DE3026924A1 - 1,3-Di:phenoxy-propan-2-ol derivs. - used as hypolipaemics to reduce tri:glyceride and cholesterol levels in the blood - Google Patents
1,3-Di:phenoxy-propan-2-ol derivs. - used as hypolipaemics to reduce tri:glyceride and cholesterol levels in the bloodInfo
- Publication number
- DE3026924A1 DE3026924A1 DE19803026924 DE3026924A DE3026924A1 DE 3026924 A1 DE3026924 A1 DE 3026924A1 DE 19803026924 DE19803026924 DE 19803026924 DE 3026924 A DE3026924 A DE 3026924A DE 3026924 A1 DE3026924 A1 DE 3026924A1
- Authority
- DE
- Germany
- Prior art keywords
- general formula
- compounds
- group
- propan
- phenoxy
- 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- Withdrawn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
- 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 title abstract description 12
- 230000000055 hyoplipidemic effect Effects 0.000 title abstract description 5
- 239000008280 blood Substances 0.000 title abstract description 3
- 210000004369 blood Anatomy 0.000 title abstract description 3
- 125000005456 glyceride group Chemical group 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract 2
- 150000001768 cations Chemical class 0.000 claims abstract 2
- 229910052801 chlorine Inorganic materials 0.000 claims abstract 2
- 229910052731 fluorine Inorganic materials 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 5
- 150000007513 acids Chemical class 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- 201000005577 familial hyperlipidemia Diseases 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- HZIVULLSUOJNPX-UHFFFAOYSA-N 3-phenoxypropoxybenzene Chemical compound C=1C=CC=CC=1OCCCOC1=CC=CC=C1 HZIVULLSUOJNPX-UHFFFAOYSA-N 0.000 claims 6
- 229920006395 saturated elastomer Polymers 0.000 claims 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- GYZLOYUZLJXAJU-UHFFFAOYSA-N diglycidyl ether Chemical compound C1OC1COCC1CO1 GYZLOYUZLJXAJU-UHFFFAOYSA-N 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 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
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 abstract description 3
- 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 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 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
- JZOXINJFBGAUKU-UHFFFAOYSA-N 1,3-diphenoxypropan-1-ol Chemical compound C=1C=CC=CC=1OC(O)CCOC1=CC=CC=C1 JZOXINJFBGAUKU-UHFFFAOYSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 150000003626 triacylglycerols Chemical class 0.000 description 5
- -1 1,3-disubstituted propanol Chemical class 0.000 description 4
- 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 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Chemical class 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000001828 Gelatine Substances 0.000 description 3
- 239000002775 capsule Substances 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
- 239000008120 corn starch Chemical class 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007903 gelatin capsule Substances 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
- 238000004949 mass spectrometry Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 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
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229960001214 clofibrate Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229940126601 medicinal product Drugs 0.000 description 2
- 229920001592 potato starch Chemical class 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- KSLSZOOZWRMSAP-UHFFFAOYSA-N 2-[(4-chlorophenoxy)methyl]oxirane Chemical compound C1=CC(Cl)=CC=C1OCC1OC1 KSLSZOOZWRMSAP-UHFFFAOYSA-N 0.000 description 1
- CGWDABYOHPEOAD-UHFFFAOYSA-N 2-[(4-fluorophenoxy)methyl]oxirane Chemical compound C1=CC(F)=CC=C1OCC1OC1 CGWDABYOHPEOAD-UHFFFAOYSA-N 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
- 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
- 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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 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
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical group NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 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 1
- 229930006000 Sucrose Chemical class 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 230000002378 acidificating effect Effects 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
- 150000001447 alkali salts Chemical class 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
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000740 bleeding effect Effects 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
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 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
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 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
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000005720 sucrose Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical group SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 1
- 230000020192 tolerance induction in gut-associated lymphoid tissue Effects 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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Titel: 1,3-Diphenoxypropan-2-ol-Derivate sowieTitle: 1,3-Diphenoxypropan-2-ol-Derivate as well
Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel B e s c h r e i b u nm Aus der DE-PS 24 60 689 sind 1,3-disubstituierte Propanol-(2)-Derivate bekannt, bei denen die Substituenten Phenolgruppen bzw. Thiophenolgruppen oder auch eine Anilingruppe darstellen können und der jeweilige aromatische Ring noch einen weiteren bestimmten Substituenten enthält. Bekannt geworden sind auch 1,3-Diphenoxypropanol-(2)-Derivate, die entweder noch eine besondere Ester-bzw. Säureamidfunktion besitzten (DE-OS 26 25 688) oder am sekundären Hydroxyl einen geeigneten Substituenten tragen (DE-OS 26 25 689) Diese Substanzen eignen sich als Wirkstoffe für Arzneimittel bei der Bekämpfung der Hyperlipämie, da sie sich bei guter Verträglichkeit durch eine starke lipidsenkende Wirkung auszeichnen. Process for their production and medicaments containing them B. e s c h r e i b u nm DE-PS 24 60 689 discloses 1,3-disubstituted propanol (2) derivatives known in which the substituents are phenol groups or thiophenol groups or else can represent an aniline group and the respective aromatic ring still another contains further specific substituents. 1,3-Diphenoxypropanol (2) derivatives have also become known, which either have a special ester or. Have acid amide function (DE-OS 26 25 688) or carry a suitable substituent on the secondary hydroxyl (DE-OS 26 25 689) These substances are suitable as active ingredients for drugs in the Combat hyperlipemia, as it can be characterized by strong if well tolerated distinguish lipid-lowering effect.
Es wurde nun überraschenderweise festgestellt, daß bestimmte neue i,3-Diphenoxypropan-2-ol-Derivate der im Patentanspruch 1 angegebenen Formel (1), die sich insbesondere durch eine zusätzliche Methylgruppe am C-Atom in A-Stellung der vorbekannten Proprionsäurederivate der Diphenoxypropanole unterscheiden, ebenfalls eine starke hypolipämische Wirkung besitzen, die auch gegenüber 2-(4'-Chlorphenoxy)-2-methylpropionsäure-ethylester (CLOFIBRAT) deutlich überlegen ist. Diese Verbindungen verringern bei sehr guter Verträglichkeit insbesondere den Triglyceridspiegel und bzw. oder den Cholesterinspiegel des Blutes.It has now surprisingly been found that certain new i, 3-Diphenoxypropan-2-ol derivatives of the formula (1) given in claim 1, which is characterized in particular by an additional methyl group on the C atom in the A position of the known proprionic acid derivatives of diphenoxypropanols also differ have a strong hypolipemic effect that too opposite to Clearly superior to ethyl 2- (4'-chlorophenoxy) -2-methylpropionate (CLOFIBRAT) is. With very good compatibility, these compounds reduce in particular the Triglyceride level and / or the cholesterol level in the blood.
Die Herstellung dieser neuen hypolipämisdi wirkenden Verbindungen kann in an sich bekannter Weise erfolgen, wobei man erfindungsgemäß die in Anspruch 2 angegebenen Verfahren anwendet.The manufacture of these new hypolipaemic compounds can be carried out in a manner known per se, according to the invention being the one in claim 2 applies.
Wenn die Herstellung der freien Säuren nach Formel (1) gewünscht wird, werden die entsprechenden Ester, vorzugsweise ethylester nach Formel (1), in vorteilhafter Weise mittels wäßrig-alkoholischer Alkalilauge versteift. Aus den hierbei in alkalischer Lösung vorliegenden Alkalisalzen können dann die Säuren durch Zugabe von Mineralsäuren, z.B. mit Salzsäure freigesetzt werden.If the preparation of the free acids according to formula (1) is desired, the corresponding esters, preferably ethyl esters according to formula (1), are more advantageous Way stiffened by means of aqueous-alcoholic alkali. From the here in alkaline Alkali salts present in the solution can then be removed from the acids by adding mineral acids, e.g. released with hydrochloric acid.
Die Herstellung der verschiedenen Salze nach Formel (1) kann in der Weise erfolgen, daß man die Säuren in wäßrig-alkoholischem Milieu mit Basen der Alkali- bzw. Erdalkalireihe, mit Aluminiumbasen, ferner mit Ammoniak oder anderen therapeutsch 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 Can react therapeuteutsch usable amines according to known methods.
Die Esterverbindungen nach Formel (1) können, soweit deren Herstellung nicht gemäß den in Anspruch 2 beschriebenen Verfahren erfolgt, nach Standardverfahren durch Veresterung der Carbonsäuren nach Formel (1) mit dem entsprechenden Alkohol unter Verwendung eines sauren Katalysators in an sich bekannter Weise erhalten werden.The ester compounds according to formula (1) can, insofar as their preparation not carried out according to the method described in claim 2, according to standard methods by esterification of the carboxylic acids according to formula (1) with the corresponding alcohol can be obtained using an acidic catalyst in a manner known per se.
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 W1aisstärke, 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 physikalischen Eigenschaften des Wirkstoffes wird eine Verarbeitung zu Granulaten bevorzugt, wobei als Hilfsstoffe Kartoffel- oder Maisstärke, mikronisierte Cellulose, Cellulosederivate, Gelatine oder auchhochdisperse 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 physical properties of the active ingredient are appropriate, processing to granules preferred, with potato or corn starch, micronized as auxiliaries Cellulose, cellulose derivatives, gelatine or highly disperse 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 Polyethylenglykolen 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.butyl-phenoxy)-propan- 2-ol 21.4 g (0.1 Mol) 3-(4'-Hydroxyphenyl)-2-methylpropionsäure-methylester1) und 1.32 g (0.024 Mol) Natriummethylat werden in 150 ml Methanol gelöst und nach Zugabe von 20.6 g (0.1 Mol) 3-(4'-tert.-Butylphenoxy)-1,2-epoxypropan 16 Stdn. unter Rückfluß erhitzt.Example 1 3- [4 '- (2-Methoxycarbonylpropyl) -phenoxy] -1- (4'-tert-butyl-phenoxy) -propane- 2-ol 21.4 g (0.1 mol) methyl 3- (4'-hydroxyphenyl) -2-methylpropionate1) and 1.32 g (0.024 mol) of sodium methylate are dissolved in 150 ml of methanol and after addition of 20.6 g (0.1 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 säulenchromatographisch 20 gereinigt. Farblose, hochviskose Flüssigkeit; nD = 1.5307; Ausbeute : 28.3 g (71 %).Then the solvent is in vacuo. removed the residue taken up in ether and, after shaking out several times with 1 N sodium hydroxide solution, with Washed neutral in water. After drying over sodium sulfate, the solvent becomes i.Vac. removed and the oily crude product on silica gel with chloroform column chromatography 20 cleaned. Colorless, highly viscous liquid; nD = 1.5307; Yield: 28.3 g (71%).
24 32 5 (400.5) Mol.-Gew. : 400 (massenspektrometrisch bestimmt)2) -i IR-Spektrum (Film) : e (0-H) : 3450 cm -1 r (C=0) : 1725 cm H-NtE-Spektrum (CDCl3) 3) : 1.o bis 1.4 m und 1.3 s (12) CH3C und (CH3)3C 2.7 m (4) CH2CH und OH 3.6 s (3) OCH3 4.1 m (5) CH2CHCH2 6.6 bis 7.4 m (8) Aromat.24 32 5 (400.5) mol. Wt. : 400 (determined by mass spectrometry) 2) -i IR spectrum (film): e (0-H): 3450 cm -1 r (C = 0): 1725 cm H-NtE spectrum (CDCl3) 3): 1.o to 1.4 m and 1.3 s (12) CH3C and (CH3) 3C 2.7 m (4) CH2CH and OH 3.6 s (3) OCH3 4.1 m (5) CH2CHCH2 6.6 to 7.4 m (8) aromatic.
)hergestellt durch Hydrierung von 4'-Hydroxy-2-methylzimtsäure-methylester nach bekannten Verfahren )bestimmt mittels Elektronenstoß-Ionisation (70 eV) )aufgenommen bei 60 MHZ die chemischen Verschiebungen sind in ppm gegen TMS (a= 0.0) angegeben, die relativen Intensitäten sind in Klammern beigefügt.) produced by hydrogenation of methyl 4'-hydroxy-2-methylcinnamate according to known methods) determined by means of electron impact ionization (70 eV)) recorded at 60 MHz the chemical shifts are given in ppm against TMS (a = 0.0), the relative intensities are given in brackets.
s = Singulett; d = Dublett; t = Triplett; m - Multiplett Beispiel 2 3-[4'-(2-Propoxycarbonyl-1-propenyl)-phenoxy] -1-(4'-fluorphenoxy)-propan-2-ol 0.15 g (0.006 gAtom) Natrium werden in 700 ml n-Propanol gelöst und nach Zugabe von 36.0 g (0.1 Mol) 3-[4'-Methoxycarbonyl-1-propenyl)-phenoxi -1-(4'-fluorphenoxy)-propan-2-ol [hergestellt aus 4'-Hydroxy-2-methylzimtsäure-methylester1) und 3-(4'Fluorphenoxy)-1,2-epoxypropan analog Beispiel 1] 40 Stdn. unter Rückfluß erhitzt. Anschließend werden die leicht flüchtigen Anteile i.Vak. entfernt, der Rückstand in Ether aufgenommen und nach mehrmaligem Ausschütteln mit 2 N Natronlauge, mit Wasser neutral gewaschen. Nach dem Trocknen über Natriumsulfat wird das Lösungsmittel i.Vak. entfernt und das Rohprodukt aus Di-isopropylether/Petrolether kristallisiert. Aus den Mutterlaugen läßt sich säulenchromatographisch an Kieselgel mit Chloroform noch ein weiterer Anteil an reinem Material gewinnen. Farblose Kristalle vom Schmp. 54 bis 55° C.; Ausbeute 27.7 g (71 Z). s = singlet; d = doublet; t = triplet; m - multiplet example 2 3- [4 '- (2-propoxycarbonyl-1-propenyl) -phenoxy] -1- (4'-fluorophenoxy) -propan-2-ol 0.15 g (0.006 gAtom) sodium are dissolved in 700 ml n-propanol and after addition of 36.0 g (0.1 mol) of 3- [4'-methoxycarbonyl-1-propenyl) -phenoxi -1- (4'-fluorophenoxy) -propan-2-ol [prepared from methyl 4'-hydroxy-2-methylcinnamate1) and 3- (4'-fluorophenoxy) -1,2-epoxypropane analogous to Example 1] heated under reflux for 40 hours. Then they will be easy volatile components in vacuo removed, the residue taken up in ether and after repeated shaking with 2 N sodium hydroxide solution, washed neutral with water. To drying over sodium sulfate, the solvent is in vacuo. removed and the crude product crystallized from di-isopropyl ether / petroleum ether. From the mother liquor can be Column chromatography on silica gel with chloroform still contains a further portion win pure material. Colorless crystals with a melting point of 54 to 55 ° C .; yield 27.7 g (71 T).
C22H25FO5 (388.4) Mol. Gew.: 388 (massenspektrometrisch bestinumt) IR-Spektrum (KBr) : # (O-H) 3500 cm > (C=O) 1695 cm # (C=C) 1620 cm ¹H-NMR-Spektrum (CDCl3) : 1.0 t (3) CH3CH2CH2 1.7 m (2) CH3CH2CH2 2.1 d (3) CH3C= 2.9 d (1) OH 4.2 (Schwerpunkt) m (7) CHZCHCH2 und OCH2CH2 6.7 bis 7.8 m (9) Aromat und CH= 1)hergestellt gemäß J.Amer.Chem.Soc. 80 4949 (1958) / Beispiel 3 3-[4'-(2-Allyloxycarbonyl-1-propenyl)-phenoxy] -1-(4'-chlorphenoxy)-propan-2-ol 1.12 g (0.02 Mol) Kaliumhydroxid werden unter Erwärmen in 750 ml Allylalkohol gelöst und nach Zugabe von 37.7 g (0.1 Mol) 3-[4'-(2-Methoxycarbonyl-1-propenyl)phenoxy] -1-(4'-chlorphenoxy)-propan-2-ol [hergestellt aus 4'-Hydroxy-2-methylzimtsäure-methylester und 3-(4'-Chlorphenoxy)-1,2-epoxypropan, analog Beispiel 1] 16 Stdn. unter Rückfluß erhitzt. Anschließend werden die leichtflüchtigen Anteile i.Vak. entfernt, der Rückstand in Ether aufgenormen und mit Wasser neutral gewaschen. Nach dem Trocknen über Natriumsulfat wird der Ether i.Vak. entfernt und das verbleibende ölige Rohprodukt an Kieselgel mit Chloroform säulenchromatographisch gereinigt. Farblose Kristalle vom Schmp. 57 bis 58° C (1-Chlorbutan-Petrolether); Ausbeute 26.7 g (66 %).C22H25FO5 (388.4) Mol. Weight: 388 (determined by mass spectrometry) IR spectrum (KBr): # (O-H) 3500 cm> (C = O) 1695 cm # (C = C) 1620 cm 1 H-NMR spectrum (CDCl3): 1.0 t (3) CH3CH2CH2 1.7 m (2) CH3CH2CH2 2.1 d (3) CH3C = 2.9 d (1) OH 4.2 (Focus) m (7) CHZCHCH2 and OCH2CH2 6.7 to 7.8 m (9) aromatic and CH = 1) produced according to J.Amer.Chem.Soc. 80 4949 (1958) / Example 3 3- [4 '- (2-Allyloxycarbonyl-1-propenyl) -phenoxy] -1- (4'-chlorophenoxy) -propan-2-ol 1.12 g (0.02 mol) of potassium hydroxide are added with heating dissolved in 750 ml of allyl alcohol and, after adding 37.7 g (0.1 mol) of 3- [4 '- (2-methoxycarbonyl-1-propenyl) phenoxy] -1- (4'-chlorophenoxy) -propan-2-ol [prepared from methyl 4'-hydroxy-2-methylcinnamate and 3- (4'-chlorophenoxy) -1,2-epoxypropane, analogous to Example 1] 16 hours under reflux heated. Then the volatile components are vacuumed. removed the residue Take up in ether and wash until neutral with water. After drying over sodium sulfate is the ether in vacuo. removed and the remaining oily crude product on silica gel purified by column chromatography with chloroform. Colorless crystals from m.p. 57 to 58 ° C (1-chlorobutane petroleum ether); Yield 26.7g (66%).
C22H23ClO5 (402.9) fIol.-Gew. 402 (massenspektrome;risch bestimmt) -i IR-Spektrum (KBr) : v (O-H) 351G cm -1 v (C=O) 1695 cm -1 i(C=C) 1620 cm EI-N5.R-Spektrum (CDCl3) : 2.1 d (3) CH3C= 2.7 d (1) OH 4.2 m (5) CH2CHCH2 4.7 m (2) OCH2CH= 5.3 (Schwerpunkt) m (2) CH2=CHCH2 5.9 (Schwerpunkt) m (1) CH2=CHCH2 6.7 bis 7.7 m (9) Aromat und C6H4CH= In analoger Weise zu den Beispielen 1 bis 3 wurden weitere Verbindungen der allgemeinen Formel (1) hergestellt und in nachfolgender Tabelle 1 mit physikalischen Kennzahlen aufgeführt. Aus Gründen der Vollständigkeit werden in den folgenden Tabellen die in den Beispielen beschriebenen Verbindungen nochmals angegeben.C22H23ClO5 (402.9) oil wt. 402 (mass spectrometry; determined electronically) -i IR spectrum (KBr): v (O-H) 351G cm -1 v (C = O) 1695 cm -1 i (C = C) 1620 cm EI-N5.R spectrum (CDCl3): 2.1 d (3) CH3C = 2.7 d (1) OH 4.2 m (5) CH2CHCH2 4.7 m (2) OCH2CH = 5.3 (Center of gravity) m (2) CH2 = CHCH2 5.9 (center of gravity) m (1) CH2 = CHCH2 6.7 to 7.7 m (9) Aromatic and C6H4CH = In a manner analogous to Examples 1 to 3, further compounds were made of the general formula (1) and in the following Table 1 with physical Key figures listed. For the sake of completeness, the tables below the compounds described in the examples are given again.
Tabelle 1 20° Nr. R1 A-COOR2 Schmp.(°C)*)bzw. nD **) 1 F CH=C(CH3)COOCH3 63 bis 5 (Methanol/Wasser) 2 F CH=C(CH3)COOCH2CH2CH3 54 bis 5 (Diisopropyl-/PetroSether) 3 F CH=C(CH3)COOGH2OCH3 61 bis 2 (Diisopropylether) 4 F CH2CH(CH3)COOCH2CH3 1.5304 **) 5 F CH2CH(CH3)COOCH2CH2OCH3 1.5293 **) 6 F CH2CH(CH3)COOCH2CH=CH2 1.5353 **) 7 Cl CH=C(CH3)COOCH3 63 (Chloroform) 8 Cl CH=C(CH3)COOCH2CH3 66 bis 7 (Diisopropylether) 9 Cl CH=C(CH3)COOCH(CH3)2 1.5849 **) 10 Cl CH=C(CH3)COOCH2CH=CH2 57 bis 8 (1-Chlorbutan/Petrolether) 11 Cl t CH=C(CH3)COOCH2OCH3 73 bis 6 (Diisopropylether) 12 Cl CH2CH(CH3)COOCH3 1.5523 **) 13 Cl CH2CH(CH3)COOCH2CH2OCH3 1.5438 **) 14 Cl CH2CH(CH3)COOCH2CH2CH3 1.5424 .*) 15 Cl CH2CH(CH3)COOCH2C-CH 1.5554 **) 16 (CH3) 3C CH=C(CH3)COOCH3 1.5766 **) 17 (CH3)3C CH=C(CH3)COOCH2CH2OCH3 47 bis 9 (Petrolether) 18 (CH3)3C CH=C(CH3)COOCH2CH=CH2 1.5745 **) 19 (CH3)3C CH2CH(CH3)COOCH3 1.5307 **) 20 (CH3)3C CH2CH(CH3)COOCH2CH=CH2 1.5348 **) *) Die Schmelzpunkte wurden mit einem Kofler-Heiztisch-Mikroskop ermittelt und sind nicht korrigiert.Table 1 20 ° No. R1 A-COOR2 melting point (° C) *) or. nD **) 1 F CH = C (CH3) COOCH3 63 to 5 (methanol / water) 2 F CH = C (CH3) COOCH2CH2CH3 54 to 5 (diisopropyl / petroleum ether) 3 F CH = C (CH3) COOGH2OCH3 61 to 2 (Diisopropylether) 4 F CH2CH (CH3) COOCH2CH3 1.5304 **) 5 F CH2CH (CH3) COOCH2CH2OCH3 1.5293 **) 6 F CH2CH (CH3) COOCH2CH = CH2 1.5353 **) 7 Cl CH = C (CH3) COOCH3 63 ( Chloroform) 8 Cl CH = C (CH3) COOCH2CH3 66 to 7 (diisopropyl ether) 9 Cl CH = C (CH3) COOCH (CH3) 2 1.5849 **) 10 Cl CH = C (CH3) COOCH2CH = CH2 57 to 8 (1 -Chlorobutane / petroleum ether) 11 Cl t CH = C (CH3) COOCH2OCH3 73 to 6 (diisopropyl ether) 12 Cl CH2CH (CH3) COOCH3 1.5523 **) 13 Cl CH2CH (CH3) COOCH2CH2OCH3 1.5438 **) 14 Cl CH2CH (CH3) COOCH2CH2CH3 1.5424. *) 15 Cl CH2CH (CH3) COOCH2C-CH 1.5554 **) 16 (CH3) 3C CH = C (CH3) COOCH3 1.5766 **) 17 (CH3) 3C CH = C (CH3) COOCH2CH2OCH3 47 to 9 (petroleum ether ) 18 (CH3) 3C CH = C (CH3) COOCH2CH = CH2 1.5745 **) 19 (CH3) 3C CH2CH (CH3) COOCH3 1.5307 **) 20 (CH3) 3C CH2CH (CH3) COOCH2CH = CH2 1.5348 **) * ) The melting points were determined with a Kofler hot stage microscope and are not corrected ert.
**) Viskoses Öl, durch Säulenchromatographie gereinigt und durch Brechungsindex charakterisiert.**) Viscous oil, purified by column chromatography and by refractive index characterized.
Beispiel 4 3-[4'-(2-Carboxypropyl)-phenoxy]-1-(4'-tert.butylphenoxy)-propan-2-ol 40.0 g (0.1 Mol) 3-[4'-(2-Methoxycarbonylpropyl)-phenoxy] -1-(4'-tert.butylphenoxy)-propan-2-ol werden in 90 ml Ethanol gelöst und nach Zugabe von 18.2 g (0.325 Mol) Kaliumhydroxid in 45 ml Wasser 8 Stdn. unter Rückfluß erhitzt. Anschließend werden die leichtflüchtigen Anteile i.Vak. entfernt, der Riickstand in Wasser gelöst und mit konz. Salzsäure angesäuert. Die sich ölig abscheidende organische Säure wird in Ether aufgenommen und mit Wasser gewaschen. Nach dem Trocknen über Natriumsulfat wird der Ether i. Vak. entfernt und der Rückstand an Kieselgel mit Dichlormethan/Methanol (97/3) säulenchromatographisch gereinigt.Example 4 3- [4 '- (2-Carboxypropyl) phenoxy] -1- (4'-tert-butylphenoxy) propan-2-ol 40.0 g (0.1 mol) 3- [4 '- (2-methoxycarbonylpropyl) -phenoxy] -1- (4'-tert-butylphenoxy) -propan-2-ol are dissolved in 90 ml of ethanol and, after the addition of 18.2 g (0.325 mol) of potassium hydroxide refluxed in 45 ml of water for 8 hours. Then the volatile Shares in vacuo removed, the residue dissolved in water and treated with conc. hydrochloric acid acidified. The oily organic acid which separates out is taken up in ether and washed with water. After drying over sodium sulfate, the ether is i. Vac. removed and the residue on silica gel with dichloromethane / methanol (97/3) by column chromatography cleaned.
Farbloses Öl, nß = 1.5474; Ausbeute 13.7 g (35 %).Colorless oil, NS = 1.5474; Yield 13.7g (35%).
C931i3005 (386.5) !'ol.-Gew.: 386 (massens?ektrometrisch bestimmt) -1 IR-Spektrum (CHCl ) # (O-H) 3600 bis 2500 cm 3 -1 >tC=O) 1700 cm ¹H-NMR-Spektrum (CDCl3) 1.0 bis 1.4 m und 1.3 s (12) CH3C und (CH3)3C 2.8 m (3) CH2CH 4.1 m (5) CH2CHCH2 6.6 bis 7.4 m (10) Aromat, OH, COOH 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.C931i3005 (386.5)! 'Oil weight: 386 (determined by mass ectrometrically) -1 IR spectrum (CHCl3) # (O-H) 3600 to 2500 cm 3 -1> tC = O) 1700 cm 1 H-NMR spectrum (CDCl3) 1.0 to 1.4 m and 1.3 s (12) CH3C and (CH3) 3C 2.8 m (3) CH2CH 4.1 m (5) CH2CHCH2 6.6 to 7.4 m (10) Aromat, OH, COOH In an analogous manner to Example 4 were other compounds of general formula 1 prepared and in the table below 2 listed with physical key figures. For the sake of completeness the connection described in the example is given again in the following table.
Tabelle 2 20° Nr. R1 A-COOR2 Schmp.(°C)*) bzw.nD **) 21 F C11=C(CH3)COOH 139 bis 41 (Benzol) 22 F CH2CH(CH3)COOH 1.5497 **) 23 Cl CH=C(CH3)COOH 115 (Chloroform) 24 Cl CH2CH(CH3)COOH 1.5672 **) 25 (CH3)3C CH=C(CH3)COOH 117 bis 18 (A.etonitril) 26 (CH3)3C CH2CH(CH3)COOH 1.5474 **) *) Die Schmelzpunkte wurden mit einem Kofler-h.eiztisch-Mikroskop ermittelt und sind nicht korrigiert.Table 2 20 ° No. R1 A-COOR2 melting point (° C) *) or nD **) 21 F C11 = C (CH3) COOH 139 to 41 (benzene) 22 F CH2CH (CH3) COOH 1.5497 **) 23 Cl CH = C (CH3) COOH 115 (chloroform) 24 Cl CH2CH (CH3) COOH 1.5672 **) 25 (CH3) 3C CH = C (CH3) COOH 117 to 18 (A.etonitrile) 26 (CH3) 3C CH2CH (CH3 ) COOH 1.5474 **) *) The melting points were determined with a Kofler heating table microscope and are not corrected.
**) Viskoses Öl, durch Säulenchromatographie gereinigt und durch Brechungsindex charakterisiert.**) Viscous oil, purified by column chromatography and by refractive index characterized.
Beispiel 5 3-[4'-(2-Methoxycarbonylpropyl)-phenoxy] -1-(4'-tert.butylphenoxy)-propan-2-ol enthaltendes Arzneimittel 100 g 3-[4'-(2-Methoxycarbonylpropyl)-phenoxy] -1-(4'-tert.butylphenoxy)-propan-2-ol 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-ol Medicinal product containing 100 g of 3- [4 '- (2-methoxycarbonylpropyl) -phenoxy] -1- (4'-tert-butylphenoxy) -propan-2-ol 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-Allyloxycarbonyl-1-propenyl)-phenoxy] -1-(4'-chlorphenoxy)-propan-2-ol enthaltendes Arzneimittel Eine fein gepulverte Mischung von 250 g 3-[4'-(2-Allyloxyearbonyl-1-propenyl)-phenoxyj -1-(4'-chlorphenoxy)-propan-2-ol, 133 g Maisstärke, 12 g Magnesiumstearat und 5 g Gelatine wird durch ein feinmaschiges Sieb gepreßt und anschließend in eintausend Hartgelatinekapseln trocken eingefüllt die je 250 mg Wirkstoff enthalten.Example 6 3- [4 '- (2-Allyloxycarbonyl-1-propenyl) -phenoxy] -1- (4'-chlorophenoxy) -propan-2-ol Medicinal product containing a finely powdered mixture of 250 g of 3- [4 '- (2-Allyloxyearbonyl-1-propenyl) -phenoxyj -1- (4'-chlorophenoxy) -propan-2-ol, 133 g corn starch, 12 g magnesium stearate and 5 g of gelatin is pressed through a fine-mesh sieve and then into a thousand Hard gelatine capsules filled dry, each containing 250 mg of active ingredient.
Beisziel~~ Pharmakologische Testung 1. Orale Verträglichkeit Nach oraler Applikation der Testverbindungen an Mäusen vom Stamm DJ.NE-I, mit einem Gewicht von 15 bis 20 g wurde die akute Toxizität bestimmt. Die LD50-Werte wurden nach Litchfield-Wilcoxon [J.Pharmak.Beisziel ~~ Pharmacological testing 1. Oral tolerance According to oral application of the test compounds to mice of the strain DJ.NE-I, weighing the acute toxicity was determined from 15 to 20 g. The LD50 values were according to 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-methy1propionsäure-ethylester [CLOFIBRAM 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 [CLOFIBRAM was 1900 mg / kg in this test series. The substances according to the invention were consistently better tolerated and superior to clofibrate.
2. LiDidsenk~nd~~Wi~k~nQ Die lipidsenkende Wirkung wurde an Gruppen von jeweils 10 normal gefütterten, normolipämischen, männlichen 200 bis 220 g schweren Wistarratten geprüft.2. LiDidsenk ~ nd ~~ Wi ~ k ~ nQ The lipid-lowering effect was applied 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 Z Agar und 0.85 % Natriumchlorid aufgenommen und oral verabreicht. The test compounds were in an aqueous solution of 0.25 Z 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)] durchgefiihrt. Die quantitative Analyse der Triglyceride (TG) erfolgte enzymatisch mit einem im wandel befindlichen Test-Kit nach A.W. Wahlefeld [H.U. Bergmeyer, "Methoden der enzymatischen Analyse", 3. Auflage, Bd. II, Verlag Chemie, Weinheim 1974, Seite 1870 Die lipidsenkende Wirkung ist ausgedrückt als die prozentuale Senkung des Gesamtcholesterins und der Triglyceride gegenüber der Kontrolle. 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 with a changing Test kit according to A.W. Wahlefeld [H.U. Bergmeyer, "Methods of Enzymatic Analysis", 3rd edition, Vol. II, Verlag Chemie, Weinheim 1974, page 1870 The lipid-lowering effect is expressed as the percentage reductions in total cholesterol and triglycerides versus control.
Sämtliche getesteten Verbindungen waren mindestens in einem Wert dem Clofibrat überlegen. All compounds tested were of at least one value superior to clofibrate.
Tabelle Prozentuale Senkung der Triglycerid (TG) - und Gesamtcholesterin (TC)-Spiegel im Rattenserum nach oraler Applikation der Testsubstanzen Verbindungsnummer % S e n k u n g TG TC X # Sx X # Sx Vergleichssubstanz Glofibrat 54.8 + 20.1 19.5 + 13.3 1 58.3 # 14.3 37.2 # 10.0 2 81.5 + 9.5 38.4 + 12.9 3 62.1 + 18.6 36.4 + 21.8 4 33.6 + 11.9 45.5 + 5.9 5 73.' + 5.2 41.5 + 15.4 6 43.1 + 25.5 36.4 + 11.6 7 70.8 + 4.6 40.4 + 8.9 8 47.8 + 5.9 36.5 + 10.3 9 58.4 + 5.0 41.7 + 10.2 10 71.1 + 7.7 43.2 + 14.6 11 58.3 + 10.3 56.5 + 16.7 12 82.6 + 6.7 43.7 + 8.3 13 60.4 + 15.6 50.4 + 11.8 14 76.5 + 10.8 45.4 + 12.9 15 53.6 + 9.0 47.0 + 16.5 16 65.3 + 6.9 24.2 + 12.4 17 71.1 + 8.6 38.7 + 16.4 18 67.0 + 8.6 38.2 + 14.5 19 89.1 + 5.1 46.2 + 11.4 20 45.0 + 13.7 21.8 + 13.6 21 66.1 + 14.4 35.5 + 11.3 22 54.7 + 10.5 26.8 + 16.5 23 75.3 + 14.4 30.1 + 15.5 24 85.2 + 11.7 55.4 + 8.4 25 64.0 + 11.6 32.2 + 13.6 26 86.5 + 5.7 40.7 + 8.6Table of percent reductions in triglyceride (TG) and total cholesterol (TC) level in the rat serum after oral application of the test substances compound number % S e n k u n g TG TC X # Sx X # Sx Reference substance glofibrate 54.8 + 20.1 19.5 + 13.3 1 58.3 # 14.3 37.2 # 10.0 2 81.5 + 9.5 38.4 + 12.9 3 62.1 + 18.6 36.4 + 21.8 4 33.6 + 11.9 45.5 + 5.9 5 73. ' + 5.2 41.5 + 15.4 6 43.1 + 25.5 36.4 + 11.6 7 70.8 + 4.6 40.4 + 8.9 8 47.8 + 5.9 36.5 + 10.3 9 58.4 + 5.0 41.7 + 10.2 10 71.1 + 7.7 43.2 + 14.6 11 58.3 + 10.3 56.5 + 16.7 12 82.6 + 6.7 43.7 + 8.3 13 60.4 + 15.6 50.4 + 11.8 14 76.5 + 10.8 45.4 + 12.9 15 53.6 + 9.0 47.0 + 16.5 16 65.3 + 6.9 24.2 + 12.4 17 71.1 + 8.6 38.7 + 16.4 18 67.0 + 8.6 38.2 + 14.5 19 89.1 + 5.1 46.2 + 11.4 20 45.0 + 13.7 21.8 + 13.6 21 66.1 + 14.4 35.5 + 11.3 22 54.7 + 10.5 26.8 + 16.5 23 75.3 + 14.4 30.1 + 15.5 24 85.2 + 11.7 55.4 + 8.4 25 64.0 + 11.6 32.2 + 13.6 26 86.5 + 5.7 40.7 + 8.6
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19803026924 DE3026924A1 (en) | 1980-07-16 | 1980-07-16 | 1,3-Di:phenoxy-propan-2-ol derivs. - used as hypolipaemics to reduce tri:glyceride and cholesterol levels in the blood |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19803026924 DE3026924A1 (en) | 1980-07-16 | 1980-07-16 | 1,3-Di:phenoxy-propan-2-ol derivs. - used as hypolipaemics to reduce tri:glyceride and cholesterol levels in the blood |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE3026924A1 true DE3026924A1 (en) | 1982-02-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19803026924 Withdrawn DE3026924A1 (en) | 1980-07-16 | 1980-07-16 | 1,3-Di:phenoxy-propan-2-ol derivs. - used as hypolipaemics to reduce tri:glyceride and cholesterol levels in the blood |
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| DE (1) | DE3026924A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002100812A1 (en) * | 2001-04-20 | 2002-12-19 | Eisai Co., Ltd. | Carboxylic acid derivative and salt thereof |
| US7371777B2 (en) | 2001-08-17 | 2008-05-13 | Eisai Co., Ltd. | Cyclic compound and PPAR agonist |
| 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 |
| EP1791812B1 (en) * | 2004-09-15 | 2015-11-04 | 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
- 1980-07-16 DE DE19803026924 patent/DE3026924A1/en not_active Withdrawn
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002100812A1 (en) * | 2001-04-20 | 2002-12-19 | Eisai Co., Ltd. | Carboxylic acid derivative and salt thereof |
| RU2316537C2 (en) * | 2001-04-20 | 2008-02-10 | ЭЙСАЙ Ар энл Ди МЕНЕДЖМЕНТ КО., ЛТД. | Derivatives of carboxylic acid, their pharmaceutically acceptable salts or esters, medicinal agent and pharmaceutical composition based on thereof, their using and methods for treatment and prophylaxis of diseases |
| US7544835B2 (en) | 2001-04-20 | 2009-06-09 | Eisai R&D Management Co., Ltd. | Carboxylic acid derivative and salt thereof |
| SG161743A1 (en) * | 2001-04-20 | 2010-06-29 | Eisai R&D Man Co Ltd | Carboxylic acid derivative and salt thereof |
| US7371777B2 (en) | 2001-08-17 | 2008-05-13 | Eisai Co., Ltd. | Cyclic compound and PPAR agonist |
| US9724322B2 (en) | 2003-09-19 | 2017-08-08 | Janssen Pharmaceutica N.V. | 4-(phenoxyalkyl)thio)-phenoxyacetic acids and analogs |
| EP1791812B1 (en) * | 2004-09-15 | 2015-11-04 | Janssen Pharmaceutica NV | 4-((phenoxyalkyl)thio)-phenoxyacetic acids 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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