KR880002289B1 - 2-아미노-3-(할로벤조일)-메틸페닐아세트산 및 그 유도체의 제조방법 - Google Patents
2-아미노-3-(할로벤조일)-메틸페닐아세트산 및 그 유도체의 제조방법 Download PDFInfo
- Publication number
- KR880002289B1 KR880002289B1 KR8200673A KR820000673A KR880002289B1 KR 880002289 B1 KR880002289 B1 KR 880002289B1 KR 8200673 A KR8200673 A KR 8200673A KR 820000673 A KR820000673 A KR 820000673A KR 880002289 B1 KR880002289 B1 KR 880002289B1
- Authority
- KR
- South Korea
- Prior art keywords
- amino
- compound
- sodium
- preparation
- chlorobenzoyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title description 12
- WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 title 1
- 229960003424 phenylacetic acid Drugs 0.000 title 1
- 239000003279 phenylacetic acid Substances 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 32
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000001768 cations Chemical class 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- WNCLIUXXSKAOND-UHFFFAOYSA-M sodium;2-[2-amino-3-(4-chlorobenzoyl)-5-methylphenyl]acetate Chemical compound [Na+].CC1=CC(CC([O-])=O)=C(N)C(C(=O)C=2C=CC(Cl)=CC=2)=C1 WNCLIUXXSKAOND-UHFFFAOYSA-M 0.000 claims description 4
- 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 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- WFSVKMGPJMLIQS-UHFFFAOYSA-M sodium 2-[2-amino-3-(4-fluorobenzoyl)-5-methylphenyl]acetate hydrate Chemical compound O.NC1=C(C=C(C=C1C(C1=CC=C(C=C1)F)=O)C)CC(=O)[O-].[Na+] WFSVKMGPJMLIQS-UHFFFAOYSA-M 0.000 claims description 3
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 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 2
- 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 2
- 150000002431 hydrogen Chemical group 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000020477 pH reduction Effects 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 18
- 206010061218 Inflammation Diseases 0.000 abstract description 3
- 230000004054 inflammatory process Effects 0.000 abstract description 3
- 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 abstract description 2
- 229940035676 analgesics Drugs 0.000 abstract description 2
- 239000000730 antalgic agent Substances 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract description 2
- 229910052740 iodine Inorganic materials 0.000 abstract description 2
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 17
- 239000004480 active ingredient Substances 0.000 description 13
- 239000002775 capsule Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 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
- 241001465754 Metazoa Species 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000018522 Gastrointestinal disease Diseases 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-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
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960000905 indomethacin Drugs 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000008174 sterile solution Substances 0.000 description 3
- 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
- 206010059024 Gastrointestinal toxicity Diseases 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
- 125000005907 alkyl ester group Chemical class 0.000 description 2
- 230000001760 anti-analgesic effect Effects 0.000 description 2
- 238000003556 assay Methods 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
- 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
- 235000019441 ethanol Nutrition 0.000 description 2
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical class OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 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
- 239000000843 powder Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- MJAQSCHBMPGJES-UHFFFAOYSA-M sodium (2-amino-3-benzoylphenyl)acetate Chemical compound [Na+].NC1=C(CC([O-])=O)C=CC=C1C(=O)C1=CC=CC=C1 MJAQSCHBMPGJES-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid 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 compound 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
- 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
- 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
- 108010010803 Gelatin Proteins 0.000 description 1
- 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 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
- 206010022998 Irritability Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 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
- 208000002151 Pleural effusion Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach 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
- 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 compound NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=CC=C1 SOYCMDCMZDHQFP-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 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
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent 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
- 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 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
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000010418 carrageenan Nutrition 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
- 239000003795 chemical substances by application Substances 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
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000002552 dosage form Substances 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
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 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
- -1 glocose Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000006331 halo benzoyl group Chemical group 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000011630 iodine Substances 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
- 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 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
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 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
- 238000010992 reflux Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- ZLECYLUMRPAYIA-UHFFFAOYSA-M sodium 2-[2-amino-3-(4-chlorobenzoyl)-4-methylphenyl]acetate Chemical compound NC1=C(C=CC(=C1C(C1=CC=C(C=C1)Cl)=O)C)CC(=O)[O-].[Na+] ZLECYLUMRPAYIA-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- JKKFZJKBJQWGQB-UHFFFAOYSA-M sodium;2-[2-amino-3-(2,4-dichlorobenzoyl)-5-methylphenyl]acetate Chemical compound [Na+].CC1=CC(CC([O-])=O)=C(N)C(C(=O)C=2C(=CC(Cl)=CC=2)Cl)=C1 JKKFZJKBJQWGQB-UHFFFAOYSA-M 0.000 description 1
- LXVZJYNCJIPXQV-UHFFFAOYSA-M sodium;2-[2-amino-3-(4-chlorobenzoyl)-5-fluorophenyl]acetate Chemical compound [Na+].NC1=C(CC([O-])=O)C=C(F)C=C1C(=O)C1=CC=C(Cl)C=C1 LXVZJYNCJIPXQV-UHFFFAOYSA-M 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
- 239000008215 water for injection Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 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
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Abstract
내용 없음.
Description
본 발명은 소염 및 진통작용을 갖는 신규의 하기 일반식(Ⅰ)의 2-아마노-3-(할로벤조일)메틸페닐-아세트산, 그의 알킬에스테르 및 금속염 및 이들의 제조방법에 관한 것이다.
상기식에서 R은 수소, 저급 알킬 또는 약제학적으로 허용되는 금속 양이온이며, Y는 할로겐이고, m은 1 내지 3의 정수이다.
벤조일 및 페닐잔기중에 여러 치환체를 갖는 특정 2-아미노-3-(5 및 6) 벤조일 페닐 아세트산, 이의 제법 및 용도가 미합중국 특허 제 4,045,576호에 서술되어있다. 이 참조 문헌의 화합물들은 메틸페닐 아세트산 또는 그 유도체는 아니다.
미합중국 특허 제 4,221,716호는 본 발명의 화합물 제조시 중간체로 작용하는 7-아실인돌린-2-온의 제법에 관해 서술하고 있다.
본 발명에 따른 신규 화합물은 유용한 약리학적 성질을 갖는다. 즉, 온혈동물에서 최소한의 위장관 독성을 지니면서 놀라운 소염 및 진통 작용을 나타낸다.
본 발명의 목적은 신규 화합물 및 조성물을 제공하는데 있으며, 또한 위장관내에서의 부작용을 최소화 하면서 동물, 특히 포유동물에 있어서 염증 및 통증을 치료하는 새로운 방법을 제공는하데 있다.
상기 일반식의 기의 정의에 있어 그 용어는 다음과 같은 정의를 지닌다.
'저급 알킬'은 탄소수 6까지, 바람직하게는 4개 까지의 직쇄 또는 측쇄 라디칼로서, 그 예로는 메틸, 에틸, 프로필, 이소프로필, 부틸, 2급 부틸, 3급 부틸, 아밀, 이소아밀 및 헥실이 있다.
'할로겐'은 염소, 불소, 브롬, 요드를 뜻한다.
약제학적으로는 가능한 금속양이온의 예로는 나트륨, 칼륨, 칼슘, 마그네슘, 아연, 알루미늄, 구리 및 이들의 하이드레이트가 있다.
본 발명에 따른 화합물은 하기 일반식(Ⅱ)의 7-벤조일메틸인돌린-2-온으로부터 제조한다.
상기식에서 Y및 n은 상기에서 정의된바와 같다.
이 출발물질은 미합중국 특허 제 4,045,576호 및 제 4,221,716호에 서술된 공지의 방법에 따라 제조한다.
본 발명에 따른 화합물은, 상기 일반식(Ⅱ)의 7-벤조일메틸인돌린-2-온을 염기성 수용액중에서 가수분해시켜 이들의 염을 얻고 이 염을 산성화시켜 산을 얻음으로써 제조한다.
이들의 저급 알킬 에스테르를 제조하려면, 수득된 산을 금속염으로 전환시키고 이 염을 적합한 용매중에서 알킬 할라이드와 반응시켜 목적하는 에스테르를 얻는다.
다음의 실시예에서 본 발명의 화합물의 제법을 더욱 상세히 설명한다.
[실시예 1]
나트륨 2-아미노-3-(4-플루오로벤조일)-5-메틸페닐아세테이트 모노하이드레이트의 제조.
8.0g(0.03몰)의 7-(4-플루오로벤조일)-5-메틸인돌린-2-온을 함유하는 120ml의 3N 수산화나트륨의 혼합물을 환류온도에서 16시간 가열한다.
물로 희석하여 300ml로 한후, 이 용액을 50℃에서 농염산으로 처리하여 pH8.2로 한다.
얻어진 오렌지색 용액을 여과하고 여액을 5℃로 냉각시킨 다음, 빙초산을 가하여 pH4.5로 산성화시킨다.
얻어진 황색고체를 모아 물로 세척하고 메틸렌 클로라이드중에 용해시킨다. 물을 가하고 이 혼합물을 회중탄산나트륨용액으로, pH가 7.0으로 유지될 때까지 처리한다.
수성층을 분리시켜 무수 에틸 알콜을 사용하여 공비증류시켜 물을 제거, 농축시킨다. 수득된 황색분말을 이소프로필알콜중에 용해시키고 1ml의 물을 가한다.
이 혼합물을 3일간 방치시킨후, 얻어진 황색고체를 모아 25℃ 코진공상태에서 2일간 건조시켜 표제화합물 1.6g(16.5% 수율)을 황색분말로 수득한다.
융점 : 140 내지 160℃
분석 : C16H13FNO3Na·H2O
계산치 : C ; 58.72, H ; 4.62, N ; 4.28
실측치 : C ; 58.71, H : 4.68, N : 4,26
[실시예 2]
나트륨 2-아미노-3-(4-클로로벤조일)-5-메틸페닐아세테이트의 제조.
실시예 1의 공정에 따라, 11.5g(0.04몰)의 7-(4-클로로벤조일)-5-메틸인돌린-2-온과 160ml의 3N 수산화나트륨 혼합물로부터, 2.5g(18%)의 표제화합물을 오렌지색 침상결정으로 수득한다(물로 재결정).
융점 : 262℃
분석 : C16H13C l NO3Na
계산치 : C ; 59.00, H ; 4.02, N ; 4.30
실측치 : C ; 58.82, H : 4.92, N : 4.32
[실시예 3]
나트륨 2-아미노-3-(2,4-디클로로벤조일)-5-메틸페닐아세테이트의 제조.
실시예 1의 공정에 따라, 7-(2,4-디클로로벤조일)-5-메틸인돌린-2-온 및 3N 수산화나트륨의 혼합물로부터 표제화합물을 수득한다.
[실시예 4]
나트륨 2-아미노-3-(2,3,5-트리클로로-벤조일)-6-메틸페닐 아세테이트의 제조.
실시예 1의 공정에 따라, 7-(2,3,5-트리클로로벤조일)-4-메틸인돌린-2-온 및 3N 수산화나트륨의 혼합물로부터 표제화합물을 수득한다.
[실시예 5]
나트륨 2-아미노-3-(4-클로로벤조일)-4-메틸페닐아세테이트의 제조.
실시예 1의 공정에 따라, 4-클로로벤조일-6-메틸인돌린-2-온 및 3N 수산화나트륨의 혼합물로부터 표제화합물을 수득한다.
일반적으로, 종래의 강력한 소염제는, 유효량을 동물에게 경구로 투여하였을때 위출혈 및 위궤양등의 심각한 부작용을 일으켜왔다.
본 발명에 따른 화합물은 염증감소 유효량을 경구 투여했을때, 인도메타신 및 미합중국 특허 제 4,045,576호에 제시된 2-아미노-3-벤조일페닐-아세트산 및 이들의 유도체에 비하여 이러한 위장관 장애를 줄일 수 있다는 잇점을 발견하였다.
예를들어, 실시예 2의 화합물인 나트륨 2-아미노-3-(4-클로로벤조일)-5-메틸페닐아세테이트는, 인도메타신 및 나트륨 2-아미노-3-벤조일페닐아세테이트에 비하여, 약 2배의 강력한 효과를 보여주는데 반해 위장장애는 인도메타신의 1/4, 나트륨 2-아미노-3-벤조일페닐아세테이트의 1/2밖에 되지 않는다.
실시예 2의 화합물은 나트륨 2-아미노-3-(4-클로로벤조일)-5-플루오로페닐아세테이트의 약 1/2정도의 효과를 나타내고 있지만, 위장장애면에서는 놀라웁게도 약 1/4의 위장장애를 보여준다.
소염효과는 하기 문헌에 기술된 방법의 변법에 따라 실험실 동물을 이용하여 증명하였다[참조 : Evans Blue Carrageenan Pleural Effusion Assay of Sancilio, L.F., J. Pharmacol. Exp. Ther., 168 : 199-204(1969)].
위장독성은 하기 문헌에 기술된 방법의 변법에의해 측정하였다[참조 : Tsukada 등의 Arzneim, Forsch 28 : 428-438(1978)].
본 발명에 따른 화합물은 하기 문헌에 기술된 방법의 변법 방법에 의해 증명된 바와같이 진통제로서도 작용한다[참조 : Method fo Collier등의 Brit J. Pharmacol. Chemother. 32 : 295-310(1968)].
제형 및 투여법
유효성분으로서 본 발명의 화합물을 함유하는 신규 조성물도 본 발명의 일부이다.
상술한 약리학적 활성 화합물의 유효량을 캅셀제 또는 정제형태로 경구투여, 또는 무균 용액 또는 현탁액 형태로 비경구투여, 또는 무균 용액 형태로 정맥주사하여 살아있는 동물체내에 투여할 수 있다.
본 발명에 따른 신규 조성물을 만들때, 유효성분을 적합한 담체, 즉 약제학적 담체중에 가한다. 적합한 약제학적 담체로는 전분, 젤라틴, 글로코즈, 탄산마그네슘, 유당, 맥아등이 있다.
액체조성물도 본 발명의 일부인데, 적합한 액체 약제학적 담체로는 에틸 알콜, 프로필렌글리콜, 글리세린, 글로코즈시럽등이 있다.
본 약리학적 활성 화합물은 0.1 내지 150mg의 단위 용량으로 사용하는 것이 바람직하다.
이 단위 용량은 하루에 한번 투여하거나 또는 여러번으로 나누어서 투여할 수 있다.
일일용량은 0.3 내지 450mg이다.
가장 적합한 단위 용량은 5 내지 25mg이다.
유효성분은 유효량으로 사용하여야하며 적합한 유효량은 투여하는 용량형과 관련되어 변화되는데 정확한 개인용량은 의사나 수의사의 지시하에 표준 약제학 원리에 따른다.
본 발명에 따른 유효 화합물을 다른 약리학적으로 유효한 약제와 혼합하거나 완충제, 제산제 등과 혼합할 수 있다.
본 조성물중 유효 화합물의 비율은 넓은 범위내에서 변화될 수 있다.
다음은 본 발명에 따른 조성물의 실시예이다.
1. 캅셀제
1캅셀중 유효성분의 양이 각각 5mg, 25mg, 50mg인 캅셀제를 제조한다. 유효성분의 양이 증가함에 따라 유당의 양을 조정한다.
캅셀중의 성분 1캅셀당 mg
유효성분 5.0
유 당 296.7
전 분 129.0
마그네슘 스테아레이트 4.3
유효성분의 양이 많은 캅셀제가 바람직하며 다음과 같다.
성 분 1캅셀당 mg
유효성분 25.0
유 당 306.5
전 분 99.2
마그네슘 스테아레이트 4.3
각 경우에 있어, 선택된 유효성분을 유당, 전분 및 마그네슘 스테아레이트와 균일하게 혼합하고 캅셀내에 충진시킨다.
2. 정제
1정제당 5.0mg의 유효성분을 함유하는 정제는 다음과 같이 제형한다. 유효성분의 양을 달리할 경우 디칼슘 포스페이트의 중량을 조정하여 제형한다.
1)유효성분 5.0
2)옥수수전분 13.6
3)옥수수전분(페이스트) 3.4
4)유 당 79.2
5)디칼슘 포스페이트 68.0
6)칼슘 스테아레이트 0.9
1,2,4와 5를 균질하게 혼합한다.
3을 물중의 10%페이스트로 만든다.
이 혼합물을 전분 페이스트로 입화시키고 8메쉬체에 통과시킨후 얻어진 습윤입체를 잘 건조시키고 12메쉬체에 통과시킨다. 건조된 입제를 칼슘 스테아레이트와 혼합, 타정한다.
3. 주사용제제 : 2% 무균용액
유효성분 20 mg
보존제 : 클로로부탄올 0.5% W/V
주사용수 적당량
용액을 제조하고 여과, 정제시킨후 바이알에 충진시키고 봉한 후 멸균시킨다.
본 발명 화합물, 조성물 및 본 발명에 따른 제법은 본 특허청구범위의 기본 정신에 벗어나지 않는 범위내에서 여러가지 변형이 가해질 수 있다.
Claims (10)
- 일반식(Ⅱ)의 7-벤조일메틸인돌린-2-온을 염기성 수용액중에서 가수분해시켜 그의 염을 제조한후 산성화하여 산을 수득하거나, 수득된 산을 금속염으로 전환시키거나, 생성된 금속염을 적합한 용매중에서 알킬 할라이드와 반응시킴을 특징으로 하여, 일반식(Ⅰ)의화합물을 제조하는 방법.
상기식에서 R은 수소, 저급 알킬 및 약제학적으로 허용되는 양이온중에서 선택되며, Y는 할로겐이고, n은 1 내지 3의 정수이다. - 제1항에 있어서, 제조된 화합물이 2-아미노-3-(4-플루오로벤조일)-5-메틸페닐아세트산인 방법.
- 제1항에 있어서, 제조된 화합물이 나트륨 2-아미노-3-(4-플루오로벤조일)-5-메틸페닐아세테이트 모노하이드레이트인 방법.
- 제1항에 있어서, 제조된 화합물이 2-아미노-3-(4-클로로벤조일)-5-메틸페닐아세트산인 방법.
- 제1항에 있어서, 제조된 화합물이 나트륨 2-아미노-3-(4-클로로벤조일)-5-메틸페닐아세테이트인 방법.
- 다음 일반식(Ⅰ)의 화합물.
상기식에서 R은 수소, 저급 알킬 및 약제학적으로 허용되는 양이온에서 선택되며, Y는 할로겐이고, n은 1 내지 3의 정수이다. - 제6항에 있어서, 2-아미노-3-(4-플루오로벤조일)-5-메틸페닐아세트산인 화합물.
- 제6항에 있어서, 나트륨 2-아미노-3-(4-플루오로벤조일)-5-메틸페닐아세테이트 모노하이드레이트인 화합물.
- 제6항에 있어서, 2-아미노-3-(4-클로로벤조일)-5-메틸페닐아세트산인 화합물.
- 제6항에 있어서, 나트륨 2-아미노-3-(4-클로로벤조일)-5-메틸페닐아세테이트인 화합물.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23453181A | 1981-02-17 | 1981-02-17 | |
| US234531 | 1981-02-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR830008990A KR830008990A (ko) | 1983-12-16 |
| KR880002289B1 true KR880002289B1 (ko) | 1988-10-22 |
Family
ID=22881752
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR8200673A KR880002289B1 (ko) | 1981-02-17 | 1982-02-16 | 2-아미노-3-(할로벤조일)-메틸페닐아세트산 및 그 유도체의 제조방법 |
Country Status (32)
| Country | Link |
|---|---|
| JP (1) | JPS57149256A (ko) |
| KR (1) | KR880002289B1 (ko) |
| AT (1) | AT387213B (ko) |
| AU (1) | AU7950382A (ko) |
| BE (1) | BE892156A (ko) |
| CA (1) | CA1173852A (ko) |
| CH (1) | CH651294A5 (ko) |
| DE (1) | DE3204854C2 (ko) |
| DK (1) | DK155936C (ko) |
| EG (1) | EG15798A (ko) |
| ES (1) | ES8301895A1 (ko) |
| FI (1) | FI73970C (ko) |
| FR (1) | FR2499981B1 (ko) |
| GB (1) | GB2093027B (ko) |
| GR (1) | GR76516B (ko) |
| HK (1) | HK90384A (ko) |
| HU (1) | HU187644B (ko) |
| IE (1) | IE52289B1 (ko) |
| IL (1) | IL64724A0 (ko) |
| IT (1) | IT1157001B (ko) |
| KE (1) | KE3454A (ko) |
| LU (1) | LU83928A1 (ko) |
| MY (1) | MY8500908A (ko) |
| NL (1) | NL8200607A (ko) |
| NO (1) | NO160133C (ko) |
| NZ (1) | NZ199745A (ko) |
| PL (1) | PL139815B1 (ko) |
| PT (1) | PT74441B (ko) |
| SE (1) | SE453387B (ko) |
| SG (1) | SG68584G (ko) |
| YU (1) | YU44333B (ko) |
| ZA (1) | ZA82697B (ko) |
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 |
| US6034266A (en) * | 1996-03-11 | 2000-03-07 | Fundacao Oswaldo Cruz-Fiocruz | Gem-difluoro derivative of phenylacetamide and phenylacetic acid and their pharmaceutical uses |
| BR9600975A (pt) * | 1996-03-11 | 1997-12-30 | Fundacao Oswaldo Cruz | Derivados do ácido gem-difluorfenilacético e de gem-difluorfenilacetamida processo de sua preparação e suas aplicações farmacêuticas |
| AR030346A1 (es) * | 2000-08-14 | 2003-08-20 | Alcon Inc | Metodo de tratamiento de desordenes neurodegenerativos de la retina y cabeza de nervio optico |
| AR030345A1 (es) * | 2000-08-14 | 2003-08-20 | Alcon Inc | Metodo de tratamiento de desordenes relacionados con 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 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1226344A (ko) * | 1967-07-31 | 1971-03-24 | ||
| US3997368A (en) * | 1975-06-24 | 1976-12-14 | Bell Telephone Laboratories, Incorporated | Elimination of stacking faults in silicon devices: a gettering process |
| SE400966B (sv) * | 1975-08-13 | 1978-04-17 | Robins Co Inc A H | Forfarande for framstellning av 2-amino-3-(eller 5-)bensoyl-fenylettiksyror |
| FR2366015A1 (fr) * | 1975-11-05 | 1978-04-28 | Robins Co Inc A H | Nouveaux acides amino-2 benzoyl-3 (5 et 6) phenylacetiques et leurs esters et sels de metaux alcalins, utiles notamment comme anti-inflammatoires, et leur procede de preparation |
| 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/xx not_active IP Right Cessation
- 1982-01-14 AU AU79503/82A patent/AU7950382A/en not_active Abandoned
- 1982-01-24 EG EG8228A patent/EG15798A/xx active
- 1982-02-01 JP JP57014710A patent/JPS57149256A/ja active Granted
- 1982-02-03 ZA ZA82697A patent/ZA82697B/xx unknown
- 1982-02-05 AT AT0043382A patent/AT387213B/de not_active IP Right Cessation
- 1982-02-08 FI FI820392A patent/FI73970C/fi not_active IP Right Cessation
- 1982-02-09 LU LU83928A patent/LU83928A1/fr unknown
- 1982-02-09 CH CH791/82A patent/CH651294A5/fr not_active IP Right Cessation
- 1982-02-10 IT IT67152/82A patent/IT1157001B/it active
- 1982-02-11 DE DE3204854A patent/DE3204854C2/de 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/xx unknown
- 1982-02-15 GR GR67320A patent/GR76516B/el unknown
- 1982-02-15 SE SE8200891A patent/SE453387B/sv unknown
- 1982-02-16 NO NO820468A patent/NO160133C/no unknown
- 1982-02-16 KR KR8200673A patent/KR880002289B1/ko active
- 1982-02-16 NL NL8200607A patent/NL8200607A/nl not_active Application Discontinuation
- 1982-02-16 PT PT74441A patent/PT74441B/pt not_active IP Right Cessation
- 1982-02-16 CA CA000396392A patent/CA1173852A/en not_active Expired
- 1982-02-16 DK DK067382A patent/DK155936C/da not_active IP Right Cessation
- 1982-02-16 HU HU82464A patent/HU187644B/hu unknown
- 1982-02-16 FR FR8202507A patent/FR2499981B1/fr not_active Expired
- 1982-02-16 ES ES509622A patent/ES8301895A1/es not_active Expired
- 1982-02-16 PL PL1982235095A patent/PL139815B1/pl unknown
- 1982-02-16 NZ NZ199745A patent/NZ199745A/en unknown
- 1982-02-16 BE BE0/207327A patent/BE892156A/fr not_active IP Right Cessation
-
1984
- 1984-09-17 KE KE3454A patent/KE3454A/xx unknown
- 1984-09-21 SG SG68584A patent/SG68584G/en unknown
- 1984-11-15 HK HK903/84A patent/HK90384A/xx unknown
-
1985
- 1985-12-30 MY MY908/85A patent/MY8500908A/xx unknown
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