DE3204854A1 - 2-AMINO-3- (HALOGENBENZOYL) METHYLPHENYL ACETIC ACIDS, THEIR ESTERS AND SALTS, PHARMACEUTICAL PREPARATIONS THAT CONTAIN THESE COMPOUNDS, AND THEIR USE - Google Patents
2-AMINO-3- (HALOGENBENZOYL) METHYLPHENYL ACETIC ACIDS, THEIR ESTERS AND SALTS, PHARMACEUTICAL PREPARATIONS THAT CONTAIN THESE COMPOUNDS, AND THEIR USEInfo
- Publication number
- DE3204854A1 DE3204854A1 DE19823204854 DE3204854A DE3204854A1 DE 3204854 A1 DE3204854 A1 DE 3204854A1 DE 19823204854 DE19823204854 DE 19823204854 DE 3204854 A DE3204854 A DE 3204854A DE 3204854 A1 DE3204854 A1 DE 3204854A1
- Authority
- DE
- Germany
- Prior art keywords
- compound
- amino
- sodium
- chlorobenzoyl
- compound according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims description 53
- -1 METHYLPHENYL ACETIC ACIDS Chemical class 0.000 title claims description 10
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 8
- 150000002148 esters Chemical class 0.000 title description 3
- 238000002360 preparation method Methods 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 241001465754 Metazoa Species 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 150000001768 cations Chemical class 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 5
- LSSUHHIPNSAMIU-UHFFFAOYSA-N C(C)(=O)OC1=C(C(=CC(=C1)C)C(C1=CC=C(C=C1)Cl)=O)N.[Na] Chemical compound C(C)(=O)OC1=C(C(=CC(=C1)C)C(C1=CC=C(C=C1)Cl)=O)N.[Na] LSSUHHIPNSAMIU-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 150000004682 monohydrates Chemical class 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- LJPBYWHKMWBFMQ-UHFFFAOYSA-N 2-[2-amino-3-(4-chlorobenzoyl)-5-methylphenyl]acetic acid Chemical compound CC1=CC(CC(O)=O)=C(N)C(C(=O)C=2C=CC(Cl)=CC=2)=C1 LJPBYWHKMWBFMQ-UHFFFAOYSA-N 0.000 claims 4
- 150000002431 hydrogen Chemical group 0.000 claims 4
- UJHCATOJRKRCLV-UHFFFAOYSA-N 2-[2-amino-3-(4-fluorobenzoyl)-5-methylphenyl]acetic acid Chemical compound CC1=CC(CC(O)=O)=C(N)C(C(=O)C=2C=CC(F)=CC=2)=C1 UJHCATOJRKRCLV-UHFFFAOYSA-N 0.000 claims 3
- GJMPSRSMBJLKKB-UHFFFAOYSA-N 3-methylphenylacetic acid Chemical compound CC1=CC=CC(CC(O)=O)=C1 GJMPSRSMBJLKKB-UHFFFAOYSA-N 0.000 claims 1
- 241000859095 Bero Species 0.000 claims 1
- GQSXJNIEJJXXBZ-UHFFFAOYSA-N O.C(C)(=O)OC1=C(C(=CC(=C1)C)C(C1=CC=C(C=C1)F)=O)N.[Na] Chemical compound O.C(C)(=O)OC1=C(C(=CC(=C1)C)C(C1=CC=C(C=C1)F)=O)N.[Na] GQSXJNIEJJXXBZ-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 8
- 239000002775 capsule Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 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 6
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 229910052751 metal Chemical class 0.000 description 5
- 239000002184 metal Chemical class 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 206010053155 Epigastric discomfort Diseases 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 125000005907 alkyl ester group Chemical class 0.000 description 3
- 229960000905 indomethacin Drugs 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- UFZNNOHNAOYQQP-UHFFFAOYSA-N 7-phenacyl-1,3-dihydroindol-2-one Chemical compound C=1C=CC=2CC(=O)NC=2C=1CC(=O)C1=CC=CC=C1 UFZNNOHNAOYQQP-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 2
- 229940038472 dicalcium phosphate Drugs 0.000 description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000006331 halo benzoyl group Chemical group 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- YBNYPWAZNIKXNI-UHFFFAOYSA-N 1-(4-chlorobenzoyl)-6-methyl-3H-indol-2-one Chemical compound ClC1=CC=C(C(=O)N2C(CC3=CC=C(C=C23)C)=O)C=C1 YBNYPWAZNIKXNI-UHFFFAOYSA-N 0.000 description 1
- YVKSMFUEDUPYIF-UHFFFAOYSA-N 3-oxo-2,3-diphenylpropanoic acid Chemical class C=1C=CC=CC=1C(C(=O)O)C(=O)C1=CC=CC=C1 YVKSMFUEDUPYIF-UHFFFAOYSA-N 0.000 description 1
- NDUYSRWSHUHRGD-UHFFFAOYSA-N 4-methyl-7-(2,3,5-trichlorobenzoyl)-1,3-dihydroindol-2-one Chemical compound ClC1=C(C(=O)C=2C=CC(=C3CC(NC23)=O)C)C=C(C=C1Cl)Cl NDUYSRWSHUHRGD-UHFFFAOYSA-N 0.000 description 1
- ROYCPOZLJYCXIZ-UHFFFAOYSA-N 7-(2,4-dichlorobenzoyl)-5-methyl-1,3-dihydroindol-2-one Chemical compound ClC1=C(C(=O)C=2C=C(C=C3CC(NC23)=O)C)C=CC(=C1)Cl ROYCPOZLJYCXIZ-UHFFFAOYSA-N 0.000 description 1
- GEVQCJAIVLZAMK-UHFFFAOYSA-N 7-(4-chlorobenzoyl)-5-methyl-1,3-dihydroindol-2-one Chemical compound ClC1=CC=C(C(=O)C=2C=C(C=C3CC(NC23)=O)C)C=C1 GEVQCJAIVLZAMK-UHFFFAOYSA-N 0.000 description 1
- WQRSNHWRHMQPLP-UHFFFAOYSA-N 7-(4-fluorobenzoyl)-5-methyl-1,3-dihydroindol-2-one Chemical compound C=1C(C)=CC=2CC(=O)NC=2C=1C(=O)C1=CC=C(F)C=C1 WQRSNHWRHMQPLP-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- IYIZHXIAABPNIM-UHFFFAOYSA-N C(C)(=O)OC1=C(C(=CC(=C1)C)C(C1=C(C=C(C=C1)Cl)Cl)=O)N.[Na] Chemical compound C(C)(=O)OC1=C(C(=CC(=C1)C)C(C1=C(C=C(C=C1)Cl)Cl)=O)N.[Na] IYIZHXIAABPNIM-UHFFFAOYSA-N 0.000 description 1
- NQPUKSBYJQZIBE-UHFFFAOYSA-N C(C)(=O)OC1=C(C(=CC=C1C)C(C1=C(C(=CC(=C1)Cl)Cl)Cl)=O)N.[Na] Chemical compound C(C)(=O)OC1=C(C(=CC=C1C)C(C1=C(C(=CC(=C1)Cl)Cl)Cl)=O)N.[Na] NQPUKSBYJQZIBE-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010017788 Gastric haemorrhage Diseases 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000001350 alkyl halides Chemical class 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
- SOYCMDCMZDHQFP-UHFFFAOYSA-N amfenac Chemical class NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=CC=C1 SOYCMDCMZDHQFP-UHFFFAOYSA-N 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000010868 animal carcass Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical class OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- 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
- A61K31/12—Ketones
-
- 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
- A61K31/13—Amines
-
- 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
-
- 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
-
- 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
- A61K31/185—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
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- 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
-
- 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
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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- 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
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
-
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- 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
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- 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
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- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
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Description
DR. BERG $IPI|.-»|G.;ST.ÄPR··. .* DIPL.-ING. SCHWABE' "DR. EVDR. BERG $ IPI | .- »| G.; ST.ÄPR ··. . * DIPL.-ING. SCHWABE '"DR. EV
PATENTANWÄLTE Postfach 860245 · 8000 München 86PATENTANWÄLTE PO Box 860245 8000 Munich 86
Ihr Zeichen Your ref.'Your sign Your ref. '
Unser Zeichen Our ref.Our mark Our ref.
020020
8000 MÜNCHEN 80 j i 8000 MUNICH 80 y i
Anwaltsakte-Nr.': 32Attorney file no. ': 32
A. Ή. ROBINS COMPANY, INC. Richmo.nd, Virginia / USAA. Ή. ROBINS COMPANY, INC. Richmo.nd, Virginia / USA
2-Amino-3-(halogenbenzoyl)-methylphenylessigsäuren,2-amino-3- (halobenzoyl) -methylphenylacetic acids,
deren Ester und Salze, pharmazeutische Zubereitungen,their esters and salts, pharmaceutical preparations,
welche diese Verbindungen enthalten, und ihre Verwendungwhich these compounds contain and their uses
v/xv / x
* (089) 988272 988273 988274 983310* (089) 988272 988273 988274 983310
AHR-408AHR-408
Telegramme:Telegrams:
BERGSTAPFPATENT München TELEX: 0524560 BERG dBERGSTAPF PATENT Munich TELEX: 0524560 BERG d
Bankkonten: Hypo-Bank München 4410122850 (BLZ 70020011) Swift Code: HYPO DE MM Bayec Vereinsbank München 453100 (BLZ 70020270) Postscheck MUnchen 65343-808 (BLZ 70010080)Bank accounts: Hypo-Bank Munich 4410122850 (BLZ 70020011) Swift Code: HYPO DE MM Bayec Vereinsbank Munich 453100 (bank code 70020270) Postal check Munich 65343-808 (bank code 70010080)
Λ ΛΛ Λ
Die vorliegende Erfindung betrifft gewisse neue 2-Amino-3-(halogenbenzoyl)-methylphenylessigsäuren, deren Alkylester und Metallsalze, pharmazeutische Zubereitungen, welche derartige Verbindungen enthalten, und ihre Verwendung.The present invention relates to certain new 2-amino-3- (halobenzoyl) -methylphenylacetic acids, their alkyl esters and metal salts, pharmaceutical preparations, which such Compounds included and their uses.
Gewisse 2-AmInO-S-(5- und 6-)benzoylphenylessigsäuren mit verschiedenen Substituenten an den Benzoyl- und Phenylresten, und' die Verfahren zu ihrer Herstellung und ihrer Verwendung sind in der US-PS 4 045 576 beschrieben. Methylphenylessigsäuren oder deren Derivate werden jedoch von den in dieser Patentschrift beschriebenen Verbindungen nicht umfaßt.Certain 2-AmInO-S- (5- and 6-) benzoylphenylacetic acids with various substituents on the benzoyl and phenyl radicals, and the processes for their preparation and their use are described in U.S. Patent 4,045,576. Methylphenylacetic acids or their derivatives, however, are not included in the compounds described in this patent specification.
Die US-PS 4 221 716 beschreibt ein Verfahren zur Herstellung von 7-Acylindolin-2-onen, welche Zwischenprodukte für die Herstellung der Verbindungen der vorliegenden Erfindung sind.U.S. Patent 4,221,716 describes a method of manufacture of 7-acylindolin-2-ones, which are intermediates for the Preparation of the compounds of the present invention.
Die Erfindung befaßt sich insbesondere mit 2-Amino-3-(halogeribenzoyl)-methylphenylessigsäuren, Alkylestern und Metallsalzeh der nachfolgenden allgemeinen Formel IThe invention is particularly concerned with 2-amino-3- (halogeribenzoyl) -methylphenylacetic acids, Alkyl esters and metal salts of the general formula I below
H2COOR .H 2 COOR.
c-o . ■·' (Dc-o. ■ · '(D
in welcherin which
R Wasserstoff, Niedrigalkyl oder ein pharmazeutisch verträgliches Metallkation, . Y Halogen bedeutet, undR is hydrogen, lower alkyl or a pharmaceutically acceptable metal cation,. Y means halogen, and
• m tu 9 • m do 9
• 4 * α · < • 4 * α · <
η eine ganze Zahl mit einem Wert von 1 bis 3 ist.η is an integer from 1 to 3.
Die neuen Verbindungen' der vorliegenden .Erfindung besitzen wertvolle pharmakologische Eigenschaften und sind als pharmazeutische Mittel brauchbar. Die Verbindungen besitzen hervorragende entzündungshemmende und analgetische Aktivität bei Warmblütern bei minimaler gastro-intestinaler Toxizität.The novel compounds of the present invention have valuable pharmacological properties and are considered pharmaceutical Funds usable. The compounds have excellent anti-inflammatory and analgesic activities in warm-blooded animals with minimal gastrointestinal toxicity.
Es ist daher eine Aufgabe der vorliegenden" Erfindung/ neue Verbindungen und Zubereitungen zu schaffen. Weiterhin befaßt sich die vorliegende Erfindung mit der Verwendung der Verbindungen und der Zubereitungen für die Linderung von Schmerzen und die Behandlung von Entzündungen bei Warmblütern mit einer minimalen Nebenwirkung im Magen- und Darmbereich. Weitere Aufgaben der vorliegenden Erfindung ergeben sich für den Fachmann aus der nachfolgenden Beschreibung.It is therefore an object of the present invention / to create new compounds and preparations. Furthermore, concerned the present invention relates to the use of the compounds and the preparations for relieving pain and the treatment of inflammation in warm-blooded animals with minimal gastrointestinal side effects. Further tasks of the present invention will become apparent to those skilled in the art from the following description.
Die vorliegende Erfindung schließt die oben definierten Verbindungen der allgemeinen Formel I, pharmazeutische Zubereitungen, welche die Verbindungen der allgemeinen Formel ι enthalten, und deren Verwendung zur Behandlung der oben angegebenen Zustände bei Warmblütern ein. The present invention includes the compounds defined above of the general formula I, pharmaceutical preparations which contain the compounds of the general formula ι, and their use in the treatment of the above noted conditions in warm-blooded animals.
Bezüglich der Definition der Symbole in den Formeln der vorliegenden Beschreibung sei bemerkt, daß sie .die nachfolgende Bedeutung besitzen.Regarding the definition of the symbols in the formulas herein Description, it should be noted that they have the following meaning.
Der Ausdruck "Niedrigalkyl", wie er hier verwendet wird, schließt geradkettige und verzwexgtkettige Reste mit bis zu sechs Kohlenstoffatomen einschließlich, vorzugsweise' nicht mehr als vier Kohlenstoffatome, ein, wobei als Beispiel für die Reste solche Gruppen wie Methyl, Äthyl, Propyl.·, Isopropyl, Butyl, sek.-Butyl, tert.-Butyl, Amyl, Isoamyl und Hexyl angegeben sind.The term "lower alkyl" as used herein includes straight-chain and branched-chain radicals of up to six carbon atoms including, preferably 'not more than four carbon atoms, with groups such as methyl, ethyl, propyl, isopropyl, Butyl, sec-butyl, tert-butyl, amyl, isoamyl and hexyl are specified.
Der Ausdruck "Halogen" umfaßt Chlor, Fluor, Brom und Jod.The term "halogen" includes chlorine, fluorine, bromine and iodine.
Erläuternde pharmazeutisch verträgliche Metallkationen sind Natrium, Kalium, Calcium, Magnesium, Zink, Aluminium, Kupfer und Hydrate derselben. .Illustrative pharmaceutically acceptable metal cations are sodium, potassium, calcium, magnesium, zinc, aluminum, copper and hydrates thereof. .
Die Verbindungen der vorliegenden Erfindung werden geeigneterweise aus einem 7-Benzoylmethylindolin-2-on der nachfolgenden FormelThe compounds of the present invention are useful from a 7-benzoylmethylindolin-2-one of the following formula
in welcher Y und η die gleiche Bedeutung wie oben besitzen, hergestellt. Diese Ausgangsverbindungen können nach herkömmli.chen Verfahren erhalten werden, wie sie beispielsweise in den oben erwähnten ÜS-PSen 4 045 576 und 4 221 716 beschrieben sind.· Die erfindungsgemäßen Verbindungen werden durch Hydrolyse der 7-Benzoylmethylindolin-2-one in wässeriger basischer Lösung zur Herstellung ihrer Salze hergestellt, die dann nach Ansäuern die freie Säure liefern. Um die Niedrigalkylester zu erhalten, wird die Säure in ein Metallsalz überführt, das dann in einem geeigneten Lösungsmittel mit einem Alkylhalogenid zur Herstellung des gewünschten Esters umgesetzt wird.in which Y and η have the same meaning as above, manufactured. These starting compounds can be obtained by conventional methods such as those described in, for example the abovementioned US Patents 4,045,576 and 4,221,716. The compounds according to the invention are described by Hydrolysis of the 7-benzoylmethylindolin-2-ones in an aqueous basic solution to produce their salts, which then supply the free acid after acidification. To obtain the lower alkyl ester, the acid is converted into a metal salt, which is then reacted in a suitable solvent with an alkyl halide to produce the desired ester will.
Die Herstellung der. erfindungsgemäßen Verbindungen wird mehr im Detail durch die nachfolgenden Beispiele erläutert.The manufacture of the. compounds according to the invention becomes more explained in detail by the following examples.
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.:. 320485A - ίο - .:. 320485A - ίο -
Beispiel 1 . ·. Example 1 . ·.
Herstellung von Natrium-2-amino-3-(4-fluorbenzoyl)-5-methylphenylacetat.MonohydratPreparation of sodium 2-amino-3- (4-fluorobenzoyl) -5-methylphenyl acetate, monohydrate
Eine Mischung von 8,0 g (0,03 Mol) 7-(4-Fluorbenzoyl)-5-methylindolin-2-on
in 120 ml 3n-Natriumhydroxid wurde 16 Stunden
lang am Rückfluß erhitzt. Nach Verdünnen mit Wasser auf 300 ml wurde die Lösung bei einer Temperatur von 500C mit konzenr
trierter Chlorwasserstoffsäure bis zu einem ρ -Wert von 8,2
LJ. trlort. Die erhaltene orangefarbene Lösung wurde filtriert
und das erhaltene Filtrat auf 5°C abgekühlt und mit Eisessig auf einen p„-Wert von 4,5 angesäuert. Der erhaltene gelbe
Feststoff wurde gesammelt, mit Wasser gewaschen und anschliessend in Methylenchlorid gelöst. Es wurde Wasser zugegeben und
die Mischung mit verdünnter Natriumbicarbonat-Lösung titriert, bis ein p„-Wert von 7,0 erreicht worden war. Die wässerige
Schicht wurde abgetrennt und eingeengt, indem man das.Wasser unter Zusatz von absolutem Äthylalkohol azeotrop entfernte.
Das erhaltene gelbe Pulver wurde in Isopröpylalkohol gelöst und 1 ml Wasser zugesetzt. Man ließ die Mischung 3 Tage lang
stehen, filtrierte den gebildeten gelben Feststoff ab und trocknete ihn bei 25°C 2 Tage lang im Hochvakuum. Man erhielt
1,6 g (16,5 % Ausbeute) der Titelverbindung in Form eines gelben Pulvers; Schmelzpunkt 140° bis 160°C.
Analyse für C16H13FNO3Na-H2O:
Berechnet: C 58,72 %, H 4,62 %, N 4,28 %; Gefunden : C58,71%,H4,68%,N4,26%.A mixture of 8.0 g (0.03 mol) of 7- (4-fluorobenzoyl) -5-methylindolin-2-one in 120 ml of 3N sodium hydroxide was refluxed for 16 hours. After dilution with water to 300 ml, the solution was at a temperature of 50 0 C with concentrated hydrochloric acid up to a ρ value of 8.2 LJ. trlort. The orange-colored solution obtained was filtered and the filtrate obtained was cooled to 5 ° C. and acidified with glacial acetic acid to a p n value of 4.5. The yellow solid obtained was collected, washed with water and then dissolved in methylene chloride. Water was added and the mixture was titrated with dilute sodium bicarbonate solution until a p "value of 7.0 had been reached. The aqueous layer was separated off and concentrated by removing the water azeotropically with the addition of absolute ethyl alcohol. The yellow powder obtained was dissolved in isopropyl alcohol and 1 ml of water was added. The mixture was left to stand for 3 days, the yellow solid formed was filtered off and dried at 25 ° C. for 2 days in a high vacuum. 1.6 g (16.5 % yield) of the title compound were obtained in the form of a yellow powder; Melting point 140-160 ° C. Analysis for C 16 H 13 FNO 3 Na-H 2 O:
Calculated: C 58.72%, H 4.62%, N 4.28%; Found: C58.71%, H4.68%, N4.26%.
Herstellung von Natrium-2-amino-3-(4-chlorbenzoyl)-5-methylphenylacetatPreparation of sodium 2-amino-3- (4-chlorobenzoyl) -5-methylphenyl acetate
Eine Mischung von 11,5 g (0,04 Mol) 7-(4-Chlorbenzoyl)-5-methylindolin-2-on und 160 ml 3n-Natriumhydroxid gab nach demA mixture of 11.5 g (0.04 mol) of 7- (4-chlorobenzoyl) -5-methylindolin-2-one and 160 ml of 3N sodium hydroxide was after
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Verfahren von Beispiel 1 nach ümkristallisation aus Wasser 2,5 g (18 % Ausbeute) der Titelverbindung in Form von orangefarbenen Nadeln; Schmelzpunkt 26 2°C. Analyse für C16H133 Process of Example 1 after recrystallization from water 2.5 g (18% yield) of the title compound in the form of orange-colored needles; Melting point 26-2 ° C. Analysis for C 16 H 133
Berechnet; C 59,00 %, H 4,02 %, N 4,30 %; Gefunden : C 58,82 %, H 4,09 %, N 4,32 %.Calculated; C 59.00%, H 4.02%, N 4.30%; Found: C 58.82%, H 4.09%, N 4.32%.
Beispiel 3Example 3
Herstellung von Natrium-2-amino-3-(2,4-dichlorbenzoyl) -5-methylphenylacetatPreparation of sodium 2-amino-3- (2,4-dichlorobenzoyl) -5-methylphenyl acetate
Eine Mischung von 7-(2,4-Dichlorbenzoyl)-5-methylindolin-2-on und 3n-Natriumhydroxid lieferte nach dem Verfahren des Beispiels 1 die Titelverbindung.A mixture of 7- (2,4-dichlorobenzoyl) -5-methylindolin-2-one and 3n sodium hydroxide provided by the method of Example 1 the title compound.
Herstellung von Natrium-2-amino-3-(2,3,5-trichlorbenzoyl)-6-methy1pheny1acetatPreparation of sodium 2-amino-3- (2,3,5-trichlorobenzoyl) -6-methylphenyl acetate
Eine Mischung von 7-(2,3,5-Trichlorbenzoyl)-4-methylindolin-2-on und 3n-Natriumhydroxid ergab nach dem Verfahren des Beispiels 1 die Titelverbindung.A mixture of 7- (2,3,5-trichlorobenzoyl) -4-methylindolin-2-one and 3N sodium hydroxide following the procedure of Example 1 gave the title compound.
Herstellung von Natrium-2-amino-3-(4-chlorbenzoyl)-4-methylphenylacetatPreparation of sodium 2-amino-3- (4-chlorobenzoyl) -4-methylphenyl acetate
Eine Mischung von 4-Chlorbenzoyl-6-methylindolin-2-on und 3n-Natriumhydroxid lieferte nach dem Verfahren des Beispiels die Titelverbindung.A mixture of 4-chlorobenzoyl-6-methylindolin-2-one and 3N sodium hydroxide following the procedure of the example provided the title compound.
Im allgemeinen wurde gefunden, daß früher stark wirkende, antiinflammatorische Mittel ernst zu nehmende NebenwirkungenIn general, previously potent anti-inflammatory agents have been found to have serious side effects
- /12 -- / 12 -
.:. .1'\.:.::.Ό.:ί 32048b4.:. .1'\. : . ::. Ό .: Ί 32048b4
wie Magenblutungen und Geschwürbildung hervorriefen, wenn sie an Tiere oral im wirksamen Bereich verabreicht wurden. Es wurde festgestellt, daß die Verbindungen der vorliegenden Erfindung den Vorteil aufweisen, daß bei ihrer Verabreichung im wirksamen Bereich zur Bekämpfung einer Entzündung im Vergleich zu Indomethacin und den 2-Amino-3-benzoylphenylessigsäuren und deren Derivaten, die in der US-PS 4 04 5 576 offenbart werden, eine verringerte Magenreizung auftritt. Beispielsweise wurde von der Verbindung des Beispiels 2, nämlich Natrium-2-amino-3-(4-chlorbenzoyl)-5-methylphenylacetat festgestellt, daß sie annähernd zweimalhow gastric bleeding and ulceration caused when they were orally administered to animals in the effective range. It was found that the compounds of the present Invention have the advantage that when administered in the effective range for combating inflammation compared to indomethacin and the 2-amino-3-benzoylphenylacetic acids and their derivatives described in US Pat 4,045,576, reduced gastric irritation occurs. For example, from the compound of the example 2, namely sodium 2-amino-3- (4-chlorobenzoyl) -5-methylphenyl acetate found them nearly twice
so wirksam wie Indomethacin und Natrium-2-amino-3-benzoylphenylacetat, jedoch nur etwa 1/4 der Magenreizung wie Indomethacin und etwa 1/2 der Magenreizung'wie Natrium-2-amino-3-benzoylphenylacetat bewirkt. Es wurde festgestellt, daß die Verbindung des Beispiels 2 etwa 1/2 der Wirksamkeit von Natrium-2-amino-3-(4-chlprbenzoyl)-5-fluorphenylacetat aufweist, jedoch überraschenderweise etwa 1/4 der von dieser Verbindung hervorgerufenen Magenreizung bewirkt.as effective as indomethacin and sodium 2-amino-3-benzoylphenyl acetate, but only about 1/4 of the gastric irritation such as indomethacin and about 1/2 of the gastric irritation such as sodium 2-amino-3-benzoylphenyl acetate causes. The compound of Example 2 was found to be about 1/2 the potency of Sodium 2-amino-3- (4-chloroprbenzoyl) -5-fluorophenyl acetate, but surprisingly causes about 1/4 of the gastric irritation caused by this compound.
Die antiinflammatorische Aktivität· wurde bei Laboratoriumstieren unter Anwendung einer Modifikation der "Evans Blue-.Carrageenan Pleiiral Effusion Assay" voh L. F. Sancilio,". J. Pharmacol. Exp. Ther. 168: 199-204 (1969) nachgewiesen.Anti-inflammatory activity was demonstrated in laboratory animals using a modification of the Evans Blue-Carrageenan Pleiiral Effusion Assay by LF Sancilio, "J. Pharmacol. Exp. Ther. 168 : 199-204 (1969).
Die gastrische Toxizität wurde nach einem modifizierten Verfahren von Tsukada et al., Arzneim. Forsch. 2£: 428-438 (1978) bestimmt.Gastric toxicity was determined using a modified procedure by Tsukada et al., Medic. Research 2 £: 428-438 (1978) certainly.
Die erfindungsgemäßen Verbindungen wirken auch als Analgetika, wie dies nach einem modifizierten Verfahren von Collier et al., Brit. J. Pharmacol. Chemother. , 3_2: 295-310 (1968) bestimmt würde.The compounds of the invention also act as analgesics, as shown in a modified method by Collier et al., Brit. J. Pharmacol. Chemother. , 3_2: 295-310 (1968).
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Die vorliegende Erfindung umfaßt neue Zubereitungen, welche die erfindungsgemäßen Verbindungen als aktive Bestandteile enthalten. Wirksame Mengen von irgendeiner der vorstehenden pharmakologisch aktiven Verbindungen können an c?inen lebenden Tierkörper auf irgendeinem Wege von verschiedenen Wegen verabreicht werden, beispielsweise oral in Kapseln oder Tabletten, parenteral in Form von sterilen Lösungen oder Suspensionen, und in manchen Fällen intravenös in. Form von sterilen Lösungen. Bei der Formulierung der neuen Zubereitungen der vorliegenden Erfindung wird der aktive Bestandteil in einen geeigneten Träger, erläuternderweise in einen' pharmazeutischen Träger, inkorporiert. Geeignete pharmazeutische Träger, die für die Formulierung der erfindungsgemäßen Zubereitungen brauchbar sind, schließen Stärke, Gelatine, Glucose, Magnesiumcarbonat, Lactose, Malz und dergleichen, ein. Flüssige Zubereitungen·liegen ebenfalls im Bereich der vorliegenden Erfindung und geeignete flüssige pharmazeutische Träger schließen Äthylalkohol, Propylenglykol, Glycerin, Glucosesirup, und dergleichen, ein.The present invention encompasses new preparations which contain the compounds of the invention as active ingredients contain. Effective amounts of any of the foregoing pharmacologically active compounds can be administered to living people Animal carcasses are administered by any of several routes, for example orally in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile ones Solutions. In formulating the novel preparations of the present invention, the active ingredient is turned into a suitable carrier illustratively incorporated into a pharmaceutical carrier. Suitable pharmaceutical carriers that for the formulation of the preparations according to the invention are useful include starch, gelatin, glucose, magnesium carbonate, Lactose, malt and the like. Liquid preparations are also within the scope of the present invention Invention and suitable liquid pharmaceutical carriers include ethyl alcohol, propylene glycol, glycerin, glucose syrup, and the like.
Die pharmakologisch aktiven Verbindungen können vorteilhafterweise in einer Einheitsdosis von 0,1 bis 150 mg verwendet werden. Die Einheitsdosis kann einmal täglich oder in mehreren oder geteilten Tagesdosen verabreicht werden. Die Tagesdosis kann von 0,3 bis 450 mg variieren. 5 bis 25 mg erscheinen optimal pro Einheitsdosis.The pharmacologically active compounds can advantageously can be used in a unit dose of 0.1 to 150 mg. The unit dose can be once a day or in several or divided daily doses. The daily dose can vary from 0.3 to 450 mg. 5 to 25 mg appear optimal per unit dose.
Es ist lediglich erforderlich, daß· der aktive Bestandteil eine wirksame Menge ausmacht, so daß eine geeignete wirksame Dosis verträglich mit der verwendeten Dosisform erhalten wird. Die genauen Einzeldosierungen als auch die Tagesdosierungen werden selbstverständlich nach medizinischen Standardgrundsätzen unterAll that is required is that the active ingredient be a effective amount such that a suitable effective dose is obtained compatible with the dosage form used. the Exact individual doses as well as the daily doses are of course based on standard medical principles
- /14 -- / 14 -
- 14 der Leitung eines Arztes oder Veterinärmediziners bestimmt.- 14 determined by the management of a doctor or veterinarian.
Die aktiven Mittel der Erfindung können mit anderen pharmakologisch aktiven Mitteln, oder mit Puffern, Antaciden oder dergleichen kombiniert werden, da die Verabreichung und der Anteil des aktiven Mittels in der Zubereitung in weitem Umfang variiert werden kann.The active agents of the invention can be pharmacologically linked to others active agents, or combined with buffers, antacids or the like, as the administration and the The proportion of the active agent in the preparation can be varied widely.
Nachstehend werden Beispiele für Zubereitungen gegeben, die gemäß der vorliegenden Erfindung formuliert werden.Examples of preparations formulated in accordance with the present invention are given below.
1. Kapseln 1. Capsules
Kapseln von 5 mg, 25 mg und 50 mg aktivem. Bestandteil pro Kapsel wurden hergestellt. Bei den höheren Mengen an aktivem Bestandteil kann die Einstellung über die Lactosemenge erfolgen. Capsules of 5 mg, 25 mg and 50 mg of active. Ingredients per capsule were made. With the higher amounts of active The setting can be made via the amount of lactose.
Typische Mischung für Pro Kapsel eine Kapselherstellung ·' mg Typical mixture for one capsule production per capsule · ' mg
Aktiver Bestandteil 5,0Active ingredient 5.0
•Lactose 296,7• lactose 296.7
Stärke 129,0Magnitude 129.0
Magnesiumstearat '. 4,3 Magnesium stearate '. 4.3
Gesamt 435,0 mgTotal 435.0 mg
Weitere Kapselformulierungen enthalten vorzugsweise eine höhere Dosis an aktivem Bestandteil und haben eine Zusammensetzung wie folgt:Other capsule formulations preferably contain a higher dose of active ingredient and have a composition as follows:
Pro Kapsel Bestandteil mg Per capsule ingredient mg
Aktiver Bestandteil 25,0Active ingredient 25.0
Lactose „■ 306 , 5Lactose "■ 306, 5
Stärke · 99*2Strength 99 * 2
Magnesiumstearat 4,3 Magnesium stearate 4.3
Gesamt 435,0 mgTotal 435.0 mg
- /15 -.- / 15 -.
In jedem FaU wird der ausgewählte aktive Bestandteil mit Lactose, Stärke und Magnesiumstearat gleichmäßig gemischt und die Mischung eingekapselt.In each FaU the selected active ingredient is included Lactose, starch and magnesium stearate mixed evenly and the mixture encapsulated.
2.. Tabletten 2 .. tablets
Eine typische Formulierung für eine Tablette mit einem Gehalt von 5,0 mg an aktivem Bestandteil pro Tablette wird nachfolgend angegeben. Die Formulierung kann für andere Gehalte an aktivem Bestandteil über die Einstellung des Gewichts, an Dicalciumphosphat verwendet werden.A typical formulation for a tablet containing 5.0 mg of active ingredient per tablet is given below specified. The formulation can be adjusted for other levels of active ingredient by adjusting the weight Dicalcium phosphate can be used.
(1) Aktiver Bestandteil (1) Active ingredient
(2) Maisstärke (2) corn starch
(3) Maisstärke (Paste) (3) corn starch (paste)
(4) Lactose (4) lactose
(5) Dicalciumphosphat (5) dicalcium phosphate
(6) Calciumstearat (6) calcium stearate
Gesamttotal
Man mischt (1), (2),. (4) und (5) gleichmäßig. Bestandteil (3) wird in Form einer 10%igen Paste hergestellt. Die Mischung wird mit der Stärkepaste granuliert und die feuchte Masse durch ein Sieb mit einer lichten Maschenweite von 2,38 mm (8 mesh) hindurchgegeben. Das feuchte Granulat wurde getrocknet und durch ein Sieb mit einer lichten Maschenweite von 1,41 mm (12 mesh) klassiert. Das getrocknete Granulat wurde mit dem Calciumstearat gemischt und verpreßt.Mix (1), (2) ,. (4) and (5) evenly. Component (3) is made in the form of a 10% paste. The mixture is granulated with the starch paste and the moist mass through a sieve with a mesh size of 2.38 mm (8 mesh) passed through. The moist granules were dried and passed through a sieve with a mesh size of 1.41 mm (12 mesh) sized. The dried granules were mixed with the calcium stearate and pressed.
- /16 -- / 16 -
3. Injizierbare, 2%ige sterile Lösungen3. Injectable 2% sterile solution
Pro ml Aktiver Bestandteil 20 mg20 mg per ml of active ingredient
Konservierungsmittel, z.B.Preservatives, e.g.
Chlorbutanol 0,5 %. Gew./Vol.Chlorobutanol 0.5%. Weight / volume
Wasser zur Injektion q.s.Water for injection q.s.
Man stellt die Lösung her, klärt durch Filtration, füllt sie in Ampullen, verschließt diese und behandelt im Autoklav.The solution is prepared, clarified by filtration, filled into ampoules, sealed and treated in an autoclave.
Es sei darauf hingewiesen, daß sich für· den Fachmann nach Kenntnisnahme der vorliegenden Beschreibung und der Ansprüche zahlreiche Modifikationen und Äquivalente der vorliegenden Anmeldung ergeben, die jedoch noch im Bereich der Erfindung liegen. "It should be noted that for the person skilled in the art Knowledge of the present specification and claims, numerous modifications and equivalents of the present invention Application result, which, however, are still within the scope of the invention. "
Claims (1)
Y Halogen bedeutet, und η eine ganze Zahl mit einem Wert von 1 bis 3 ist.R is hydrogen, lower alkyl or a pharmaceutically acceptable cation,
Y is halogen and η is an integer from 1 to 3.
V Halogen bedeutet, undR is hydrogen, lower alkyl or a pharmaceutically acceptable cation,
V means halogen, and
η eine ganze Zahl mit einem Wert von 1 bis 3 ist,R is hydrogen, lower alkyl or a pharmaceutically acceptable cation, ". · Y is halogen, and
η is an integer with a value from 1 to 3,
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23453181A | 1981-02-17 | 1981-02-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE3204854A1 true DE3204854A1 (en) | 1982-09-09 |
| DE3204854C2 DE3204854C2 (en) | 1994-06-16 |
Family
ID=22881752
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE3204854A Expired - Fee Related DE3204854C2 (en) | 1981-02-17 | 1982-02-11 | 2-Amino-3- (halobenzoyl) -methylphenylacetic acids, their esters and salts, pharmaceutical compositions containing these compounds |
Country Status (32)
| Country | Link |
|---|---|
| JP (1) | JPS57149256A (en) |
| KR (1) | KR880002289B1 (en) |
| AT (1) | AT387213B (en) |
| AU (1) | AU7950382A (en) |
| BE (1) | BE892156A (en) |
| CA (1) | CA1173852A (en) |
| CH (1) | CH651294A5 (en) |
| DE (1) | DE3204854C2 (en) |
| DK (1) | DK155936C (en) |
| EG (1) | EG15798A (en) |
| ES (1) | ES8301895A1 (en) |
| FI (1) | FI73970C (en) |
| FR (1) | FR2499981B1 (en) |
| GB (1) | GB2093027B (en) |
| GR (1) | GR76516B (en) |
| HK (1) | HK90384A (en) |
| HU (1) | HU187644B (en) |
| IE (1) | IE52289B1 (en) |
| IL (1) | IL64724A0 (en) |
| IT (1) | IT1157001B (en) |
| KE (1) | KE3454A (en) |
| LU (1) | LU83928A1 (en) |
| MY (1) | MY8500908A (en) |
| NL (1) | NL8200607A (en) |
| NO (1) | NO160133C (en) |
| NZ (1) | NZ199745A (en) |
| PL (1) | PL139815B1 (en) |
| PT (1) | PT74441B (en) |
| SE (1) | SE453387B (en) |
| SG (1) | SG68584G (en) |
| YU (1) | YU44333B (en) |
| ZA (1) | ZA82697B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4683242A (en) * | 1985-10-28 | 1987-07-28 | A. H. Robins Company, Incorporated | Transdermal treatment for pain and inflammation with 2-amino-3-aroylbenzeneacetic acids, salts and esters |
| US5475034A (en) * | 1994-06-06 | 1995-12-12 | Alcon Laboratories, Inc. | Topically administrable compositions containing 3-benzoylphenylacetic acid derivatives for treatment of ophthalmic inflammatory disorders |
| BR9600975A (en) * | 1996-03-11 | 1997-12-30 | Fundacao Oswaldo Cruz | Derivatives of gem-difluorphenylacetic acid and gem-difluorphenylacetamide process of their preparation and their pharmaceutical applications |
| US6034266A (en) * | 1996-03-11 | 2000-03-07 | Fundacao Oswaldo Cruz-Fiocruz | Gem-difluoro derivative of phenylacetamide and phenylacetic acid and their pharmaceutical uses |
| AR030346A1 (en) | 2000-08-14 | 2003-08-20 | Alcon Inc | METHOD OF TREATMENT OF NEURODEGENERATIVE DISORDERS OF THE RETINA AND HEAD OF OPTICAL NERVE |
| AR030345A1 (en) * | 2000-08-14 | 2003-08-20 | Alcon Inc | METHOD OF TREATMENT OF DISORDERS RELATED TO ANGIOGENESIS |
| AU2002247284A1 (en) | 2001-04-02 | 2002-10-15 | Alcon, Inc. | Method of treating ocular inflammatory and angiogenesis-related disorders using an amide derivative of flubiprofen or ketorolac |
| TWI358290B (en) | 2004-12-02 | 2012-02-21 | Alcon Inc | Topical nepafenac formulations |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1793057A1 (en) * | 1967-07-31 | 1971-09-30 | Allen & Hanburys Ltd | Phenylacetic acids, processes for their production and medicinal preparations containing these compounds |
| DE2636582A1 (en) * | 1975-08-13 | 1977-02-24 | Robins Co Inc A H | 2-AMINO-3- (5- AND 6-) BENZOYLPHENYL ACID ACIDS, THEIR ESTERS AND METAL SALTS AND PROCESS FOR THE PREPARATION OF THE ACIDS Cited |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3997368A (en) * | 1975-06-24 | 1976-12-14 | Bell Telephone Laboratories, Incorporated | Elimination of stacking faults in silicon devices: a gettering process |
| FR2366015A1 (en) * | 1975-11-05 | 1978-04-28 | Robins Co Inc A H | Amino-benzoyl-phenylacetic acid derivs - antiinflammatory, hypocholesterolemic and blood platelet agglomeration inhibitory activity |
| IL61945A (en) * | 1980-02-19 | 1984-09-30 | Robins Co Inc A H | 2-amino-3-(hydroxy(phenyl)methyl)phenylacetic acids,esters and amides and pharmaceutical compositions containing them |
-
1982
- 1982-01-07 IL IL64724A patent/IL64724A0/en not_active IP Right Cessation
- 1982-01-14 AU AU79503/82A patent/AU7950382A/en not_active Abandoned
- 1982-01-24 EG EG8228A patent/EG15798A/en active
- 1982-02-01 JP JP57014710A patent/JPS57149256A/en active Granted
- 1982-02-03 ZA ZA82697A patent/ZA82697B/en unknown
- 1982-02-05 AT AT0043382A patent/AT387213B/en not_active IP Right Cessation
- 1982-02-08 FI FI820392A patent/FI73970C/en not_active IP Right Cessation
- 1982-02-09 LU LU83928A patent/LU83928A1/en unknown
- 1982-02-09 CH CH791/82A patent/CH651294A5/en not_active IP Right Cessation
- 1982-02-10 IT IT67152/82A patent/IT1157001B/en active
- 1982-02-11 DE DE3204854A patent/DE3204854C2/en not_active Expired - Fee Related
- 1982-02-12 GB GB8204137A patent/GB2093027B/en not_active Expired
- 1982-02-15 IE IE310/82A patent/IE52289B1/en not_active IP Right Cessation
- 1982-02-15 YU YU325/82A patent/YU44333B/en unknown
- 1982-02-15 SE SE8200891A patent/SE453387B/en unknown
- 1982-02-15 GR GR67320A patent/GR76516B/el unknown
- 1982-02-16 NZ NZ199745A patent/NZ199745A/en unknown
- 1982-02-16 HU HU82464A patent/HU187644B/en unknown
- 1982-02-16 ES ES509622A patent/ES8301895A1/en not_active Expired
- 1982-02-16 CA CA000396392A patent/CA1173852A/en not_active Expired
- 1982-02-16 PT PT74441A patent/PT74441B/en not_active IP Right Cessation
- 1982-02-16 NL NL8200607A patent/NL8200607A/en not_active Application Discontinuation
- 1982-02-16 FR FR8202507A patent/FR2499981B1/en not_active Expired
- 1982-02-16 BE BE0/207327A patent/BE892156A/en not_active IP Right Cessation
- 1982-02-16 PL PL1982235095A patent/PL139815B1/en unknown
- 1982-02-16 KR KR8200673A patent/KR880002289B1/en active
- 1982-02-16 NO NO820468A patent/NO160133C/en unknown
- 1982-02-16 DK DK067382A patent/DK155936C/en not_active IP Right Cessation
-
1984
- 1984-09-17 KE KE3454A patent/KE3454A/en unknown
- 1984-09-21 SG SG68584A patent/SG68584G/en unknown
- 1984-11-15 HK HK903/84A patent/HK90384A/en unknown
-
1985
- 1985-12-30 MY MY908/85A patent/MY8500908A/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1793057A1 (en) * | 1967-07-31 | 1971-09-30 | Allen & Hanburys Ltd | Phenylacetic acids, processes for their production and medicinal preparations containing these compounds |
| US3828093A (en) * | 1967-07-31 | 1974-08-06 | Allen & Hanburys Ltd | Benzoylphenylacetic acids and related compounds |
| DE2636582A1 (en) * | 1975-08-13 | 1977-02-24 | Robins Co Inc A H | 2-AMINO-3- (5- AND 6-) BENZOYLPHENYL ACID ACIDS, THEIR ESTERS AND METAL SALTS AND PROCESS FOR THE PREPARATION OF THE ACIDS Cited |
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Legal Events
| Date | Code | Title | Description |
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| 8128 | New person/name/address of the agent |
Representative=s name: SCHWABE, H., DIPL.-ING. SANDMAIR, K., DIPL.-CHEM. |
|
| 8110 | Request for examination paragraph 44 | ||
| 8127 | New person/name/address of the applicant |
Owner name: A. H. ROBINS CO., INC. (N.D.GES.D.STAATES DELAWARE |
|
| 8128 | New person/name/address of the agent |
Representative=s name: SCHWABE, H., DIPL.-ING. SANDMAIR, K., DIPL.-CHEM. |
|
| D2 | Grant after examination | ||
| 8364 | No opposition during term of opposition | ||
| 8339 | Ceased/non-payment of the annual fee |