NO145839B - ANALOGY PROCEDURE FOR PREPARATION OF HYPOLIPIDEMIC P-AMINOBENOIC ACIDS - Google Patents
ANALOGY PROCEDURE FOR PREPARATION OF HYPOLIPIDEMIC P-AMINOBENOIC ACIDS Download PDFInfo
- Publication number
- NO145839B NO145839B NO770151A NO770151A NO145839B NO 145839 B NO145839 B NO 145839B NO 770151 A NO770151 A NO 770151A NO 770151 A NO770151 A NO 770151A NO 145839 B NO145839 B NO 145839B
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- Norway
- Prior art keywords
- hypolipidemic
- ester
- preparation
- acids
- compound
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims abstract description 13
- 230000000055 hyoplipidemic effect Effects 0.000 title claims abstract description 9
- 239000002253 acid Substances 0.000 title claims description 6
- 150000007513 acids Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 23
- -1 4-methylaminobenzoic acid compound Chemical class 0.000 claims description 17
- 150000002148 esters Chemical class 0.000 claims description 14
- 239000002262 Schiff base Substances 0.000 claims description 7
- 150000004753 Schiff bases Chemical class 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical class NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 abstract description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 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 description 9
- 239000000203 mixture Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- DXMXVBCFPHMKGZ-UHFFFAOYSA-N 4-(1,3-benzodioxol-5-ylmethylamino)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NCC1=CC=C(OCO2)C2=C1 DXMXVBCFPHMKGZ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 229960004050 aminobenzoic acid Drugs 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 2
- 239000001095 magnesium carbonate Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940081310 piperonal Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical group NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 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 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000173371 Garcinia indica Species 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 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
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- JGDITNMASUZKPW-UHFFFAOYSA-K aluminium trichloride hexahydrate Chemical compound O.O.O.O.O.O.Cl[Al](Cl)Cl JGDITNMASUZKPW-UHFFFAOYSA-K 0.000 description 1
- 229940009861 aluminum chloride hexahydrate Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- NDVOXAWNJXIRLQ-UHFFFAOYSA-N ethyl 4-(1,3-benzodioxol-5-ylmethylamino)benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1NCC1=CC=C(OCO2)C2=C1 NDVOXAWNJXIRLQ-UHFFFAOYSA-N 0.000 description 1
- MWBBKLNJJBISRF-UHFFFAOYSA-N ethyl 4-[1,3-benzodioxol-5-yl(methyl)amino]benzoate Chemical compound C(C)OC(C1=CC=C(C=C1)N(C)C1=CC2=C(OCO2)C=C1)=O MWBBKLNJJBISRF-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000003516 hyperlipidaemic effect Effects 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 230000000871 hypocholesterolemic effect Effects 0.000 description 1
- 230000000999 hypotriglyceridemic effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000013310 margarine Nutrition 0.000 description 1
- 239000003264 margarine Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Analogifremgangsmåte for fremstilling av hypolipidemiske p-aminobenzoesyrer.Analogous process for the preparation of hypolipidemic p-aminobenzoic acids.
Description
Denne oppfinnelse angår fremstilling av nye p-aminobenzoesyrer med hypolipidemisk virkning. This invention relates to the production of new p-aminobenzoic acids with hypolipidemic action.
Det er anerkjent at kolesterol og triglycerider spiller en hovedrolle ved dannelsen av arterosklerotiske belegg ved å fremskynde avsetningen av blod-lipider på arterieveggen. It is recognized that cholesterol and triglycerides play a major role in the formation of atherosclerotic plaques by accelerating the deposition of blood lipids on the arterial wall.
4-(1,3-benzodioksol-5-ylmetylamino)benzoesyre-etylester og 4-[(2-naftalenylmetyl)amino]-benzoesyre er beskrevet i litteraturen, se tysk patent 716.668 og Chemical Abstracts 58, 521f. Ingen av forbindelsene er angitt å være nyttig til å senke serum-lipidnivåene hos dyr. 4-(1,3-Benzodioxol-5-ylmethylamino)benzoic acid ethyl ester and 4-[(2-naphthalenylmethyl)amino]benzoic acid are described in the literature, see German Patent 716,668 and Chemical Abstracts 58, 521f. Neither compound has been shown to be useful in lowering serum lipid levels in animals.
I henhold til foreliggende oppfinnelse tilveiebringes hypolipidemiske forbindelser med den generelle formel: According to the present invention, hypolipidemic compounds are provided with the general formula:
hvor R betyr 9-antracenyl, 1,3-benzodioksol-5-yl, 2-naftalenyl eller 1-naftalenyl, og R' betyr hydrogen eller C^_^-alkyl, forutsatt at R er forskjellig fra 1,3-benzodioksol-5-yl når R' er etyl, og at R er forskjellig fra 2-naftalenyl når R' er hydrogen, where R is 9-anthracenyl, 1,3-benzodioxol-5-yl, 2-naphthalenyl or 1-naphthalenyl, and R' is hydrogen or C^_^-alkyl, provided that R is different from 1,3-benzodioxol- 5-yl when R' is ethyl, and that R is different from 2-naphthalenyl when R' is hydrogen,
og farmasøytisk godtagbare salter derav. and pharmaceutically acceptable salts thereof.
Farmasøytisk godtagbare salter er syreaddisjonssalter av de baser som vil danne et salt med en karboksylsyre og som ikke har en skadelig fysiologisk virkning ved administrering til et dyr i doser som er i overensstemmelse med god farmakologisk virkning. Egnede baser omfatter således f.eks. alkalimetall- og jcrdalkalimetallhydroksyder, -karbonater og -bikarbonater, så som natriumhydroksyd, kaliumhydroksyd, kalsiumhydroksyd, kalium-karbonat, natriumbikarbonat eller magnesiumkarbonat; ammoniakk; Pharmaceutically acceptable salts are acid addition salts of those bases which will form a salt with a carboxylic acid and which do not have a deleterious physiological effect when administered to an animal in doses consistent with good pharmacological action. Suitable bases thus include e.g. alkali metal and alkali metal hydroxides, carbonates and bicarbonates, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium bicarbonate or magnesium carbonate; ammonia;
og primære, sekundære og tertiære aminer. Også aluminiumsalter kan fremstilles ved å behandle det tilsvarende natriumsalt med et passende aluminiumkompleks så som aluminiumklorid-heksahydrat. and primary, secondary and tertiary amines. Aluminum salts can also be prepared by treating the corresponding sodium salt with a suitable aluminum complex such as aluminum chloride hexahydrate.
Forbindelsene som fremstilles i henhold til oppfinnelsen, er krystallinske, fast stoffer som er oppløselige i mange vanlige organiske oppløsningsmidler så som f.eks. aceton, benzen, The compounds produced according to the invention are crystalline, solid substances which are soluble in many common organic solvents such as e.g. acetone, benzene,
alkoholer eller flytende alkaner. alcohols or liquid alkanes.
De ovenfor beskrevne forbindelser har vist hypolipidemisk virkning i dyr og særlig i pattedyr. Hypolipidemisk virkning som anvendt her, betyr den virkning at blod-lipidinnholdet senkes, og særlig kolesterol- og triglycerid-innholdet i serum, selv om ikke alle de fremstilte forbindelser vil oppvise både hypo-kolesterolemisk og hypotriglyceridemisk virkning. De nye forbindelser er derfor egnet til anvendelse ved behandling av serum-hyperlipidemi hos pattedyr og er særlig egnet til behandling av hyperkolesterolemi og hypertriglyceridemi, som er unormalt høye mengder av lipider, henholdsvis kolesterol eller triglycerider, The compounds described above have shown hypolipidemic effects in animals and especially in mammals. Hypolipidemic effect as used here means the effect that the blood lipid content is lowered, and in particular the cholesterol and triglyceride content in serum, although not all of the compounds produced will exhibit both hypo-cholesterolaemic and hypotriglyceridemic effects. The new compounds are therefore suitable for use in the treatment of serum hyperlipidemia in mammals and are particularly suitable for the treatment of hypercholesterolemia and hypertriglyceridemia, which are abnormally high amounts of lipids, respectively cholesterol or triglycerides,
i serum. Forbindelsene kan administreres oralt eller parenteralt ,ved subkutan,' intravenøs eller intraperitoneal injeksjon eller ved implantering, idet oral administrering foretrekkes. in serum. The compounds can be administered orally or parenterally, by subcutaneous, intravenous or intraperitoneal injection or by implantation, oral administration being preferred.
Den hypolipidemiske mengde av p-aminobenzoesyre-forbindelsene som administreres til et dyr, dvs. den mengde som er effektiv til å senke betydelig serum-lipidnivået, kan variere avhengig av slike faktorer som det behandlede dyr, den anvendte p-aminobénzoesyreforbindelse, det ønskede lipid-nivå' som skal oppnås, hvorvidt dyret er hyperlipidemisk, administrerings-perioden og administreringsmetoden. Generelt varierer en effektiv daglig dose fra 1 til 400 mg/kg kroppsvekt, idet en daglig dose fra ca. 5 til 30 mg/kg kroppsvekt foretrekkes. The hypolipidemic amount of the p-aminobenzoic acid compounds administered to an animal, i.e., the amount effective to significantly lower the serum lipid level, may vary depending on such factors as the animal treated, the p-aminobenzoic acid compound used, the desired lipid -level' to be achieved, whether the animal is hyperlipidaemic, the administration period and the administration method. In general, an effective daily dose varies from 1 to 400 mg/kg body weight, with a daily dose from approx. 5 to 30 mg/kg body weight is preferred.
For oral administrering kan farmasøytiske preparater av p-aminobenzoesyrene fremstilles ved vanlig teknikk. Denne teknikk omfatter granulering og sammenpresning, når dette er nødvendig, eller vekselvis blanding og oppløsning eller suspendering av bestanddelene alt efter hva som passer for det ønskede sluttprodukt. En rekke forskjellige farmasøytiske former kan anvendes for forbindelsene. F.eks. kan den rene forbindelse anvendes, eller den kan blandes med et fast bæremiddel. Vanligvis foretrekkes uorganiske, farmasøytiske bæremidler, og særlig faste, uorganiske bæremidler. En grunn for dette er det store antall uorganiske materialer som er kjent for å være farmasøytisk sikre og godtagbare, såvel som meget praktiske ved fremstilling av preparater. Preparatene kan tilberedes som tabletter, pulvere, kapsler, oppslemninger, pastiller eller piller, og slike preparater kan fremstilles ved standard teknikk. Tablettpreparater kan være belagte eller ubelagte, og de kan være brusende eller ikke-brusende. Vanlige hjelpestoffer for tablettfremstilling kan anvendeso F.eks. kan inerte fortynningsmidler så som magnesiumkarbonat eller laktose, sprengmidler så som maisstivelse eller alginsyre, og smøremidler så som magnesiumstearat, anvendes. For oral administration, pharmaceutical preparations of the p-aminobenzoic acids can be prepared by conventional techniques. This technique includes granulation and compression, when this is necessary, or alternately mixing and dissolving or suspending the components depending on what is suitable for the desired end product. A number of different pharmaceutical forms can be used for the compounds. E.g. the pure compound may be used, or it may be mixed with a solid carrier. Inorganic pharmaceutical carriers, and especially solid inorganic carriers, are generally preferred. One reason for this is the large number of inorganic materials which are known to be pharmaceutically safe and acceptable, as well as being very practical when preparing preparations. The preparations can be prepared as tablets, powders, capsules, slurries, lozenges or pills, and such preparations can be prepared by standard techniques. Tablet preparations may be coated or uncoated, and they may be effervescent or non-effervescent. Usual excipients for tablet production can be used, e.g. inert diluents such as magnesium carbonate or lactose, disintegrants such as corn starch or alginic acid, and lubricants such as magnesium stearate can be used.
Hvis et flytende bæremiddel anvendes, kan preparatet If a liquid carrier is used, the preparation can
være i form av en myk gelatinkapsel, en sirup, en flytende opp-løsning eller suspensjon. be in the form of a soft gelatin capsule, a syrup, a liquid solution or suspension.
Hydrokarbon-oppløseligheten i de fleste av forbindelsene fremstilt ifølge oppfinnelsen er tilstrekkelig høy til at farmasøytisk godtagbare oljer kan anvendes som bæremidler, The hydrocarbon solubility in most of the compounds produced according to the invention is sufficiently high that pharmaceutically acceptable oils can be used as carriers,
F.eks. kan man anvende vegetabilske eller animalske oljer så som solsikkeolje, safflorolje, maisolje eller tran. Glycerol kan også anvendes. Med dette sistnevnte oppløsningsmiddel kan fra 2 til 30% vann tilsettes. Når vann alene er bæremiddel, eller i når forbindelsens oppløselighet i olje er lav, kan preparatene administreres i form av en oppslemning. E.g. you can use vegetable or animal oils such as sunflower oil, safflower oil, corn oil or cod liver oil. Glycerol can also be used. With this latter solvent, from 2 to 30% water can be added. When water alone is the carrier, or when the solubility of the compound in oil is low, the preparations can be administered in the form of a slurry.
Emulsjonspreparater kan fremstilles under anvendelse av slike emulgeringsmidler som sorbitantrioleat, polyoksyetylen-sorbitanmonooleat, lecitin, akasiegummi eller tragakantgummi„ Vannbaserte suspensjoner kan fremstilles ved hjelp av fuktemidler så som polyetylenoksyd-kondensasjonsprodukter av alkylfenoler, fettalkoholer eller fettsyrer med suspenderingsmidler, f.eks. Emulsion preparations can be prepared using such emulsifiers as sorbitan trioleate, polyoxyethylene sorbitan monooleate, lecithin, gum acacia or gum tragacanth„ Water-based suspensions can be prepared using wetting agents such as polyethylene oxide condensation products of alkylphenols, fatty alcohols or fatty acids with suspending agents, e.g.
et hydrofilt kolloid så som polyvinylpyrrolidon. Emulsjonene og suspensjonene kan inneholde vanlige hjelpestoffer så som søtnings-midler, glidemidler, farvematerialer eller konserveringsmidler. a hydrophilic colloid such as polyvinylpyrrolidone. The emulsions and suspensions may contain common auxiliary substances such as sweeteners, lubricants, coloring materials or preservatives.
p-aminobenzoesyrene kan også innarbeides i et nærings-middel som f.eks. smør, margarin, spiselige oljer, kasein eller karbohydrater. Slike næringsblandinger er tilpasset for å bli administrert som en delvis eller total diett eller som et supplement til dietten. Slike blandinger inneholder fortrinnsvis fra 0,02 The p-aminobenzoic acids can also be incorporated into a food such as e.g. butter, margarine, edible oils, casein or carbohydrates. Such nutrient mixtures are adapted to be administered as a partial or total diet or as a supplement to the diet. Such mixtures preferably contain from 0.02
til 2,0 vekt% av den aktive bestanddel ved administrering som total diett. Preparatene kan inneholde høyere konsentrasjoner av den aktive bestanddel ved administrering som et supplement. to 2.0% by weight of the active ingredient when administered as a total diet. The preparations may contain higher concentrations of the active ingredient when administered as a supplement.
For parenteral anvendelse kan forbindelsene tilberedes For parenteral use, the compounds can be prepared
med sterile bestanddeler, og blandes og pakkes aseptisk. De kan administreres intravenøst eller intramuskulært. Egnede opp-løsningsmidler for fremstilling av preparater for slik bruk, er flerverdige alifatiske alkoholer og blandinger derav. Særlig tilfredsstillende er de farmasøytisk godtagbare glykoler så som propylenglykol, og blandinger derav. Glycerol er særlig egnet. Opptil 25-30 volum% vann kan eventuelt innføres i bæremidlet. with sterile components, and is mixed and packaged aseptically. They can be administered intravenously or intramuscularly. Suitable solvents for the preparation of preparations for such use are polyhydric aliphatic alcohols and mixtures thereof. Particularly satisfactory are the pharmaceutically acceptable glycols such as propylene glycol, and mixtures thereof. Glycerol is particularly suitable. Up to 25-30% by volume of water can optionally be introduced into the carrier.
En 80% vandig propylenglykoloppløsning er et særlig egnet opp-løsningsmiddelsystem. En pH på ca. 7,4 og en isotonisk karakter som er forlikelig med kroppens isotoniske karakter, er ønskelig. Den basiske karakter kan reguleres ved tilsetning av base i nød-vendig utstrekning, og en særlig egnet base er monoetanolamin. An 80% aqueous propylene glycol solution is a particularly suitable solvent system. A pH of approx. 7.4 and an isotonic character that is compatible with the body's isotonic character is desirable. The basic character can be regulated by adding base to the necessary extent, and a particularly suitable base is monoethanolamine.
Det kan ofte være ønskelig å innføre et lokalbedøvelsesmiddel av den type som er vanlig kjent. It may often be desirable to introduce a local anesthetic of the type that is commonly known.
Den prosentvise mengde av den nye forbindelse som anvendes sammen med det farmasøytiske bæremiddel, kan varieres. Det er nødvendig at den aktive forbindelse utgjør en slik andel at man oppnår en passende dose, og det foretrekkes å anvende farmasøytiske preparater inneholdende minst 10 vekt% av forbindelsen. Aktiviteten øker med konsentrasjonen av den aktive bestanddel i bæremidlet, men de preparater som inneholder en betydelig mengde bæremiddel, f.eks. minst 1% og fortrinnsvis minst 5%, foretrekkes eftersom de gjør det lettere å administrere forbindelsen. The percentage amount of the novel compound used together with the pharmaceutical carrier can be varied. It is necessary that the active compound constitutes such a proportion that a suitable dose is obtained, and it is preferred to use pharmaceutical preparations containing at least 10% by weight of the compound. The activity increases with the concentration of the active ingredient in the carrier, but those preparations which contain a significant amount of carrier, e.g. at least 1% and preferably at least 5%, are preferred since they facilitate administration of the compound.
De aktive forbindelser fremstilles i henhold til oppfinnelsen ved å omsette p-aminobenzoesyre eller en ester derav med formelen Nt^-Ce^-COOR' i et inert oppløsningsmiddel med et aldehyd med formelen R-CHO. The active compounds are prepared according to the invention by reacting p-aminobenzoic acid or an ester thereof with the formula Nt^-Ce^-COOR' in an inert solvent with an aldehyde of the formula R-CHO.
Den resulterende Schiff base reduseres for fremstilling av det tilsvarende p-aminobenzoesyrederivat. En hensiktsmessig metode for utførelse av denne siste prosess omfatter blanding av Schiff basen med et overskudd av etanol og vann. Fortynnet vandig natriumhydroksyd, f.eks. ca. 1 molekvivalent av Schiff-basen, The resulting Schiff base is reduced to produce the corresponding p-aminobenzoic acid derivative. An appropriate method for carrying out this last process comprises mixing the Schiff base with an excess of ethanol and water. Dilute aqueous sodium hydroxide, e.g. about. 1 molar equivalent of the Schiff base,
kan eventuelt settes til blandingen. Natriumborhydrid, NaBH^, can optionally be added to the mixture. Sodium borohydride, NaBH^,
(1 molekvivalent) tilsettes ved romtemperatur og omrøres inntil det oppløses. Blandingen oppvarmes derefter til tilbakeløpstemperatur i 1-2 timer. Blandingen helles på is og surgjøres. Produktet kan frafiltreres som et bunnfall og renses videre ved kjente metoder. (1 molar equivalent) is added at room temperature and stirred until dissolved. The mixture is then heated to reflux temperature for 1-2 hours. The mixture is poured over ice and acidified. The product can be filtered off as a precipitate and further purified by known methods.
Eventuelt kan en fremstilt ester Optionally, a prepared ester can
omdannes til den tilsvarende syre, eller en syre omdannes til den ønskede ester, eller en ester omdannes til en annen ønsket ester. is converted to the corresponding acid, or an acid is converted to the desired ester, or an ester is converted to another desired ester.
De følgende eksempler skal tjene til å illustrere oppfinnelsen . The following examples shall serve to illustrate the invention.
Eksempel 1 Example 1
4-( 1, 3- benzodioksol- 5- ylmetylamino) benzoesyre 4-(1,3-benzodioxol-5-ylmethylamino)benzoic acid
En blanding av 22,5 g (0,15 mol) piperonal og 24,8 g A mixture of 22.5 g (0.15 mol) piperonal and 24.8 g
(0,15 mol) etyl-p-aminobenzoat i 500 ml benzen ble tilbakeløps-behandlet inntil 0,15 mol vann var oppsamlet i en felle. Reaksjons-blandingen ble avkjølt, og gule krystaller ble dannet. Blandingen ble filtrert, og det krystallinske produkt ble vasket med benzen og vakuumtørret. Denne Schiff-base veiet 31,97 g (0,107 mol). (0.15 mol) of ethyl p-aminobenzoate in 500 ml of benzene was refluxed until 0.15 mol of water was collected in a trap. The reaction mixture was cooled and yellow crystals formed. The mixture was filtered, and the crystalline product was washed with benzene and vacuum dried. This Schiff base weighed 31.97 g (0.107 mol).
Schiff-basen ble oppløst i 500 ml vannfri etanol og opp-varmet til 40°C. Natriumborhydrid (4,5 g) ble tilsatt, og den resulterende oppslemning ble tilbakeløpsbehandlet i 45 minutter. Reaksjonsmassen ble avkjølt, hellet over 800 ml isvann, og den The Schiff base was dissolved in 500 ml of anhydrous ethanol and heated to 40°C. Sodium borohydride (4.5 g) was added and the resulting slurry was refluxed for 45 minutes. The reaction mass was cooled, poured over 800 ml of ice water, and it
rå 4-(1,3-benzodioksol-5-yl-metylamino)benzoesyre-etylester ble utfelt. Bunnfallet ble oppsamlet og vasket med vann. Efter vakuumtørring fikk man 30,4 g hvit, krystallinsk ester. crude 4-(1,3-benzodioxol-5-yl-methylamino)benzoic acid ethyl ester was precipitated. The precipitate was collected and washed with water. After vacuum drying, 30.4 g of white, crystalline ester was obtained.
Esteren hadde et smeltepunkt på 120-122°C. Elementæranalyse: The ester had a melting point of 120-122°C. Elemental analysis:
4-(1,3-benzodioksol-5-ylmetylamino)benzoesyre ble fremstilt fra den ovenfor fremstilte ester som følger. 15 g av esteren ble blandet med 150 ml 20%ig natriumhydroksyd og 150 ml etylalkohol. Den resulterende oppslemning ble tilbakeløps-behandlet i 4 timer og derefter avkjølt. Den resulterende klare oppløsning ble hellet på 800 g is. Reaksjonsmassen ble surgjort med konsentrert HC1. Krystallinsk 4-(1,3-benzodioksol-5-ylmetylamino)benzoesyre ble dannet og ble frafiltrert, vasket med vann og tørret. Produktet ble omkrystallisert fra acetonitril. Forbindelsen hadde et smeltepunkt på 193-196°C. 4-(1,3-Benzodioxol-5-ylmethylamino)benzoic acid was prepared from the above-prepared ester as follows. 15 g of the ester were mixed with 150 ml of 20% sodium hydroxide and 150 ml of ethyl alcohol. The resulting slurry was refluxed for 4 hours and then cooled. The resulting clear solution was poured onto 800 g of ice. The reaction mass was acidified with concentrated HCl. Crystalline 4-(1,3-benzodioxol-5-ylmethylamino)benzoic acid was formed and was filtered off, washed with water and dried. The product was recrystallized from acetonitrile. The compound had a melting point of 193-196°C.
Elementæranalyse: Elemental analysis:
Alternativt kan den frie benzoesyre» fremstilles direkte ved omsetning av piperonal med p-aminobenzoesyre. Den resulterende Schiff-base kan reduseres med natriumborhydrid som beskrevet ovenfor. Alternatively, the free benzoic acid can be prepared directly by reacting piperonal with p-aminobenzoic acid. The resulting Schiff base can be reduced with sodium borohydride as described above.
Ved å følge de ovenfor beskrevne generelle fremgangsmåter ble en rekke p-aminobenzoesyrederivater og deres estere med den generelle formel: By following the general procedures described above, a number of p-aminobenzoic acid derivatives and their esters of the general formula:
fremstilt. produced.
I tabell I er data for forbindelsene oppsummert. In Table I, data for the compounds are summarized.
Den hypolipidemiske virkning av forbindelsene fremstilt ifølge oppfinnelsen er undersøkt i rotter. Ved denne fremgangs-måte oppløses en forbindelse i aceton, tas opp på en silikagel og blandes med malt forstoff for å gi konsentrasjoner på The hypolipidemic effect of the compounds prepared according to the invention has been investigated in rats. In this procedure, a compound is dissolved in acetone, taken up on a silica gel and mixed with ground precursor to give concentrations of
0,125 vekt% av forbindelsen i forstoffet. Det behandlede f6r-stoff ble administrert til hannrotter med en vekt på 150-160 g over en periode på 14 dager. Efter foringsperioden ble rottene avlivet, og blodprøver ble oppsamlet„ Leveren ble tatt ut, veiet og frosset for senere analyse. De relative mengder av serum-kolesterol i blodprøvene ble bestemt ved Henly-metoden; 0.125% by weight of the compound in the precursor. The treated f6r substance was administered to male rats weighing 150-160 g over a period of 14 days. After the feeding period, the rats were euthanized and blood samples were collected. The liver was removed, weighed and frozen for later analysis. The relative amounts of serum cholesterol in the blood samples were determined by the Henly method;
A.A. Henly, Analyst, 82, 286 (1957). Lever-kolesterol ble målt ved Sperry-Webb-metoden; Journal of Biological Chemistry 187,97 A.A. Henly, Analyst, 82, 286 (1957). Liver cholesterol was measured by the Sperry-Webb method; Journal of Biological Chemistry 187.97
(1950). De relative mengder av triglycerider i blod- og lever-prøvene ble bestemt ved Van Handel og Zilversmit-metoden; (1950). The relative amounts of triglycerides in the blood and liver samples were determined by the Van Handel and Zilversmit method;
J. Lab. Clin. Med. 50, 152 (1957) og Clin. Chem. 7, 249 (1961). Ved å benytte som standard de gjennomsnittlige mengder hos kontrollrottene som var behandlet på tilsvarende måte bortsett fra at bare silikagel var satt til det malte forstoff, fikk man de gjennomsnittlige resultater hos de behandlede grupper. J. Lab. Clin. With. 50, 152 (1957) and Clin. Chem. 7, 249 (1961). By using as a standard the average amounts in the control rats that had been treated in a similar way except that only silica gel had been added to the milled precursor, the average results in the treated groups were obtained.
De data som er gjengitt i tabell II viser resultatene The data reproduced in Table II show the results
av undersøkelsene. of the surveys.
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US3868416A (en) * | 1973-10-01 | 1975-02-25 | American Cyanamid Co | Hypolipidemic 4-(monoalkylamino)benzoic acid derivatives |
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NO145839C (en) | 1982-06-09 |
IE44858L (en) | 1977-07-19 |
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CH628340A5 (en) | 1982-02-26 |
SE435175B (en) | 1984-09-10 |
CA1072969A (en) | 1980-03-04 |
DK8177A (en) | 1977-07-20 |
GB1521458A (en) | 1978-08-16 |
DK153471C (en) | 1988-11-21 |
DE2702058A1 (en) | 1977-07-28 |
ATA31277A (en) | 1978-06-15 |
NO770151L (en) | 1977-07-20 |
GB1521459A (en) | 1978-08-16 |
AU2114077A (en) | 1978-07-13 |
JPS5289660A (en) | 1977-07-27 |
FR2338040A1 (en) | 1977-08-12 |
FR2338040B1 (en) | 1980-04-30 |
BE850516A (en) | 1977-07-19 |
JPS6233230B2 (en) | 1987-07-20 |
NL7700480A (en) | 1977-07-21 |
DE2702058C2 (en) | 1985-09-19 |
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