STILL, 6.6 to 7.4 m (8) Aromat In analog Way to Examples 1 to 3 were further compounds of the general formula (1) and listed in the following table 1 with physical indicators. For the sake of completeness, those in the examples are shown in the following table described compounds are given again.
Tabelle 1 Nr. R¹ A-COOR² Schmp. (°C)x) bzw. nd20xx) 1 F CH=C(CH3)COOCH3 78 bis 9 (a) 2 F CH=C(CH3)COOCH2CH2CH3 65 bis 6 (b) 3 F CH=C(CH3)COOCH2OCH3 96 bis 7 (b) 4 F CH2CH(CH3)COOCH2CH3 1.5315 ) 5 F CH2CH(CH3)COOCH2CH2OCH3 1.5293 xx) 6 F CH2CH(CH3)COOCH2CH=CH2 1.5363 xx) 7 Cl CH=C(CH3)COOCH2CH3 85 bis 6 (c) 8 Cl CH=C(CH3)COOCH(CH3)2 79 bis 80 (b) 9 Cl CH=C(CH3)COOCH2OCH3 89 bis 90 (d) 10 Cl CH=C(CH3)COOCH2CH=CH2 69 bis 70 (e) 11 Cl CH2CH(CH3)COOCH2CH2CH3 29 bis 30 (e) 12 Cl CH2CH(CH3)COOCH2CH2OCH3 1.5433 xx) 13 Cl CH2CH(CH3)COOCH2C#CH 31 bis 3 (e) 14 (CH3)3C CH=C(CH3)COOCH3 100 bis 4 (f) 15 (CH3)3C CH=C(CH3)COOCH2CH2OCH3 ó? bis 3 (e) 16 (CH3)3C CH2CH(CH3)COOCH3 45 bis 7 (b) 17 (CH3)3C CH2CH(CH3)COOCH(CH3)2 49 bis 51 (e) 18 (CH3)3C CH2CH(CH3)COOCH2OCH3 1.5286 xx) 19 (CH3)3C CH2CH(CH3)COOCH2CH=CH2 1.5355 xx) Kristalle aus: a = Ethylacetat/Petrolether b = Diisopropylether c = Butylchlorid/Petrolether d = Tetrahydrofuran/Diisopropylether e = Ether/Petrolether f = Ether.Table 1 No. R¹ A-COOR² m.p. (° C) x) or nd20xx) 1 F CH = C (CH3) COOCH3 78 to 9 (a) 2 F CH = C (CH3) COOCH2CH2CH3 65 to 6 (b) 3 F CH = C (CH3) COOCH2OCH3 96 to 7 (b) 4 F CH2CH (CH3) COOCH2CH3 1.5315) 5 F CH2CH (CH3) COOCH2CH2OCH3 1.5293 xx) 6 F CH2CH (CH3) COOCH2CH = CH2 1.5363 xx) 7 Cl CH = C ( CH3) COOCH2CH3 85 to 6 (c) 8 Cl CH = C (CH3) COOCH (CH3) 2 79 to 80 (b) 9 Cl CH = C (CH3) COOCH2OCH3 89 to 90 (d) 10 Cl CH = C (CH3 ) COOCH2CH = CH2 69 to 70 (e) 11 Cl CH2CH (CH3) COOCH2CH2CH3 29 to 30 (e) 12 Cl CH2CH (CH3) COOCH2CH2OCH3 1.5433 xx) 13 Cl CH2CH (CH3) COOCH2C # CH 31 to 3 (e) 14 ( CH3) 3C CH = C (CH3) COOCH3 100 to 4 (f) 15 (CH3) 3C CH = C (CH3) COOCH2CH2OCH3 ó? to 3 (e) 16 (CH3) 3C CH2CH (CH3) COOCH3 45 to 7 (b) 17 (CH3) 3C CH2CH (CH3) COOCH (CH3) 2 49 to 51 (e) 18 (CH3) 3C CH2CH (CH3) COOCH2OCH3 1.5286 xx) 19 (CH3) 3C CH2CH (CH3) COOCH2CH = CH2 1.5355 xx) Crystals from: a = ethyl acetate / petroleum ether b = diisopropyl ether c = butyl chloride / petroleum ether d = tetrahydrofuran / diisopropyl ether e = ether / petroleum ether f = ether.
Die Schnelzpunkte wurden mit einem Kofler-Heiztisch-Mikroskop enrittelt und sind nicht korrigiert.The melting points were scored with a Kofler hot stage microscope and are not corrected.
xx) Viskoses Öl, durch Säulenchromatographie gereinigt und durch Brechungsindex charakterisiert.xx) Viscous oil, purified by column chromatography and by refractive index characterized.
Beispiel 4 3-[4'-(2-Carboxy-1-propenyl)-phenoxy]-1-(4'-chlorphenoxy)propan-2-on 14.5 ml (0.2 Mol) wasserfreies Dimethylsulfoxid in -180 ml trockenem Dichlormethan werden unter starkem Rühren bei - 70°C langsam mit 21 ml (0.15 Mol) Trifluoressigsäureanhydrid in 21 ml trockenem Dichlormethan versetzt. Die dabei entstandene Suspension wird noch 10 Min. gerührt und anschließend langsam mit einer Lösung von 36.3 g (0.1 Mol) 3-[4'-(2-Carboxy-1-propenyl)-phenoxy]-1-(4'-chlorphenoxy)-propan-2-ol in 73 ml trockenem Dichlormethan und 18 ml Dimethylsulfoxid versetzt, so daß-die Temperatur nicht über - 50°C ansteigt.Example 4 3- [4 '- (2-Carboxy-1-propenyl) -phenoxy] -1- (4'-chlorophenoxy) propan-2-one 14.5 ml (0.2 mol) of anhydrous dimethyl sulfoxide in -180 ml of dry dichloromethane are slowly mixed with 21 ml (0.15 mol) of trifluoroacetic anhydride at -70 ° C. with vigorous stirring added in 21 ml of dry dichloromethane. The resulting suspension is stirred for another 10 minutes and then slowly with a solution of 36.3 g (0.1 mol) 3- [4 '- (2-Carboxy-1-propenyl) -phenoxy] -1- (4'-chlorophenoxy) -propan-2-ol in 73 ml of dry Dichloromethane and 18 ml of dimethyl sulfoxide are added so that the temperature does not exceed - 50 ° C increases.
Nach 30 Min. werden 42 ml Triethylamin vorsichtig zugefügt und das Reaktionsgemisch durch Entfernen des Kältebades allmählich auf Raumtemperatur gebracht. Die klare Reaktionslösung wird mit Wasser versetzt und das ausgefallene Oxidationsp-rodukt abgetrennt.After 30 minutes, 42 ml of triethylamine are carefully added and the The reaction mixture was gradually brought to room temperature by removing the cold bath. The clear reaction solution is mixed with water and the precipitated oxidation product severed.
Die organische Phase wird mit Natriumsulfat getrocknet und das Lösungsmittel i.Vak. entfernt. Der Rückstand und das ausgefallene Oxidationsprodukt werden kristallisiert. Farblose Kristalle vom Schmp. 150 bis 15100 (Aceton); Ausbeute: 14.2 g (39%).The organic phase is dried with sodium sulfate and the solvent i.Vac. removed. The residue and the precipitated oxidation product are crystallized. Colorless crystals from m.p. 150 to 15100 (acetone); Yield: 14.2 g (39%).
C19H17ClO5 (360.8) Mol.-Gew. 360 (massenspektrometrisch bestimmt) IR-Spektrum (KBr) #(C=O) : 1750 cm-1 (Keton) -1 1665 cm 1 (Carbonsäure) H-NMR-Spektrum (CDCl3/d6-DMSO) : 2.1 d (3) CH3 4.9 s (4) 2 CH2O, 6.7 bis 7.7 m (9) Atomat. und CK= In analoger Weise zum Beispiel 4 wurden weitere Verbindungen der allgemeinen Formel (1) hergestellt und in nachfolgender Tabelle 2 mit physikalischen Kennzahlen aufgeführt. Aus Gründen der Vollständigkeit wird in folgender Tabelle die im Beispiel beschriebene Verbindung nochmals angegeben.C19H17ClO5 (360.8) mol. Wt. 360 (determined by mass spectrometry) IR spectrum (KBr) # (C = O): 1750 cm -1 (ketone) -1 1665 cm -1 (carboxylic acid) H-NMR spectrum (CDCl3 / d6-DMSO): 2.1 d (3) CH3 4.9 s (4) 2 CH2O, 6.7 to 7.7 m (9) atom. and CK = In a manner analogous to Example 4, further compounds of the general Formula (1) and in the following table 2 with physical parameters listed. For the sake of completeness, the table in the example described connection is given again.
Tabelle 2 Nr. R A-COOR Schmp. (°C) 20 F CH=C(CH3)COOH 149 bis 51 (a) 21 F CH2CH(CH3)COOH 82 bis 3 (b) 22 Cl CH=C(CH3)COOH 150 bis 51 (c) 23 Cl CH2CH(CH3)COOH 89 bis 90 (d) 24 (CH3)3C CH=C(CH3)COOH 119 bis 20 (e) 25 (0H3)30 CH2CH(CH3)COOH 114 bis 15 (f) Kristalle aus: a = Ethylacetat, b = Diisopropylether, c = Aceton d = Benzol/Petrolether, e = Tetrachlorkohlenstoff, f = Chloroform.Table 2 No.R A-COOR m.p. (° C) 20 F CH = C (CH3) COOH 149-51 (a) 21 F CH2CH (CH3) COOH 82-3 (b) 22 Cl CH = C (CH3) COOH 150 to 51 (c) 23 Cl CH2CH (CH3) COOH 89 to 90 (d) 24 (CH3) 3C CH = C (CH3) COOH 119 to 20 (e) 25 (0H3) 30 CH2CH (CH3) COOH 114 to 15 ( f) Crystals from: a = ethyl acetate, b = diisopropyl ether, c = acetone, d = benzene / petroleum ether, e = carbon tetrachloride, f = chloroform.
Beispiel 5 3-[4'-(2-Methoxycarbonylpropyl)-phenoxy]-1-(4'-tert.butylphenoxy)-propan-2-on enthaltnedes Arzneimittel 100 g 3-[4'-(2-Methoxycarbonylpropyl)-phenoxy] 1-(4'-tert.butylphenoxy)-propan-2-on werden mit 100 g Polyethylenglykol vermischt und in eintausend ovale Weichgelatinekapseln zu 200 mg Inhalt abgefüllt.Example 5 3- [4 '- (2-Methoxycarbonylpropyl) phenoxy] -1- (4'-tert-butylphenoxy) propan-2-one The medicament contains 100 g of 3- [4 '- (2-methoxycarbonylpropyl) -phenoxy] 1- (4'-tert-butylphenoxy) -propan-2-one are mixed with 100 g of polyethylene glycol and placed in one thousand oval soft gelatin capsules filled with 200 mg content.
Beispiel 6 3- [4'-(2-Carboxy-l -propenyl) -phenoxy -1-(4'-chlorphenox)-propan-2-on enthaltendes Arzneimittel 100 g 3-[4'-(2-Carboxy-1-propenyl)-phenoxy]-1-(4'-chlorphenoxy)-propan-2-on werden mit 16 g Maisstärke und 6 g hochdispersem Siliciumdioxid gut vermischt, anschließend mit einer Lösung von 2 g Stearinsäure, 6 g Acetylcellulose und 6 g Stearin in 70 ml Isopropanol befeuchtet und granuliert. Das getrocknete Granulat wird durch ein Sieb geschlagen und nach dem Vermischen mit 16 g Maisstärke, 16 g Talk und 2 g Magnesiumstearat u eintausend Drageekernen verpreßt. Nach erziehen mit einem Sirup von 2 g Lacca, 7.5 g Gummi arabicum, 0.15 g Farbstoff, 2 g kolloidalem Siliciumdioxid, 25 g Talk und 53.35 g Saccharose werden nach dem Trocknen eintausend 260 mg schwere Dragees mit je 100 mag Wirkstoff erhalten.Example 6 3- [4 '- (2-Carboxy-1-propenyl) -phenoxy -1- (4'-chlorophenox) -propan-2-one Medicinal product containing 100 g of 3- [4 '- (2-Carboxy-1-propenyl) -phenoxy] -1- (4'-chlorophenoxy) -propan-2-one are mixed well with 16 g of corn starch and 6 g of highly dispersed silicon dioxide, then with a solution of 2 g stearic acid, 6 g acetyl cellulose and 6 g stearin in 70 ml of isopropanol moistened and granulated. The dried granulate is through a Sieve beaten and after mixing with 16 g corn starch, 16 g talc and 2 g magnesium stearate u pressed a thousand tablet cores. After training with a syrup of 2 g Lacca, 7.5 g gum arabic, 0.15 g color, 2 g colloidal silicon dioxide, 25 g talc and 53.35 g sucrose are after drying one thousand 260 mg coated tablets with 100 mag active ingredient each.
Beispiel 7 Pharmakologische Testung 1. Orale Verträglichkeit Nach oraler Applikation der Testverbindungen an Mäusen vom Stamm NMR-I, mit einem Gewicht von 15 bis 20 g wurde die akute Toxizität bestimmt. Die LD50-NTerte wurden nach Litchfield-Wilcoxon [J.Pharmak.Example 7 Pharmacological Testing 1. Oral Compatibility According to oral application of the test compounds to mice of strain NMR-I, weighing the acute toxicity was determined from 15 to 20 g. The LD50-N values were after Litchfield-Wilcoxon [J. Pharmak.
exp. Therap. 96, 99 (1949)] berechnet und beziehen sich auf den achten Tag nach der Behandlung. exp. Therap. 96, 99 (1949)] and refer to the eighth Day after treatment.
Die LD50 für 2-(4'-Chlorphenoxy)-2-methylpropionsäure-ethylester [CLOFIBRAT] betrug in dieser Versuchsreihe 1900 mg/kg. Die erfindungsgemäßen Substanzen waren durchweg verträglicher und dem Clofibrat überlegen. The LD50 for 2- (4'-chlorophenoxy) -2-methylpropionic acid ethyl ester [CLOFIBRAT] was 1900 mg / kg in this test series. The substances according to the invention were consistently better tolerated and superior to clofibrate.
2. Lipidsenkende Wirkung Die lipidsenkende Wirkung wurde an Gruppen von jeweils 10 normal gefütterten, normolipämischen, männlichen 200 bis 220 g schweren Wistarratten geprüft.2. Lipid-lowering effect The lipid-lowering effect was given to groups of 10 normally fed normolipemic males weighing 200 to 220 g Wistar rats checked.
Die Testverbindungen wurden in einer wäßrigen Lösung von 0.25 % Agar und 0.85 % Natriumchlorid aufgenommen und oral verabreicht. The test compounds were in an aqueous solution of 0.25% agar and 0.85% sodium chloride and administered orally.
Nach Applikation von 4 x 100 mg/kg über einen Zeitraum von 3 Tagen wurden die Tiere im Anschluß an einen vierstündigen Futterentzug durch Herzpunktion entblutet. After application of 4 x 100 mg / kg over a period of 3 days the animals were subjected to cardiac puncture following a four-hour food deprivation bleeding.
Die Bestimmung des Gesamtcholesterins (TC) wurde enzymatisch nach T.J. Bronzert und H.B. Brewer [Clin.Chem. 23, 2089 (1977)] durchgeführt. Die quantitative Analyse der Triglyceride (TG) erfolgte enzymatisch mit einem im Handel befindlichen Test-Kit nach A.W. Wahlefeld [H.U. Bergaeyer, "Methoden der enzymatischen Analyse", 3. Auflage, Bd. II, Verlag Chemie, Weinheim 1974, Seite 1878] Die lipidsenkende Wirkung ist ausgedrückt als die prozentuale Senkung des Gesamtcholesterins und der Triglyceride gegenüber der Kontrolle. S"::tliche getesteten Verbindungen waren mindes-tens in einem Wert dem Clofibrat überlegen. The determination of total cholesterol (TC) was enzymatically based on T.J. Bronzert and H.B. Brewer [Clin. Chem. 23, 2089 (1977)]. The quantitative Analysis of the triglycerides (TG) was carried out enzymatically using a commercially available one Test kit according to A.W. Wahlefeld [H.U. Bergaeyer, "Methods of Enzymatic Analysis", 3rd edition, Vol. II, Verlag Chemie, Weinheim 1974, page 1878] The lipid-lowering Effect is expressed as the percentage reduction in total cholesterol and the Triglycerides versus control. All compounds tested were at least superior to clofibrate in one value.
Tabelle 3 Prozentuale Senkung der Triglycerid (TG)- und Gesamtcholesterin (TC)-Spiegel im Rattenserum nach oraler Applikation der Testsubstanzen Verbindungsnummer v S e n k u n g TG TC X # Sx X # Sx Vergleichssubstanz Clofibrat 54.8 + 20.1 19.5 + 13.3 1 54.0 + 5.0 31.7 + 10.6 2 63.4 + 5.1 33.6 + 13.9 3 39.4 + 13.5 23.4 + 13.9 4 35.7 + 34.2 38.6 + 10.5 5 41.4 + 16.2 38.6 + 17.7 6 61.6 + 7.8 34.0 + 16.1 7 71.6 + 8.4 45.6 + 13.8 8 61.1 + 11.2 28.6 + 12.3 9 60.3 + 7.9 28.9 + 16.9 10 84.0 + 8.7 56.8 + 13.2 11 82.2 + 10.2 38.5 + 13.7 12 50.3 + 6.7 54.8 + 10.7 13 76.6 + 11.0 37.2 + 17.1 14 49.9 + 6.6 21.3 + 8.2 15 61.0 + 11.1 23.6 + 9.4 16 71.0 + 7.3 27.3 + 18.5 17 63.8 + 8.4 9.9 + 12.5 18 51.2 + 11.4 27.4 + 15.7 19 77.4 + 12.7 33.5 + 12.5 20 80.7 + 9.8 52.9 + 32.9 21 56.9 + 19.9 36.4 + 24.3 22 86.0 + 6.8 53.0 + 6.1 23 84.6 + 7.5 46.2 + 8.9 24 62.4 + 8.0 29.9 + 13.2 25 58.6 + 14.1 26.4 + 15.0Table 3 Percentage reductions in triglyceride (TG) and total cholesterol (TC) level in the rat serum after oral application of the test substances compound number v S e n k u n g TG TC X # Sx X # Sx Reference substance clofibrate 54.8 + 20.1 19.5 + 13.3 1 54.0 + 5.0 31.7 + 10.6 2 63.4 + 5.1 33.6 + 13.9 3 39.4 + 13.5 23.4 + 13.9 4 35.7 + 34.2 38.6 + 10.5 5 41.4 + 16.2 38.6 + 17.7 6 61.6 + 7.8 34.0 + 16.1 7 71.6 + 8.4 45.6 + 13.8 8 61.1 + 11.2 28.6 + 12.3 9 60.3 + 7.9 28.9 + 16.9 10 84.0 + 8.7 56.8 + 13.2 11 82.2 + 10.2 38.5 + 13.7 12 50.3 + 6.7 54.8 + 10.7 13 76.6 + 11.0 37.2 + 17.1 14 49.9 + 6.6 21.3 + 8.2 15 61.0 + 11.1 23.6 + 9.4 16 71.0 + 7.3 27.3 + 18.5 17 63.8 + 8.4 9.9 + 12.5 18 51.2 + 11.4 27.4 + 15.7 19 77.4 + 12.7 33.5 + 12.5 20 80.7 + 9.8 52.9 + 32.9 21 56.9 + 19.9 36.4 + 24.3 22 86.0 + 6.8 53.0 + 6.1 23 84.6 + 7.5 46.2 + 8.9 24 62.4 + 8.0 29.9 + 13.2 25 58.6 + 14.1 26.4 + 15.0
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|---|---|---|---|
| DE19803028776 DE3028776A1 (en) | 1980-07-29 | 1980-07-29 | Hypolipaemic 1,3-di:phenoxy-propanone derivs. - prepd. by oxidn. of hydroxy-propoxy cpds. with di:methyl sulphoxide |
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| DE19803028776 DE3028776A1 (en) | 1980-07-29 | 1980-07-29 | Hypolipaemic 1,3-di:phenoxy-propanone derivs. - prepd. by oxidn. of hydroxy-propoxy cpds. with di:methyl sulphoxide |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8633184B2 (en) | 2006-04-18 | 2014-01-21 | Janssen Pharmaceutica N.V. | Benzoazepin-oxy-acetic acid derivatives as PPAR-delta agonists used for the increase of HDL-C, lower LDL-C and lower cholesterol |
| US8669288B2 (en) | 2005-09-14 | 2014-03-11 | Janssen Pharmaceutica N.V. | Lysine salts of 4-((phenoxyalkyl)thio)-phenoxyacetic acid derivatives |
| EP1794116B1 (en) * | 2004-09-15 | 2015-06-03 | Janssen Pharmaceutica NV | 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs |
| US9724322B2 (en) | 2003-09-19 | 2017-08-08 | Janssen Pharmaceutica N.V. | 4-(phenoxyalkyl)thio)-phenoxyacetic acids and analogs |
-
1980
- 1980-07-29 DE DE19803028776 patent/DE3028776A1/en not_active Withdrawn
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9724322B2 (en) | 2003-09-19 | 2017-08-08 | Janssen Pharmaceutica N.V. | 4-(phenoxyalkyl)thio)-phenoxyacetic acids and analogs |
| EP1794116B1 (en) * | 2004-09-15 | 2015-06-03 | Janssen Pharmaceutica NV | 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs |
| NO338655B1 (en) * | 2004-09-15 | 2016-09-26 | Janssen Pharmaceutica Nv | 4 - ((phenoxyalkyl) thio) phenoxyacetic acid and analogs |
| US8669288B2 (en) | 2005-09-14 | 2014-03-11 | Janssen Pharmaceutica N.V. | Lysine salts of 4-((phenoxyalkyl)thio)-phenoxyacetic acid derivatives |
| US8633184B2 (en) | 2006-04-18 | 2014-01-21 | Janssen Pharmaceutica N.V. | Benzoazepin-oxy-acetic acid derivatives as PPAR-delta agonists used for the increase of HDL-C, lower LDL-C and lower cholesterol |
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