NO743815L - - Google Patents
Info
- Publication number
- NO743815L NO743815L NO743815A NO743815A NO743815L NO 743815 L NO743815 L NO 743815L NO 743815 A NO743815 A NO 743815A NO 743815 A NO743815 A NO 743815A NO 743815 L NO743815 L NO 743815L
- Authority
- NO
- Norway
- Prior art keywords
- compound
- physiologically acceptable
- acid addition
- compound according
- acceptable acid
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 60
- 239000002253 acid Substances 0.000 claims description 24
- 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 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 14
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 9
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 7
- 235000012000 cholesterol Nutrition 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 7
- 210000002966 serum Anatomy 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 6
- 229960004889 salicylic acid Drugs 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 150000002632 lipids Chemical class 0.000 claims description 4
- -1 3-pyridylmethyl ester Chemical class 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- IUARHVXKYGPXEP-UHFFFAOYSA-N 2-[2-(4-chlorophenoxy)-2-methylpropanoyl]oxybenzoic acid Chemical compound C=1C=CC=C(C(O)=O)C=1OC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 IUARHVXKYGPXEP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000007903 gelatin capsule Substances 0.000 description 6
- 210000002784 stomach Anatomy 0.000 description 6
- 241000700198 Cavia Species 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000011010 flushing procedure Methods 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 229960003512 nicotinic acid Drugs 0.000 description 4
- 235000001968 nicotinic acid Nutrition 0.000 description 4
- 239000011664 nicotinic acid Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 229920001592 potato starch Polymers 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- MVQVNTPHUGQQHK-UHFFFAOYSA-N 3-pyridinemethanol Chemical compound OCC1=CC=CN=C1 MVQVNTPHUGQQHK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 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 3
- KUEUWHJGRZKESU-UHFFFAOYSA-N Niceritrol Chemical compound C=1C=CN=CC=1C(=O)OCC(COC(=O)C=1C=NC=CC=1)(COC(=O)C=1C=NC=CC=1)COC(=O)C1=CC=CN=C1 KUEUWHJGRZKESU-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229960000827 niceritrol Drugs 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- IWBWXPBNVXPLRS-UHFFFAOYSA-N pyridin-3-ylmethyl 2-hydroxybenzoate Chemical compound OC1=CC=CC=C1C(=O)OCC1=CC=CN=C1 IWBWXPBNVXPLRS-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 229920000945 Amylopectin Polymers 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 230000000622 irritating effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 229960001860 salicylate Drugs 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 230000000304 vasodilatating effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- DSGKWFGEUBCEIE-UHFFFAOYSA-N (2-carbonochloridoylphenyl) acetate Chemical compound CC(=O)OC1=CC=CC=C1C(Cl)=O DSGKWFGEUBCEIE-UHFFFAOYSA-N 0.000 description 1
- QMDUEBURHKSKDG-UHFFFAOYSA-N 1-pyridin-3-ylethanol Chemical compound CC(O)C1=CC=CN=C1 QMDUEBURHKSKDG-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- OODRWLGKUBMFLZ-UHFFFAOYSA-N 2-(4-chlorophenoxy)-2-methylpropanoyl chloride Chemical compound ClC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 OODRWLGKUBMFLZ-UHFFFAOYSA-N 0.000 description 1
- NAKABSUZLYLPNN-UHFFFAOYSA-N 2-(pyridine-3-carbonyloxy)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1OC(=O)C1=CC=CN=C1 NAKABSUZLYLPNN-UHFFFAOYSA-N 0.000 description 1
- WGNUNYPERJMVRM-UHFFFAOYSA-N 3-pyridylacetic acid Chemical compound OC(=O)CC1=CC=CN=C1 WGNUNYPERJMVRM-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 240000002470 Amphicarpaea bracteata Species 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010017865 Gastritis erosive Diseases 0.000 description 1
- 241001466453 Laminaria Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010067171 Regurgitation Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000012928 buffer substance Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 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
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 239000007911 effervescent powder Substances 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 125000005639 glycero group Chemical group 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 229950007593 homonicotinic acid Drugs 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000011356 non-aqueous organic solvent Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000009519 pharmacological trial Methods 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
Description
Terapeutisk virksomme pyridinderivaterTherapeutically active pyridine derivatives
av salicylsyre.of salicylic acid.
Foreliggende oppfinnelse vedrører nye forbindelserThe present invention relates to new compounds
med terapeutisk virkning og fysiologisk akseptable salter derav.with therapeutic effect and physiologically acceptable salts thereof.
De nye forbindelsene som er pyridinderivater av salicylsyre,The new compounds which are pyridine derivatives of salicylic acid,
viser spesielt nyttige serumlipid-senkende egenskaper samt meget få bivirkninger. Oppfinnelsen angår også fremgangsmåte for fremstilling av forbindelsene, farmasøytiske preparater inneholdende disse forbindelser samt en metode- for behandling av visse sykdommer ved administrering av emterapeutisk effektiv mengde av en forbindelse ifølge oppfinnelsen sammen med en farmasøytisk akseptabel bærer. shows particularly useful serum lipid-lowering properties as well as very few side effects. The invention also relates to a method for producing the compounds, pharmaceutical preparations containing these compounds as well as a method for treating certain diseases by administering an emtherapeutically effective amount of a compound according to the invention together with a pharmaceutically acceptable carrier.
Faktorene som forårsaker arteriosklerose og flere andre sykdommer i det vaskulære system er mange og meget kompliserte. Det synes imidlertid å være helt klart at en øket konsentrasjon av serumlipider har sterk sammenheng med grunnleggende patogene mekanismer og at en nedsettelse av konsentrasjonen av serumlipider har positiv virkning ved behandling av slike vaskulære tilstander. The factors that cause arteriosclerosis and several other diseases in the vascular system are many and very complicated. However, it seems to be quite clear that an increased concentration of serum lipids has a strong connection with basic pathogenic mechanisms and that a reduction in the concentration of serum lipids has a positive effect in the treatment of such vascular conditions.
Det er funnet at nikotinsyre og noen derivater derav-, som i noen tid har vært kjent for å vise god dilatérende effekt på de perifere blodkar, har en betydelig evne til å senke innholdet av serumlipider, dvs. kolesterol, fosfolipider, triglycerider og frie fettsyrer. Det er imidlertid nødvendig med slike doseringer som lett forårsaker bivirkninger. En slik bivirkning er den vasodilaterende effekt, som i dette tilfellet er generelt uønsket og som i form av rødming eller blodgjennomstrømning kan være meget forstyrrende. It has been found that nicotinic acid and some derivatives thereof, which for some time have been known to show a good dilating effect on the peripheral blood vessels, have a significant ability to lower the content of serum lipids, i.e. cholesterol, phospholipids, triglycerides and free fatty acids . However, such dosages are necessary which easily cause side effects. One such side effect is the vasodilatory effect, which in this case is generally undesirable and which in the form of redness or blood flow can be very disturbing.
Som et eksempel på disse tidligere kjente forbindelser kan nevnes esteren av salicylsyre og 3_hydroksymetylpyridin, som er beskrevet i britisk patent nr. 1.079-726 og som har formelen: As an example of these previously known compounds, mention can be made of the ester of salicylic acid and 3-hydroxymethylpyridine, which is described in British patent no. 1,079-726 and which has the formula:
Denne forbindelse (i det nedenstående betegnet "I") har foruten sine gode vasodilaterende egenskaper vist seg å ha meget god In addition to its good vasodilatory properties, this compound (in the following denoted "I") has been shown to have very good
virkning når det gjelder å senke konsentrasjonen av kolesterol i plasma. I de store doser som er nødvendig for å senke serum-kolesterol-nivået, forårsaker imidlertid forbindelse I én sterk gjennomstrømning og også hyppige erosjoner i maven. effect when it comes to lowering the concentration of cholesterol in plasma. In the large doses necessary to lower the serum cholesterol level, however, compound I causes one strong flow and also frequent erosions in the stomach.
Ifølge oppfinnelsen er det nå overraskende funnet at forbindelser med den generelle formel: According to the invention, it has now surprisingly been found that compounds with the general formula:
hvor n er 1 eller 2\R, når n er 1, er valgt fra gruppen bestående av forgrenede alkylgrupper inneholdende 3~7karbonatomer, og hvor p er 0 eller 1; og hvor R, når n er 2, er valgt fra gruppen bestående av rette og forgrenede alkylgrupper■inneholdende 1-7 karbonatomer, og where n is 1 or 2\R, when n is 1, is selected from the group consisting of branched alkyl groups containing 3~7 carbon atoms, and where p is 0 or 1; and where R, when n is 2, is selected from the group consisting of straight and branched alkyl groups■containing 1-7 carbon atoms, and
hvor p er 0 eller 1, samt fysiologisk akseptable syreaddisjonssalter derav, utviser et betydelig forbedret forhold mellom den ønskede hovedvirkning, dvs. nedsettelse av kolesterol i serum og gjennom-strømningsvirkningene samt den skadelige virkning på maven. where p is 0 or 1, as well as physiologically acceptable acid addition salts thereof, exhibit a significantly improved relationship between the desired main effect, i.e. reduction of cholesterol in serum and the flow-through effects as well as the harmful effect on the stomach.
Eksempler på forbindelser ifølge oppfinnelsen er: Examples of compounds according to the invention are:
Følgende forbindelser, som omfattes av formel II ovenfor, er foretrukne: a- ( p-klor f enoksy) - isobutyrylsalicylsyr.e 3-pyridylmetylest er: The following compounds, which are covered by formula II above, are preferred: a-(p-chlorophenoxy)-isobutyrylsalicylic acid.e 3-pyridylmethyl ester is:
acetylsalicylsyre 3~pyridyletylester: De nye forbindelsene med formel II kan fremstilles ved hjelp av i og for seg kjente metoder slik som a) omsetning av en forbindelse med den generelle formel: Acetylsalicylic acid 3-pyridyl ethyl ester: The new compounds of formula II can be prepared using methods known per se such as a) reacting a compound with the general formula:
med en forbindelse med den .generelle formel: with a compound of the general formula:
hvor n og R hår den ovenfor angitte betydning og hvor X er en karbok-sylgruppe eller et funksjonelt derivat derav, f.eks. et metallsalt, et syrehalogenid, en ester, et' syreanhydrid, et blandet anhydrid, og hvor Y er valgt fra gruppen bestående av hydroksy, halogen, alkyl-sulfonyloksy og aryl-sulfonyloksy; eller b) omsetning.av en forbindelse med den generelle formel: where n and R have the above meaning and where X is a carboxyl group or a functional derivative thereof, e.g. a metal salt, an acid halide, an ester, an acid anhydride, a mixed anhydride, and wherein Y is selected from the group consisting of hydroxy, halogen, alkylsulfonyloxy and arylsulfonyloxy; or b) conversion of a compound with the general formula:
med en forbindelse med den generelle formel: with a compound of the general formula:
hvor R, n og X har den ovenfor angitte betydning, og hvor Z er H eller et alkalimetall eller et kvartært ammoniumion. where R, n and X have the meaning given above, and where Z is H or an alkali metal or a quaternary ammonium ion.
Forbindelsene som benyttes som utgangsmaterialer kan. fremstilles ifølge kjente.metoder. The compounds used as starting materials can. are produced according to known methods.
De ovennevnte reaksjoner kan utføres i vandige eller ikke-vandige organiske oppløsningsmidler..Når reaksjonen utføres mellom et syrehalogenid og en hydroksyforbindelse, kan hydrogen- halogenidet som frigjøres ved reaksjonen nøytraliseres, og reaksjonen katalyseres med en base, f.eks. et tertiært main slik som pyridin og trietylamin. The above-mentioned reactions can be carried out in aqueous or non-aqueous organic solvents. When the reaction is carried out between an acid halide and a hydroxy compound, the hydrogen halide released by the reaction can be neutralized, and the reaction catalysed with a base, e.g. a tertiary main such as pyridine and triethylamine.
I klinisk bruk vil de nye forbindelser normalt admini-streres oralt eller ved injeksjon i form av et farmasøytisk preparat'omfattende den aktive bestanddel i'.'form av den opprinnelige forbindelse eller eventuelt i form av fri base eller et farmasøytisk akseptabelt salt derav, vanligvis i kombinasjon med en farmasøytisk In clinical use, the new compounds will normally be administered orally or by injection in the form of a pharmaceutical preparation comprising the active ingredient in the form of the original compound or possibly in the form of a free base or a pharmaceutically acceptable salt thereof, usually in combination with a pharmaceutical
akseptabel bærer som kan være er fast, halvfast eller flytende for-tynningsmiddel eller en inntagbar kapsel. acceptable carrier which may be a solid, semi-solid or liquid diluent or an ingestible capsule.
Den aktive forbindelse omfatter vanligvis mellom 0,1 og 99 vekt-% av preparatet, f.eks. mellom 0,5 og 20 vekt-% for preparater The active compound usually comprises between 0.1 and 99% by weight of the preparation, e.g. between 0.5 and 20% by weight for preparations
for "inj eks j onsf ormål og mellom 0,1 og 50<y>ekt-% for preparater for oral administrasjon. for injection purposes and between 0.1 and 50<y>ect-% for preparations for oral administration.
For fremstilling av farmasøytiske preparater i form av doseringsenheter for oral anvendelse inneholdende en forbindelse fremstilt ifølge oppfinnelsen, kan den aktive bestanddel blandes med en vast, pulverformig bærer, f.eks. laktose, sakkarose, sorbitol,. mannitol, en stivelse slik. som potetstivelse, maisstivelse, amylopektin, laminariapulver eller sitruspulver, et cellulosederivat eller gelatin og kan også inneholde smøremidler slik som magnesium-eller kalsiumstearat eller en "Carbowax<®>" eller andre polyetylen-glykol vokser, og sammenpresses for dannelse av tabletter' eller sentre,for dragéer.. Hvis dragéer skal fremstilles, kan sentrene belegges f.eks. med konsentrerte sukkeroppløsninger som kan inneholde gummiarabikum, talk og/eller titandioksyd, eller alternativt belegges med en lakk oppløst i lett flyktige organiske oppløsnings-midler eller blandinger av organiske oppløsningsmidler. Fargestoffer kan tilsettes til beleggene f.eks. for å skille mellom forskjellige innhold av aktiv forbindelse. For fremstilling av myke gelatinkapsler (perleformede lukkede kapsler) bestående av gelatin, og, f.eks. glycerol eller lignende lukkede kapsler, kan den aktive forbindelse sammenblandes med en "Carbowax<®>". Harde gelatinkapsler kan inneholde granulater av--den aktive forbindelse med faste, pulverformige bærere slik som laktose, sakkarose, sorbitol, mannitol, . stivelser, (f.eks. potetstivelse, maisstivelse og amylopektin), cellulosederivater eller gelatin, og' kan også inneholde magnesiumstearat eller stearinsyre. For the production of pharmaceutical preparations in the form of dosage units for oral use containing a compound prepared according to the invention, the active ingredient can be mixed with a solid, powdery carrier, e.g. lactose, sucrose, sorbitol,. mannitol, a starch like this. such as potato starch, corn starch, amylopectin, laminaria powder or citrus powder, a cellulose derivative or gelatin and may also contain lubricants such as magnesium or calcium stearate or a "Carbowax<®>" or other polyethylene glycol wax, and compressed to form tablets' or centers ,for dragées.. If dragées are to be produced, the centers can be coated, e.g. with concentrated sugar solutions which may contain gum arabic, talc and/or titanium dioxide, or alternatively coated with a varnish dissolved in easily volatile organic solvents or mixtures of organic solvents. Dyes can be added to the coatings, e.g. to distinguish between different contents of active compound. For the production of soft gelatin capsules (bead-shaped closed capsules) consisting of gelatin, and, e.g. glycerol or similar closed capsules, the active compound can be mixed with a "Carbowax<®>". Hard gelatin capsules may contain granules of the active compound with solid, powdered carriers such as lactose, sucrose, sorbitol, mannitol, . starches, (eg potato starch, corn starch and amylopectin), cellulose derivatives or gelatin, and may also contain magnesium stearate or stearic acid.
Ved å benytte flere lag av den aktive forbindelse separert ved hjelp av belegg som oppløses langsomt, oppnår .tabletter med forlenget virkning. En annen måte å fremstille tabletter med forlenget virkning på er å oppdele dosen av den aktive forbindelse i granulater med belegg med forskjellig tykkelse og sammenpresse granulatene til tabletter sammen med bæreren.. Den aktive forbindelse kan også inkorporeres i langsomt oppløselige tabletter laget f.eks. av fett og vokshoIdige stoffer eller fordeles jevnt i en tablett av et uoppløselig stoff slik som et fysiologisk inert plastmateriale. By using several layers of the active compound separated by means of coatings that dissolve slowly, tablets with prolonged action are obtained. Another way of preparing tablets with prolonged action is to divide the dose of the active compound into granules with a coating of different thickness and compress the granules into tablets together with the carrier. The active compound can also be incorporated into slowly dissolving tablets made e.g. of fat and waxy substances or distributed evenly in a tablet of an insoluble substance such as a physiologically inert plastic material.
Brusende pulvere fremstilles ved å blande den aktive bestanddel med ikke-toksiske karbonater eller hydrogenkarbonater, slik som kalsiumkarbonat, kaliumkarbonat og kaliumhydrogenkarbonat, faste, ikke-toksiske syrer slik som vinsyre og sitronsyre, og f.eks. aroma. Effervescent powders are prepared by mixing the active ingredient with non-toxic carbonates or hydrogen carbonates, such as calcium carbonate, potassium carbonate and potassium hydrogen carbonate, solid, non-toxic acids such as tartaric acid and citric acid, and e.g. aroma.
Flytende preparater for oral anvendelse kan være i form av siruper eller suspensjoner, f.eks. oppløsninger inneholdende fra Liquid preparations for oral use can be in the form of syrups or suspensions, e.g. solutions containing from
ca. 0,1 til 20 vekt-% aktiv forbindelse, sukker og en blanding av etanol, vann, glycerol,,propylenglykol og eventuell aroma, sakkarin og/eller karboksymetylcellulose som dispergeringsmiddel. about. 0.1 to 20% by weight active compound, sugar and a mixture of ethanol, water, glycerol, propylene glycol and any aroma, saccharin and/or carboxymethyl cellulose as dispersant.
For parenteral anvendelse ved injeksjon, kan preparater omfatte en vandig oppløsning av et vannoppløselig farmasøytisk akseptabelt salt av de aktive syrer ifølge oppfinnelsen, hensikts-messig i 'en konsentrasjon på 0,5_10%, og eventuelt også et stabili-seringsmiddel og/eller et bufferstoff i vandig oppløsning. Doseringsenheter av oppløsningen kan med fordel inneholdes i ampuller. For parenteral use by injection, preparations may comprise an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active acids according to the invention, suitably in a concentration of 0.5-10%, and optionally also a stabilizing agent and/or a buffer substance in aqueous solution. Dosage units of the solution can advantageously be contained in ampoules.
Som saltdannende midler kan anvendes f.eks. mineralsyrer slik som saltsyre, svovelsyre, fosforsyre eller organiske syrer slik som eddiksyre, melkesyre, sitronsyre og flere andre syrer som gir fysiologisk akseptable addisjonssalter. As salt-forming agents can be used, e.g. mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid or organic acids such as acetic acid, lactic acid, citric acid and several other acids which give physiologically acceptable addition salts.
Administrasjon ad oral vei er den foretrukne administra-sjonsform ved klinisk bruk. Oral administration is the preferred form of administration for clinical use.
Den benyttede dosering er avhengig av pasientens indivi-euelle behov, mens administrasjon av omkring 0,5-2 g av den aktive forbindelse 3 ganger daglig kan angis som en mulig dosering ved terapeutisk behandling av hyperkolesterolemi hos mennesker. Nevnte dosering er hovedsakelig ment for oral -administrasjon. The dosage used depends on the patient's individual needs, while administration of around 0.5-2 g of the active compound 3 times a day can be indicated as a possible dosage for the therapeutic treatment of hypercholesterolaemia in humans. Said dosage is mainly intended for oral administration.
Oppfinnelsen illustreres ved hjelp av nedenstående eksempler. Foruten de fysikalske og kjemiske data som er angitt, The invention is illustrated using the examples below. In addition to the physical and chemical data indicated,
er NMR- og IR-spektra registrert for alle sluttproduktene.NMR and IR spectra are recorded for all end products.
Disse spektra har god overensstemmelse med de gitte strukturer. These spectra are in good agreement with the given structures.
Eksempel 1. a-(p-klorfenoksy)-isobutyrylsalicylsyre 3- pyridylmetylester Example 1. α-(p-chlorophenoxy)-isobutyrylsalicylic acid 3-pyridyl methyl ester
3-pyridylmetylsalicylat (239 g) og trietylamin (104 g) 3-pyridyl methyl salicylate (239 g) and triethylamine (104 g)
ble oppløst i 2,5 1 toluen. Oppløsningen ble avkjølt i et isbad og a-(p-klorfenoksy)-isobutyrylklorid (239 g) ble tilsatt under omrøring i løpet av 3 timer. Reaksjonsblandingen ble omrørt natten over ved romtemperatur og tilslutt tilbakeløpskokt i 1 time. Etter avkjøling ble trietylaminhydroklorid som var dannet, fra-■ filtrert og oppløsningen behandlet med aktivkull, filtrert, og oppløsningsmidlet fordampet. Resten ble omkrystallisert fra etyl-eter hvilket ga 305 g (71$) av et nesten hvitt stoff. Smeltepunkt: 83,5-84,5°C; was dissolved in 2.5 1 toluene. The solution was cooled in an ice bath and α-(p-chlorophenoxy)-isobutyryl chloride (239 g) was added with stirring over 3 hours. The reaction mixture was stirred overnight at room temperature and finally refluxed for 1 hour. After cooling, triethylamine hydrochloride which had formed was filtered off and the solution treated with activated carbon, filtered and the solvent evaporated. The residue was recrystallized from ethyl ether to give 305 g (71%) of an off-white substance. Melting point: 83.5-84.5°C;
Analyse, beregnet: 64,87$ C, 4,73$ H, 8,33$ Cl, 3,29$ N. Funnet: 65,0$ C, 4,8$ H, 8,4$ Cl, 3>2$ N. Analysis, Calcd: 64.87$ C, 4.73$ H, 8.33$ Cl, 3.29$ N. Found: 65.0$ C, 4.8$ H, 8.4$ Cl, 3> 2$N.
Eksem pel 2. Pivalylsal icylsyre 3~ pyridylmetylester. Example 2. Pivalylsal icyl acid 3~ pyridyl methyl ester.
Pivalylklorid (24,1 g) ble omsatt med 3_pyridylmetylsalicylat (45,8 g) under de samme betingelser som i eksempel 1. Etter separeringen av trietylaminklorid,-ble reaksjonsoppløsningen vasket to ganger,med en vandig oppløsning av natriumhydrogenkarbonat (1$) og deretter en gang med vann, og ble behandlet med aktivkull og tørket over magnesiumsulfat. Fordampning av oppløsningsmidlet ga en lyse brun olje som ble oppløst i 200 ml tørr eter. Ved dråpevis tilsetning av eter mettet med saltsyre ble et produkt utfelt og dette ble omkrystallisert fra 60 ml tørr aceton. Hydrokloridet ble rystet i 250 ml tørr benzen, og nøytralisert med trietylamin. Etter separering av trietylaminhydrokloridet og fordampning under vakuum ble det oppnådd 36,5 g (58$) av en lys gul væske. Pivalyl chloride (24.1 g) was reacted with 3-pyridyl methyl salicylate (45.8 g) under the same conditions as in Example 1. After the separation of triethylamine chloride, the reaction solution was washed twice with an aqueous solution of sodium bicarbonate (1$) and then once with water, and was treated with activated charcoal and dried over magnesium sulfate. Evaporation of the solvent gave a light brown oil which was dissolved in 200 ml of dry ether. By dropwise addition of ether saturated with hydrochloric acid, a product was precipitated and this was recrystallized from 60 ml of dry acetone. The hydrochloride was shaken in 250 ml of dry benzene, and neutralized with triethylamine. After separation of the triethylamine hydrochloride and evaporation under vacuum, 36.5 g (58$) of a pale yellow liquid were obtained.
n22 = 1.5382 n22 = 1.5382
Analyse, beregnet: 68,99$ C, 6,11$ H, 4,47$ N.Analysis, calculated: 68.99$ C, 6.11$ H, 4.47$ N.
Funnet: 69,1$ C, 6,2$ H, 4,5$ N.Found: 69.1$ C, 6.2$ H, 4.5$ N.
Eksempel 3- Nikotinylsalicylsyre 3- pyridylmetylester. Example 3- Nicotinyl salicylic acid 3- pyridyl methyl ester.
Nikotinylsalicylsyre (12,2 g) og tionylklorid ■ ('15 nil) i 150 ml tørr benzen ble omrørt ved romtemperatur natten over. Benzen og overskudd tionylklorid ble fordampet under vakuum. Benzen ble tilsatt og inndampningen gjentatt. Den pulverformige rest b'le oppløst i 150 ml tørr pyridin og avkjølt i et isbad, hvoretter 3-pyridylmetanol (6 g) ble tilsatt dråpevis under omrøring. Nicotinyl salicylic acid (12.2 g) and thionyl chloride ('15 nil) in 150 ml of dry benzene were stirred at room temperature overnight. Benzene and excess thionyl chloride were evaporated under vacuum. Benzene was added and the evaporation repeated. The powdery residue was dissolved in 150 ml of dry pyridine and cooled in an ice bath, after which 3-pyridyl methanol (6 g) was added dropwise with stirring.
.Reaksjonsblandingen fikk anledning til å nå romtemperatur og hensatt natten over. Pyridinet ble inndampet i vakuum, hvoretter resten ble helt i isvann.. Ved nøytralisering med natriumhydrogenkarbonat ble det utskilt en olje, som etter avkjøling og separering krystalliserte. Omkrystallisering fra 35 ml toluen og 15 ml .The reaction mixture was allowed to reach room temperature and left overnight. The pyridine was evaporated in vacuo, after which the residue was poured into ice water. Upon neutralization with sodium bicarbonate, an oil was separated, which crystallized after cooling and separation. Recrystallization from 35 ml of toluene and 15 ml
ligroin ga 9 g (54$) av et hvitt produkt.ligroin gave 9 g ($54) of a white product.
Smeltepunkt 74 , 5-75,5°C.Melting point 74 , 5-75.5°C.
Analyse, beregnet: 68,26$ C, 4,22$ H, 8,38$ N..Analysis, calculated: 68.26$ C, 4.22$ H, 8.38$ N..
Funnet: 68,4$ C, 4,3$ H, 8,3$ N-Found: 68.4$ C, 4.3$ H, 8.3$ N-
E ksempel 4. Acetyls. alicy lsyre 3~ pyridylety lester .E xample 4. Acetyls. alicyl acid 3~ pyridylethyl ester .
Til en isavkjølt oppløsning av acetylsalicylsyreklorid (9.i 5 g) i 100 ml toluen, ble det dråpevis i løpet av 1 time tilsatt en oppløsning av 3-pyridyletanol (5,9 gV og trietylamin (4,9"g) i 100- ml toluen. Omrøring ble fortsatt ved romtemperatur natten over hvoretter blandingen ble tilbakeløpskokt i 1 time. To an ice-cooled solution of acetylsalicylic acid chloride (9.in 5 g) in 100 ml toluene, a solution of 3-pyridylethanol (5.9 gV and triethylamine (4.9 g) in 100- ml toluene Stirring was continued at room temperature overnight after which the mixture was refluxed for 1 hour.
Etter avkjøling og separering av utfelt 3-etylamin-hydroklorid, ble blandingen vasket to ganger med natriumkarbbnat-oppløsning og tilsutt med vann. Tørking over magnesiumsulfat og inndampning av oppløsningsmidlet ga en olje, som ble oppløst i 175 ml tørr eter. Hydrokloridet ble utfelt med eter mettet med saltsyre og vasket grundig med eter. Etter oppløsning i isavkjølt vann og nøytralisering med natriumkarbonat, ble den frigjorte base ekstrahert med eter. Eteroppløsningen ble. tørket over magnesium-sulf at og■inndampet. En rest på 9 g (66$) av en nesten fargeløs After cooling and separation of precipitated 3-ethylamine hydrochloride, the mixture was washed twice with sodium carbonate solution and added with water. Drying over magnesium sulfate and evaporation of the solvent gave an oil, which was dissolved in 175 ml of dry ether. The hydrochloride was precipitated with ether saturated with hydrochloric acid and washed thoroughly with ether. After dissolution in ice-cooled water and neutralization with sodium carbonate, the liberated base was extracted with ether. The ether solution was dried over magnesium sulfate and ■evaporated. A residue of 9g (66$) of an almost colorless
væske ble oppnåss.liquid was obtained.
22 22
nD = 1-5520 nD = 1-5520
Analyse, beregnet: 67 ,36$ C, 5,30$ H, 4,91$ N..Analysis, calculated: 67 .36$ C, 5.30$ H, 4.91$ N..
Funnet: 67,3$ C, 5,2$ H, 4,9$ N.Found: 67.3$ C, 5.2$ H, 4.9$ N.
Eksempel 5- 3- pyridylacetylsalicylsyre 3- pyridylmetylest er. Example 5- 3- pyridyl acetylsalicylic acid 3- pyridyl methyl ester.
3-pyridyleddiksyre (75 g) og 3-pyridylmetylsalicylat (42 g) i 500 ml etylacetat, ble avkjølt til -25°C, hvoretter en oppløsning av N,N'-dicykloheksylkarbodiimid (113 g) i 200 ml etylacetat ble tilsatt dråpevis i løpet av 1 time under omrøring. Etter ytterligere 4 timers avkjøling fikk reaksjonsblandingen nå rom- 3-pyridylacetic acid (75 g) and 3-pyridyl methyl salicylate (42 g) in 500 ml ethyl acetate were cooled to -25°C, after which a solution of N,N'-dicyclohexylcarbodiimide (113 g) in 200 ml ethyl acetate was added dropwise in during 1 hour with stirring. After a further 4 hours of cooling, the reaction mixture was now
temperatur i løpet av natten. Bunnfallet som var dannet, ble separert og oppløsningen vasket først med natriumhydrogenkarbonat-oppløsning og deretter med vann, og ble så tørket over magnesiumsulfat og oppløsningsmidlet inndampet. Resten, en brunaktig olje, ble blandet med varm etylacetat-ligroin (1:4). Avkjøling ga et gulaktig bunnfall som etter omkrystallisering fra eter ga 31 g' temperature during the night. The precipitate formed was separated and the solution washed first with sodium bicarbonate solution and then with water, then dried over magnesium sulfate and the solvent evaporated. The residue, a brownish oil, was mixed with hot ethyl acetate-ligroine (1:4). Cooling gave a yellowish precipitate which after recrystallization from ether gave 31 g'
(49$) av et hvitt produkt.($49) of a white product.
Smeltepunkt 72,0-73,0°C.Melting point 72.0-73.0°C.
Analyse, beregnet: 68,96$ C, 4,63$ H, 8,04$ N.Analysis, calculated: 68.96$ C, 4.63$ H, 8.04$ N.
Funnet: 68,8$ C, 4,5$ H, 8,1$ N.Found: 68.8$ C, 4.5$ H, 8.1$ N.
Følgende eksempler illustrerer hvordan de nye forbindelser kan inkorporeres i farmasøytiske preparater. The following examples illustrate how the new compounds can be incorporated into pharmaceutical preparations.
E ksempel 6. Preparat av myke gelatinkapsler.Example 6. Preparation of soft gelatin capsules.
500 g a-(p-klorfenoksy)-isobutyrylsalicylsyre 3_pyridyl- . metylester, ble blandet med 500 g maisolje hvoretter blandingen ble fylt i myke gelatinkapsler, idet hver kapsel inneholdt 500 mg av blandingen (dvs. 250 mg aktiv forbindelse). 500 g a-(p-chlorophenoxy)-isobutyrylsalicylic acid 3_pyridyl- . methyl ester, was mixed with 500 g of corn oil after which the mixture was filled into soft gelatin capsules, each capsule containing 500 mg of the mixture (ie 250 mg of active compound).
E ksempel 7- Fremstilling av myke gelatinkapsler.E xample 7- Production of soft gelatin capsules.
500 g acetylsalicylsyre 3-pyridyletylester ble blandet med 750 g peanøttolje hvoretter blandingen ble fylt i myke gelatinkapsler, idet hver kapsel inneholdt 500 mg av blandingen (dvs. 200 mg aktiv forbindelse). 500 g of acetylsalicylic acid 3-pyridyl ethyl ester was mixed with 750 g of peanut oil after which the mixture was filled into soft gelatin capsules, each capsule containing 500 mg of the mixture (ie 200 mg of active compound).
E ksempel 8. Frem stilling av tabletter.E xample 8. Preparation of tablets.
5 kg a-(p-klorfenoksy)-isobutyrylsalicylsyre 3-pyridylmetylester, ble blandet med 2 kg silisiumdioksyd ("Aerosil"), hvor etter 4,5 kg potetstivelse og 5 kg laktose ble innblandet og blandingen fuktet med en stivelsespasta frems-tilt fra 0,5 kg potetstivelse og destillert vann, hvoretter blandingen ble granulert gjennom en sikt. Granulatet ble tørket og siktet hvoretter 0,2 kg magnesiumstearat ble innblandet. Tilslutt ble blandingen presset til tabletter som hver veide 688 mg. 5 kg of α-(p-chlorophenoxy)-isobutyrylsalicylic acid 3-pyridyl methyl ester were mixed with 2 kg of silicon dioxide ("Aerosil"), where after 4.5 kg of potato starch and 5 kg of lactose were mixed in and the mixture moistened with a starch paste prepared from 0.5 kg of potato starch and distilled water, after which the mixture was granulated through a sieve. The granulate was dried and sieved, after which 0.2 kg of magnesium stearate was mixed in. Finally, the mixture was pressed into tablets each weighing 688 mg.
Eksempel 9 - Fremstilling av en emulsjon.Example 9 - Preparation of an emulsion.
100 g acetylsalicylsyre 3-pyridyletylester ble oppløst100 g of acetylsalicylic acid 3-pyridyl ethyl ester was dissolved
i 2500 g. peanøttolje. Fra den således oppnådde oppløsning, 90 g gummi.i.arabikum, aroma og farge (q.s.) og 2500 g vann, ble det fremstilt en emulsjon. in 2500 g. peanut oil. An emulsion was prepared from the solution thus obtained, 90 g of gum arabic, aroma and color (q.s.) and 2500 g of water.
E ksempel IQ. Fremstilling av en sirup.E xample IQ. Preparation of a syrup.
100 g a-(p-klorf enoksy)-isobutyrylsalicylsyre 3-pyridylmetylester ble oppløst i 300 g 95% etanol hvor 300 g glycero.l, aroma og farge (q.s.) og vann 1000 ml, ble innblandet. En sirup ble der-ved oppnådd. 100 g of a-(p-chlorophenoxy)-isobutyrylsalicylic acid 3-pyridyl methyl ester was dissolved in 300 g of 95% ethanol where 300 g of glycero.l, aroma and color (q.s.) and water 1000 ml were mixed. A syrup was thereby obtained.
Eksempel 11. Fremstilling av brusende tabletter.Example 11. Production of effervescent tablets.
100 g a- (p-klorf enoksy )-isobutyrylsalicylsyre ' 3-^pyridylmetylester, 1^0 g pulverformig sitronsyre, 100 g pulverformig natriumhydrogenkarbonat, 3,5 g magnesiumstearat og aroma (q.s.), ble blandet og blandingen presset til tabletter som hver inneholdt 200 mg aktiv forbindelse. 100 g of α-(p-chlorophenoxy)-isobutyryl salicylic acid, 3-^pyridyl methyl ester, 1^0 g of powdered citric acid, 100 g of powdered sodium bicarbonate, 3.5 g of magnesium stearate and aroma (q.s.) were mixed and the mixture pressed into tablets each contained 200 mg of active compound.
Eksempel 12. Fremstilling av' tabletter med forlenget virkning. Example 12. Preparation of extended-acting tablets.
200 g acetylsalicylsyre 3-pyridyletylester ble sammen-smeltet med 50 g stearinsyre og 50 g karnaubavoks. Den således oppnådde blanding ble avkjølt og malt til en partikkelstørrelse på 200 g of acetylsalicylic acid 3-pyridyl ethyl ester was fused with 50 g of stearic acid and 50 g of carnauba wax. The mixture thus obtained was cooled and ground to a particle size of
maksimalt 1 mm. Den dermed oppnådde masse ble blandet med 5 g magnesiumstearat og presset til tabletter som hver veide 610 mg. Hver tablett inneholder således 400 mg aktiv forbindelse. maximum 1 mm. The mass thus obtained was mixed with 5 g of magnesium stearate and pressed into tablets each weighing 610 mg. Each tablet thus contains 400 mg of active compound.
Farmakologiske forsøkPharmacological trials
De farmakologiske virkninger til de nye forbindelser ble undersøkt og bestemt ifølge nedenstående forsøksmetoder: The pharmacological effects of the new compounds were investigated and determined according to the following test methods:
R eduksjon av plas me kolesterolR eduction of plasma cholesterol
Hunrotter med en legemsvekt på 160-190 g sultes i 2,5 dager, hvilket forårsaker en svak hyperkolesterolemi. I løpet av denne perioden tilfører man dyrene 5 ganger ved hjelp av en sonde forsøkspreparater, som består av suspensjoner av de forskjellige forbindelser som skal undersøkes i 1% vandige oppløsninger av natriumsaltet av karboksymetylcellulose (CMC-Na). En kontrollgruppe med rotter mottar tilsvarende behandling under anvendelse av kun CMC-Na. To timer etter den siste administrasjon oppsamles plasma for analyse av totalinnholdet av kolesterol. Den administrerte mengde forsøksmateriale utgjør 100 mg/kg ved hver administrasjon. 5"10 rotter testes i hver gruppe. Som referansestoffer benyttes nikotinsyre, "Perycit (pentaerytritoltetranikotinat) og den ovenfor angitte forbindelse I. Resultater er gitt i nedenstående tabell 1. Reduksjonen av kolesterolinnholdet i plasma ble beregnet som % av plasmanivået av kolesterol i kontrollgruppen. Female rats with a body weight of 160-190 g are starved for 2.5 days, which causes a slight hypercholesterolaemia. During this period, the animals are administered test preparations 5 times by means of a probe, which consist of suspensions of the various compounds to be examined in 1% aqueous solutions of the sodium salt of carboxymethylcellulose (CMC-Na). A control group of rats receives a similar treatment using only CMC-Na. Two hours after the last administration, plasma is collected for analysis of the total cholesterol content. The administered amount of test material amounts to 100 mg/kg at each administration. 5"10 rats are tested in each group. Nicotinic acid, "Perycit (pentaerythritol tetranicotinate) and the above-mentioned compound I are used as reference substances. Results are given in table 1 below. The reduction of the cholesterol content in plasma was calculated as % of the plasma level of cholesterol in the control group.
B ivirkning: Blodgjennomstrømning hos marsvin.B impact: Blood flow in guinea pigs.
Til sultede hvite marsvin ble forsøksstoffene administrert ved hjelp av en sonde i doser på 10 mg/kg. Denne dose av nikotinsyre utvikler normalt en gjennomstrømningsreaksjon eller rødming i. To starved white guinea pigs, the test substances were administered by means of a probe in doses of 10 mg/kg. This dose of nicotinic acid normally develops a flow-through reaction or flushing in the.
ørene og på halsen hos marsvin. Forsøkspreparatene ble administrert til dyrene og intensiteten av gjenhomstrømningsreaksjonen ble bedømt ved hjelp av en poengskala: 0,§, 1, 2 og 3 poeng, respektivt, hver 5 minutt. Disse avlesninger i løpet av 1 time ble deretter addert.- 12 marsvin ble undersøkt for hver preparat. Bivirkningen til forsøksforbindelsene med hensyn til utvikling av rødming eller gjennomstrømning ble bedømt ifølge nedenstående skala: the ears and on the neck of guinea pigs. The test preparations were administered to the animals and the intensity of the regurgitation reaction was assessed using a point scale: 0.§, 1, 2 and 3 points, respectively, every 5 minutes. These readings during 1 hour were then added. - 12 guinea pigs were examined for each preparation. The side effect of the test compounds with regard to the development of flushing or flow was assessed according to the scale below:
+++ tilsvarer 288-432 poent = sterk gjennomstrømning+++ corresponds to 288-432 points = strong throughput
++ " 144-287 " = moderat gjennomstrømning++ " 144-287 " = moderate throughput
+ " 72-143 " = mindre gjennomstrømning 0 " 0-71 " = ingen gjennomstrømning Forekomsthyppigheten av dyr med gjennomstrømning eller rødming ble også bestemt basert på det kriterium at rødming ble betraktet å forekomme når dyret med minst tre på hverandre følgende avlesninger ble gitt minst 1 poeng på den benyttede skala. + " 72-143 " = less flow 0 " 0-71 " = no flow The frequency of animals with flow or flushing was also determined based on the criterion that flushing was considered to occur when the animal with at least three consecutive readings was given at least 1 point on the scale used.
De oppnådde resultater er vist i nedenstående tabell 1. Bivirkninger med salicylat-holdige forbindelser: irriterende virkning på maven. ; The results obtained are shown in table 1 below. Side effects with salicylate-containing compounds: irritating effect on the stomach. ;
Dette forsøk ble utført ifølge G. Åberg og K.S. Larsson, Acta Pharmacol. et toxicol. 1970, 28, 249. Til sultede rotter ble This experiment was carried out according to G. Åberg and K.S. Larsson, Acta Pharmacol. a toxicol. 1970, 28, 249. To starved rats became
det via en sonde administrert suspensjoner med^ et volum på 0,5 ml/suspensions with a volume of 0.5 ml/
100 g legemsvekt. Den administrerte dose for hver forbindelse var 100 mg/kg og suspensjonene ble fremstilt' i form av 1% vandige opp-løsninger av CMC-Na. Tre timer etter administrasjonen av forbindelsen, ble dyrene avlivet og deres mave undersøkt med et stereomikroskop med hensyn til forekomsten av små, blødende mikroerosjoner. Minst 10 dyr ble undersøkt pr. gruppe_og resultatet ble gitt som forekomsten av marsvin med mave-erosjoner. Dette forsøk indikerer den 100 g body weight. The dose administered for each compound was 100 mg/kg and the suspensions were prepared in the form of 1% aqueous solutions of CMC-Na. Three hours after the administration of the compound, the animals were sacrificed and their stomachs were examined with a stereomicroscope for the presence of small, bleeding microerosions. At least 10 animals were examined per group_and the result was given as the incidence of guinea pigs with gastric erosions. This experiment indicates that
irriterende virkning med salicylat-holdige forbindelser på maven, irritating effect with salicylate-containing compounds on the stomach,
' (r! mens nikotinsyre eller en beslektet ester derav slik som "Perycit ikke gir opphav til noen skade på maven under disse- forsøksbetingelser. (r! while nicotinic acid or a related ester thereof such as "Perycit" does not give rise to any damage to the stomach under these experimental conditions.
Som referansestoffer ved denne undersøkelse ble benyttet CMC-Na, CMC-Na was used as reference substances in this investigation,
salicylsyre, acetylsalicylsyre og den ovenfor angitte forbindelse I. Resultatene er gitt i nedenstående tabell 2.. salicylic acid, acetylsalicylic acid and the above-mentioned compound I. The results are given in table 2 below.
Fra de ovenstående tabeller fremgår det klart at de From the above tables it is clear that they
nye forbindelser som fremstilles ifølge oppfinnelsen utviser en meget god kolesterolsenkende effekt samtidig som de forårsaker en grad av bivirkninger som er tydelig under den som bevirkes av tidligere kjente f orbinde.lser. new compounds produced according to the invention exhibit a very good cholesterol-lowering effect while at the same time causing a degree of side effects that is clearly below that caused by previously known compounds.
Claims (1)
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AU (1) | AU7451674A (en) |
BE (1) | BE821410A (en) |
DE (1) | DE2448036A1 (en) |
DK (1) | DK553974A (en) |
FI (1) | FI309274A (en) |
FR (1) | FR2248847A1 (en) |
LU (1) | LU71169A1 (en) |
NL (1) | NL7413950A (en) |
NO (1) | NO743815L (en) |
SE (1) | SE377691B (en) |
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1973
- 1973-10-24 SE SE7314402A patent/SE377691B/xx unknown
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1974
- 1974-10-09 DE DE19742448036 patent/DE2448036A1/en active Pending
- 1974-10-21 AU AU74516/74A patent/AU7451674A/en not_active Expired
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- 1974-10-23 NO NO743815A patent/NO743815L/no unknown
- 1974-10-23 FR FR7435592A patent/FR2248847A1/en not_active Withdrawn
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SE377691B (en) | 1975-07-21 |
AU7451674A (en) | 1976-04-29 |
SE7314402A (en) | 1975-04-25 |
JPS5070372A (en) | 1975-06-11 |
FI309274A (en) | 1975-04-25 |
BE821410A (en) | 1975-04-24 |
NL7413950A (en) | 1975-04-28 |
LU71169A1 (en) | 1975-06-24 |
DE2448036A1 (en) | 1975-05-15 |
FR2248847A1 (en) | 1975-05-23 |
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