NO770152L - PROCEDURES FOR THE PREPARATION OF PHYSIOLOGICALLY ACTIVE P-BENZYLAMINOBENZOIC ACID DERIVATIVES. - Google Patents
PROCEDURES FOR THE PREPARATION OF PHYSIOLOGICALLY ACTIVE P-BENZYLAMINOBENZOIC ACID DERIVATIVES.Info
- Publication number
- NO770152L NO770152L NO770152A NO770152A NO770152L NO 770152 L NO770152 L NO 770152L NO 770152 A NO770152 A NO 770152A NO 770152 A NO770152 A NO 770152A NO 770152 L NO770152 L NO 770152L
- Authority
- NO
- Norway
- Prior art keywords
- schiff base
- acid
- benzoic acid
- aminobenzoic acid
- compounds
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 20
- 238000002360 preparation method Methods 0.000 title description 13
- NYNAMTQEBMCHNG-UHFFFAOYSA-N 4-(benzylamino)benzoic acid Chemical class C1=CC(C(=O)O)=CC=C1NCC1=CC=CC=C1 NYNAMTQEBMCHNG-UHFFFAOYSA-N 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims description 29
- ALYNCZNDIQEVRV-UHFFFAOYSA-N aniline-p-carboxylic acid Natural products NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 claims description 18
- 239000002262 Schiff base Substances 0.000 claims description 13
- 150000004753 Schiff bases Chemical class 0.000 claims description 13
- -1 hydroxy, carboxy Chemical group 0.000 claims description 13
- 229960004050 aminobenzoic acid Drugs 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- BKBMPNPZYZWGSX-UHFFFAOYSA-N 4-[(3-methoxyphenyl)methylamino]benzoic acid Chemical compound COC1=CC=CC(CNC=2C=CC(=CC=2)C(O)=O)=C1 BKBMPNPZYZWGSX-UHFFFAOYSA-N 0.000 claims description 2
- GABPQBSNSDBMBK-UHFFFAOYSA-N 4-[(4-fluorophenyl)methylamino]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NCC1=CC=C(F)C=C1 GABPQBSNSDBMBK-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 claims 2
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 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
- 230000000055 hyoplipidemic effect Effects 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- FVOJFMSKOLXBAW-UHFFFAOYSA-N 4-[(4-propan-2-ylphenyl)methylamino]benzoic acid Chemical compound C1=CC(C(C)C)=CC=C1CNC1=CC=C(C(O)=O)C=C1 FVOJFMSKOLXBAW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- YPTUAQWMBNZZRN-UHFFFAOYSA-N dimethylaminoboron Chemical compound [B]N(C)C YPTUAQWMBNZZRN-UHFFFAOYSA-N 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 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
- 239000002253 acid Substances 0.000 description 2
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- WTWBUQJHJGUZCY-UHFFFAOYSA-N cuminaldehyde Chemical compound CC(C)C1=CC=C(C=O)C=C1 WTWBUQJHJGUZCY-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000004615 ingredient 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
- 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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 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
- IFXSWTIWFGIXQO-AOOOYVTPSA-N 2-chloro-5-[(3s,5r)-3,5-dimethylpiperidin-1-yl]sulfonylbenzoic acid Chemical group C1[C@@H](C)C[C@@H](C)CN1S(=O)(=O)C1=CC=C(Cl)C(C(O)=O)=C1 IFXSWTIWFGIXQO-AOOOYVTPSA-N 0.000 description 1
- ZWUSBSHBFFPRNE-UHFFFAOYSA-N 3,4-dichlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1Cl ZWUSBSHBFFPRNE-UHFFFAOYSA-N 0.000 description 1
- TVKKKDGJQZTLHL-UHFFFAOYSA-N 4-[(2-fluorophenyl)methylamino]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NCC1=CC=CC=C1F TVKKKDGJQZTLHL-UHFFFAOYSA-N 0.000 description 1
- QIANQKPXNXBLNW-UHFFFAOYSA-N 4-[(4-chlorophenyl)methylamino]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NCC1=CC=C(Cl)C=C1 QIANQKPXNXBLNW-UHFFFAOYSA-N 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 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
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 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
- 241000906446 Theraps Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 150000001298 alcohols 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
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 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
- 239000010775 animal oil Substances 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- WPYMKLBDIGXBTP-VQEHIDDOSA-N benzoic acid Chemical compound OC(=O)C1=CC=C[13CH]=C1 WPYMKLBDIGXBTP-VQEHIDDOSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 150000001559 benzoic acids Chemical class 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
- 239000003638 chemical reducing agent 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
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch 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
- 238000001035 drying Methods 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 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
- 239000012467 final product Substances 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
- 239000012362 glacial acetic acid 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
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000002994 raw material Substances 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
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium 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
- 239000000243 solution Substances 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 238000004611 spectroscopical analysis 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
- 229950005201 tibric acid Drugs 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
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Description
Denne oppfinnelse angår analogifremgangsmåte for fremstilling av p-benzylaminobenzoesyrer med hypolipidemisk aktivitet. This invention relates to an analogous process for the production of p-benzylaminobenzoic acids with hypolipidemic activity.
Det er anerkjent at kolesterol og triglycerider spiller en hovedrolle ved dannelsen av arterosklerotiske belegg ved å fremskynde avsetning 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.
Inntil nylig er meget få hypolipidemiske benzoesyrer beskrevet. Det viktigste hypolipidemiske derivat av benzoesyre som hittil er beskrevet, er tibrinsyre, se U.S. patent 3.843.662 og U.S. patent 3.855.255, og dessuten Ryan et al. Clinc. Pharmacol. Therap., 1J5, 218 (1974). Det foreligger også to andre omtaler av hypolipidemisk virkning hos p-aminobenzoesyreanaloger, se tysk offentliggjørelsesskrift 2.316.914 og belgisk patent 815.703. Alkylamino-benzoesyrederivater er også beskrevet som hypolipidemiske midler, se U.S. patent 3.868.416. Until recently, very few hypolipidemic benzoic acids have been described. The most important hypolipidemic derivative of benzoic acid described to date is tibric acid, see U.S. Pat. patent 3,843,662 and U.S. Pat. patent 3,855,255, and also Ryan et al. Clin. Pharmacol. Therap., 1J5, 218 (1974). There are also two other references to the hypolipidemic effect of p-aminobenzoic acid analogues, see German publication 2,316,914 and Belgian patent 815,703. Alkylamino-benzoic acid derivatives are also described as hypolipidemic agents, see U.S. Pat. patent 3,868,416.
I henhold til foreliggende oppfinnelse fremstilles nye hypolipidemiske forbindelser med den generelle formel: According to the present invention, new hypolipidemic compounds are produced with the general formula:
hvor n betyr et helt tall fra 1 til 3; R betyr halogen, C1_1Q-alkyl, C^_^Q-alkoksy, C^_^Q-alkyltio, hydroksy, karboksy, C - cykloalkyl, C2_5-alkenyl, C2_5-alkenyloksy, benzyl, fenyl, fenoksy, benzyloksy, amino eller di-C1_5-alkylamino; og R' betyr hydrogen eller C1_5~alkyl, med det forbehold at når R er amino eller dimetylamino, er n minst 2; når R er metoksy og n er 1, er where n means an integer from 1 to 3; R means halogen, C1_1Q-alkyl, C^_^Q-alkyl, C^_^Q-alkylthio, hydroxy, carboxy, C - cycloalkyl, C2_5-alkenyl, C2_5-alkenyloxy, benzyl, phenyl, phenoxy, benzyloxy, amino or di-C 1-5 -alkylamino; and R' means hydrogen or C1-5~alkyl, with the proviso that when R is amino or dimethylamino, n is at least 2; when R is methoxy and n is 1, is
metoksygruppen i meta-stilling; og hvis R omfatter både metoksy og hydroksy, er n 3, og den tredje substituent på ringen er forskjellig fra propyl. the methoxy group in the meta position; and if R comprises both methoxy and hydroxy, n is 3 and the third substituent on the ring is different from propyl.
Når n er større enn 1, er R ikke begrenset til flere substituenter av samme type, men kan bety en hvilken som helst kombinasjon av de ovennevnte grupper. When n is greater than 1, R is not limited to several substituents of the same type, but may mean any combination of the above-mentioned groups.
De mest foretrukne forbindelser er 4-(m-metoksybenzyl-amino)benzoesyre og 4-(p-fluorbenzylamino)bénzoesyre„ The most preferred compounds are 4-(m-methoxybenzylamino)benzoic acid and 4-(p-fluorobenzylamino)benzoic acid.
Foreliggende oppfinnelse omfatter også fremstilling av farmasøytisk godtagbare salter av p-benzylaminobenzoesyrene. 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 jordalkalimetallhydroksyder, -karbonater og -bikarbonater, så som natriumhydroksyd, kaliumhydroksyd, kalsiumhydroksyd, kalium-karbonat, natriumbikarbonat eller magnesiumkarbonat; ammoniakk; og primære, sekundære og tertiære aminer. Også aluminiumsalter kan fremstilles ved å behandle det tilsvarende natriumsalt med et passende aluminiumkompleks så som aluminiumklorid-heksahydrat. The present invention also includes the preparation of pharmaceutically acceptable salts of the p-benzylaminobenzoic acids. 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 alkaline earth metal hydroxides, carbonates and bicarbonates, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium bicarbonate or magnesium carbonate; ammonia; 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, faste stoffer som er oppløselige i mange vanlige organiske oppløsningsmidler så som'f.eks. aceton, benzen, alkoholer eller flytende alkaner. The compounds produced according to the invention are crystalline solids which are soluble in many common organic solvents such as e.g. acetone, benzene, 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-benzylaminobenzoesyreforbindelsene 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-benzylaminobenzyesyreforbindelse, detønskede 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-benzylaminobenzoic 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-benzylaminobenzoic acid compound used, the desired lipid level which must be achieved, whether the animal is hyperlipidaemic, the administration period and the administration method. In general, an effective varies. daily dose 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 fremstilles ved å følge vanlig teknikk for en farmasøytisk kjemiker. 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 farmasøytisk teknikk. Tablettpreparater kan være belagte eller ubelagte, og de kan være brusende eller ikke-brusende. Vanlige hjelpestoffer for tablettfremstilling kan anvendes. F.eks. kan inerte fortynningsmidler så som magnesiumkarbonat eller laktose, spréngmidler så som maisstivelse eller alginsyre, og smøremidler så som magnesiumstearat, anvendes. For oral administration, pharmaceutical preparations may be prepared following the usual techniques of a pharmaceutical chemist. This technique includes granulation and compression, when necessary, or alternately mixing and dissolving or suspending the ingredients as appropriate 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 pharmaceutical 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 være i form av en myk gelatinkapsel, en sirup, en flytende opp-løsning eller suspensjon. If a liquid carrier is used, the preparation can be in the form of a soft gelatin capsule, a syrup, a liquid solution or suspension.
Hydrokarbon-bppløseligheten 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 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, acacia gum or tragacanth gum. 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-benzylaminobcnzoesyrene 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 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. The p-benzylaminobenzoic 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 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 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. For parenteral use, the compounds may be prepared with sterile ingredients, and 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. Det kan ofte væreønskelig å innføre et lokalbedøvelsesmiddel av den type som er vanlig kjent. 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. 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.
p-benzylaminobenzoesyreforbindelsene kan fremstillesThe p-benzylaminobenzoic acid compounds can be prepared
ved i og for seg kjente metoder. Generelt fremstilles forbindelsene ved omsetning av p-aminobenzoesyre i et inert opp-løsningsmiddel med det ønskede benzaldehyd. Den resulterende Schiff-base kan reduseres på kjent måte for fremstilling av den tilsvarende p-behzylaminobenzoesyre. En hensiktsmessig metode for utførelse av denne siste fremgangsmåte omfatter å blande Schiff-basen med et overskudd av etanol og vann. ' Fortynnet, vandig natriumhydroksyd, f.eks. ca, 1 molekvivalent av Schiff-basen, kan éventuelt settes til blandingen. Et reduksjonsmiddel så som natriumbohydrid eller dimetylaminoboran tilsettes ved romtemperatur og omrøres inntil det er oppløst. Blandingen opp-varmes derefter til tilbakeløpstemperatur i 1-2 timer. Blandingen helles på is og surgjøres. Produktet kan frafUtreres som et bunnfall og renses videre ved kjente metoder i nødvendig utstrekning. by methods known per se. In general, the compounds are prepared by reacting p-aminobenzoic acid in an inert solvent with the desired benzaldehyde. The resulting Schiff base can be reduced in a known manner to produce the corresponding p-behzylaminobenzoic acid. An appropriate method for carrying out this last method comprises mixing the Schiff base with an excess of ethanol and water. ' Dilute, aqueous sodium hydroxide, e.g. approx. 1 molar equivalent of the Schiff base can optionally be added to the mixture. A reducing agent such as sodium bohydride or dimethylaminoborane 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 to the extent necessary.
De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere. The following examples shall serve to further illustrate the invention.
Eksempel 1Example 1
Syntese av 4-( 4- isopropylbenzylamino) benzoesyreSynthesis of 4-(4-isopropylbenzylamino)benzoic acid
En blanding av 37,94 g (0,277 mol) p-aminobenzoesyre og 41,0 g (0,277 mol) p-isopropylbenzaldehyd i 500 ml benzen ble tilbakeløpsbehandlet i 5 timer.Azeotrop-vann som ble dannet, A mixture of 37.94 g (0.277 mol) p-aminobenzoic acid and 41.0 g (0.277 mol) p-isopropylbenzaldehyde in 500 ml benzene was refluxed for 5 hours. Azeotrope water which formed,
ble oppsamlet i en Dean-Stark-felle. Reaksjonsmassen ble avkjølt og de dannede krystaller ble frafiltrert og vasket. Råproduktet (Schiff base) veiet 72,23 g. Schiff-basen (0,27 mol) ble satt til 1 liter iseddik og avkjølt til 15°C. Til den resulterende masse ble det satt dråpevis 19,86 g (0,34 mol) dimetylaminoboran oppløst i en minimal mengde eddiksyre. Reaksjonstemperaturen ble holdt under 20°C. Da tilsetningen var fullstendig, ble blandingen oppvarmet til tilbakeløpstemperatur i 15-30 minutter. Dette . resulterte i en klar oppløsning. Reaksjonsmassen ble avkjølt til romtemperatur og hellet i 1500 ml isvann. Rått 4-(4-isopropylbenzylamino) benzoesyre ble utfelt, og produktet ble frafiltrert, vasket og tørret under redusert trykk. Råproduktet ble omkrystallisert fra acetonitril for å gi 32,2 g 4-(4-isopropylbenzylamino) -benzoesyre . Forbindelsen hadde et smeltepunkt på 170-173°C. was collected in a Dean-Stark trap. The reaction mass was cooled and the formed crystals were filtered off and washed. The crude product (Schiff base) weighed 72.23 g. The Schiff base (0.27 mol) was added to 1 liter of glacial acetic acid and cooled to 15°C. To the resulting mass was added dropwise 19.86 g (0.34 mol) of dimethylaminoborane dissolved in a minimal amount of acetic acid. The reaction temperature was kept below 20°C. When the addition was complete, the mixture was heated to reflux for 15-30 minutes. This . resulted in a clear resolution. The reaction mass was cooled to room temperature and poured into 1500 ml of ice water. Crude 4-(4-isopropylbenzylamino)benzoic acid was precipitated, and the product was filtered off, washed and dried under reduced pressure. The crude product was recrystallized from acetonitrile to give 32.2 g of 4-(4-isopropylbenzylamino)-benzoic acid. The compound had a melting point of 170-173°C.
Elementæranalyse viste karbon 75,83%, hydrogen 7,03%Elemental analysis showed carbon 75.83%, hydrogen 7.03%
og nitrogen 5,2 7%. Teoretisk analyse av forbindelsen erand nitrogen 5.2 7%. Theoretical analysis of the connection is
karbon 75,81%, hydrogen 7,11% og nitrogen 5,20%.carbon 75.81%, hydrogen 7.11% and nitrogen 5.20%.
Eksempel 2Example 2
Syntese av 4-( 4- klorbenzylamino) benzoesyreSynthesis of 4-(4-chlorobenzylamino)benzoic acid
En blanding av p-klorbenzaldehyd (17,5 g, 1,25 mol) og p-aminobenzoesyre (17,1 g, 1,25 mol) i 1,5 liter benzen ble tilbakeløpsbehandlet inntil den teoretiske mengde vann var oppsamlet. Reaksjonsmassen ble avkjølt og filtrert. De hvitaktige krystaller ble tørret under redusert trykk. Efter tørring veidde Schiff basen 29,8 g (1,15 mol, 91%).Schiff-basen ble oppløst il liter etanol ved tilsetning av 46 g (1,15 mol) NaOH i 150 ml vann. Derefter ble 1,3 mol NaBH^ i 200 ml 1^0 tilsatt, og den resulterende blanding ble oppvarmet til tilbakeløpstemperatur i 2 timer. Reaksjonsmassen ble avkjølt og omrørt natten over. Oppslemningen ble surgjort med konsentrert HC1 og fortynnet med A mixture of p-chlorobenzaldehyde (17.5 g, 1.25 mol) and p-aminobenzoic acid (17.1 g, 1.25 mol) in 1.5 liters of benzene was refluxed until the theoretical amount of water was collected. The reaction mass was cooled and filtered. The whitish crystals were dried under reduced pressure. After drying, the Schiff base weighed 29.8 g (1.15 mol, 91%). The Schiff base was dissolved in 1 liter of ethanol by adding 46 g (1.15 mol) of NaOH in 150 ml of water. Then 1.3 mol of NaBH 3 in 200 ml of 1 H 2 O was added and the resulting mixture was heated to reflux temperature for 2 hours. The reaction mass was cooled and stirred overnight. The slurry was acidified with concentrated HCl and diluted with
1 liter H2O. Denne blanding ble filtrert, vasket og tørret.1 liter of H2O. This mixture was filtered, washed and dried.
Den rå 4- r (4-klorbenzylamino)benzoesyre veidde 31,6 g. Produktet ble omkrystallisert fra isopropanol for å gi 21,3 g (71%) av forbindelsen. The crude 4-r-(4-chlorobenzylamino)benzoic acid weighed 31.6 g. The product was recrystallized from isopropanol to give 21.3 g (71%) of the compound.
Forbindelsen ble funnet å ha et smeltepunkt på 210-213°C. Elementæranalyse viste karbon 64,2%, hydrogen 4,82% og nitrogen 5,63%. Teoretisk analyse av forbindelsen er karbon 64,25%, hydrogen 4,62% og nitrogen 5,35%. The compound was found to have a melting point of 210-213°C. Elemental analysis showed carbon 64.2%, hydrogen 4.82% and nitrogen 5.63%. Theoretical analysis of the compound is carbon 64.25%, hydrogen 4.62% and nitrogen 5.35%.
Eksempel 3Example 3
Syntese av 4-( 3, 4- diklorbenzylamino) benzoesyreSynthesis of 4-(3,4-dichlorobenzylamino)benzoic acid
Omsetningen ble utført på samme måte som i eksempel 2 bortsett fra at bare 0,1 mol av hver reaksjonskomponent ble anvendt. Den rå Schiff base (26,53 g) ble fremstilt fra 13,7 g p-aminobenzoesyre og 17,5 g 3,4-diklorbenzaldehyd. The reaction was carried out in the same way as in example 2 except that only 0.1 mol of each reaction component was used. The crude Schiff base (26.53 g) was prepared from 13.7 g of p-aminobenzoic acid and 17.5 g of 3,4-dichlorobenzaldehyde.
Schiff basen ble redusert med dimetylaminoboran (5,8 g, 0,1 mol) ved romtemperatur i eddiksyre som i eksempel 2. Den rå 4-(3,4-diklorbenzylamino)-benzoesyre ble omkrystallisert fra acetonitril for å gi 21,75 g av sluttproduktet. Forbindelsen'ble funnet å ha et smeltepunkt på 180-204°C. The Schiff base was reduced with dimethylaminoborane (5.8 g, 0.1 mol) at room temperature in acetic acid as in Example 2. The crude 4-(3,4-dichlorobenzylamino)-benzoic acid was recrystallized from acetonitrile to give 21.75 g of the final product. The compound was found to have a melting point of 180-204°C.
Strukturen ble bekreftet ved spektroskopiske data.The structure was confirmed by spectroscopic data.
Alle de her beskrevne forbindelser kan fremstilles fra den tilsvarende Schiff base ved reduksjon som beskrevet ovenfor. All the compounds described here can be prepared from the corresponding Schiff base by reduction as described above.
Estrene av p-benzylaminobenzoesyreforbindelsene fremstilles hensiktsmessig fra den passende p-aminobenzoesyreester som f.eks. p-aminobenzoesyre-etylester. Ved en slik fremgangsmåte omsettes p-aminobenzoesyreesteren med det passende behzaldehyd på samme måte som beskrevet for p-aminobenzoesyren. The esters of the p-benzylaminobenzoic acid compounds are conveniently prepared from the appropriate p-aminobenzoic acid ester such as, e.g. p-aminobenzoic acid ethyl ester. In such a method, the p-aminobenzoic acid ester is reacted with the appropriate behzaldehyde in the same way as described for the p-aminobenzoic acid.
Ved å følge de generelle fremgangsmåter beskrevet ovenfor, er en rekke andre p-benzylaminobenzoesyrer og estere med den følgende generelle formel: Following the general procedures described above, a number of other p-benzylaminobenzoic acids and esters are of the following general formula:
fremstilt. produced.
Tabell I representerer en oppsummering av resultatene. Table I represents a summary of the results.
Eksempel 48 Example 48
I tillegg til de ovenfor beskrevne forbindelser ble orto-halogenderivatet 4-(2-fluorbenzylamino)benzoesyre fremstilt under anvendelse av de ovenfor beskrevne fremgangsmåter. Forbindelsen ble omkrystallisert fra isopropylalkohol og hadde et smeltepunkt på 169-172°C. In addition to the compounds described above, the ortho-halogen derivative 4-(2-fluorobenzylamino)benzoic acid was prepared using the methods described above. The compound was recrystallized from isopropyl alcohol and had a melting point of 169-172°C.
Elementæranalyse viste karbon 68,56%, hydrogen 4,93% og nitrogen 5,71%. Teoretisk analyse var karbon 68,86%, Elemental analysis showed carbon 68.56%, hydrogen 4.93% and nitrogen 5.71%. Theoretical analysis was carbon 68.86%,
hydrogen 4,96% og nitrogen 5,89%.hydrogen 4.96% and nitrogen 5.89%.
Den hypolipidemiske virkning av forbindelsene fremstilt ifølge oppfinnelsen er undersøkt i rotter. Ved denne fremgangsmåte oppløses en forbindelse i aceton, tas opp på en silikagel og blandes med malt férstoff for å gi konsentrasjoner på The hypolipidemic effect of the compounds prepared according to the invention has been investigated in rats. In this method, a compound is dissolved in acetone, taken up on a silica gel and mixed with ground raw material to give concentrations of
0,125 vekt% av forbindelsen i f6rstoffet. Det behandlede f6r-stoff ble administrert til hannrotter med en vekt på 150-160 g over en periode på 14 dager. Efter f6ringsperioden 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 feed. 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 f6rstoff, 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 was added to the ground substance, the average results in the treated groups were obtained.
De data som er gjengitt i tabell II viser resultateneThe data reproduced in Table II show the results
av undersøkelsene. of the surveys.
Claims (3)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US65008976A | 1976-01-19 | 1976-01-19 | |
US65008876A | 1976-01-19 | 1976-01-19 |
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NO770152L true NO770152L (en) | 1977-07-20 |
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ID=27095775
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NO770152A NO770152L (en) | 1976-01-19 | 1977-01-18 | PROCEDURES FOR THE PREPARATION OF PHYSIOLOGICALLY ACTIVE P-BENZYLAMINOBENZOIC ACID DERIVATIVES. |
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JP (1) | JPS5289639A (en) |
AU (1) | AU510758B2 (en) |
BE (1) | BE850517A (en) |
DE (1) | DE2701854A1 (en) |
DK (1) | DK19677A (en) |
FR (1) | FR2338246A1 (en) |
GB (1) | GB1560281A (en) |
NO (1) | NO770152L (en) |
SE (1) | SE7700489L (en) |
Families Citing this family (12)
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DE2964790D1 (en) * | 1978-06-23 | 1983-03-24 | Dow Chemical Co | Hypoglycemic phenylpropynylamino benzoic acids, their salts, pharmaceutical compositions containing said compounds and their application |
US4143151A (en) * | 1978-07-03 | 1979-03-06 | The Dow Chemical Company | Method for treating hyperglycemia in mammals using arylamino benzoic acids |
GB9514160D0 (en) * | 1994-07-25 | 1995-09-13 | Zeneca Ltd | Aromatic compounds |
GB9417532D0 (en) * | 1994-08-31 | 1994-10-19 | Zeneca Ltd | Aromatic compounds |
GB9420557D0 (en) * | 1994-10-12 | 1994-11-30 | Zeneca Ltd | Aromatic compounds |
TW502026B (en) | 1995-06-20 | 2002-09-11 | Zeneca Ltd | Aromatic compounds useful as antagonists of e-type prostaglandins, processes for the preparation thereof, pharmaceutical compositions comprising the compounds, and intermediates |
TW434240B (en) * | 1995-06-20 | 2001-05-16 | Zeneca Ltd | Aromatic compounds, preparation thereof and pharmaceutical composition comprising same |
EP0752421B1 (en) * | 1995-07-07 | 2005-10-12 | AstraZeneca AB | Ortho-substituted aromatic compounds, containing three (het)aryl moieties, their preparation and their use as prostaglandin E2-(PGE2)-antagonists |
CA2677706A1 (en) * | 2007-02-22 | 2008-08-28 | Irm Llc | Compounds and methods for modulating g protein-coupled receptors |
WO2008121570A1 (en) * | 2007-03-29 | 2008-10-09 | Irm Llc | Compounds and methods for modulating g protein-coupled receptors |
IT201600130047A1 (en) * | 2016-12-22 | 2018-06-22 | Univ Degli Studi Di Salerno | Hydroxybenzene derivatives bearing an N-aryl-substituted imin group and their use in the treatment of solid tumors |
CN107162930B (en) * | 2017-06-13 | 2019-11-22 | 黄淮学院 | Fluorescence probe of superoxide anion and its preparation method and application, fibre-optical probe and preparation method thereof for identification |
-
1977
- 1977-01-14 AU AU21344/77A patent/AU510758B2/en not_active Expired
- 1977-01-18 GB GB1994/77A patent/GB1560281A/en not_active Expired
- 1977-01-18 NO NO770152A patent/NO770152L/en unknown
- 1977-01-18 FR FR7701294A patent/FR2338246A1/en not_active Withdrawn
- 1977-01-18 DE DE19772701854 patent/DE2701854A1/en not_active Withdrawn
- 1977-01-18 SE SE7700489A patent/SE7700489L/en unknown
- 1977-01-19 BE BE174189A patent/BE850517A/en unknown
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- 1977-01-19 DK DK19677A patent/DK19677A/en unknown
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AU2134477A (en) | 1978-07-20 |
BE850517A (en) | 1977-07-19 |
JPS5289639A (en) | 1977-07-27 |
DE2701854A1 (en) | 1977-07-21 |
FR2338246A1 (en) | 1977-08-12 |
DK19677A (en) | 1977-07-20 |
GB1560281A (en) | 1980-02-06 |
AU510758B2 (en) | 1980-07-10 |
SE7700489L (en) | 1977-07-20 |
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