GB2093027A - 2-amino-3-(halobenzoyl)-methylphenylacetic acids, esters and salts thereof - Google Patents
2-amino-3-(halobenzoyl)-methylphenylacetic acids, esters and salts thereof Download PDFInfo
- Publication number
- GB2093027A GB2093027A GB8204137A GB8204137A GB2093027A GB 2093027 A GB2093027 A GB 2093027A GB 8204137 A GB8204137 A GB 8204137A GB 8204137 A GB8204137 A GB 8204137A GB 2093027 A GB2093027 A GB 2093027A
- Authority
- GB
- United Kingdom
- Prior art keywords
- amino
- compound
- sodium
- halobenzoyl
- salts
- 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
- 150000003839 salts Chemical class 0.000 title abstract description 7
- 150000002148 esters Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 241001465754 Metazoa Species 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 150000001768 cations Chemical class 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 21
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 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 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 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 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 1
- 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 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 abstract description 6
- 239000002184 metal Substances 0.000 abstract description 6
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 3
- 230000001760 anti-analgesic effect Effects 0.000 abstract description 2
- 206010059024 Gastrointestinal toxicity Diseases 0.000 abstract 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 13
- 238000000034 method Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 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
- 229920002472 Starch Polymers 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 239000000243 solution Substances 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
- 239000013543 active substance Substances 0.000 description 3
- 125000005907 alkyl ester group Chemical class 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
- 229960000905 indomethacin Drugs 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000008174 sterile solution Substances 0.000 description 3
- 210000002784 stomach Anatomy 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
- 239000002253 acid Substances 0.000 description 2
- 238000004458 analytical method Methods 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
- 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
- 238000009472 formulation Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- IBIKHMZPHNKTHM-RDTXWAMCSA-N merck compound 25 Chemical compound C1C[C@@H](C(O)=O)[C@H](O)CN1C(C1=C(F)C=CC=C11)=NN1C(=O)C1=C(Cl)C=CC=C1C1CC1 IBIKHMZPHNKTHM-RDTXWAMCSA-N 0.000 description 2
- 239000000843 powder 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
- 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 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 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
- 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
- 206010053155 Epigastric discomfort Diseases 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
- 206010022998 Irritability Diseases 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
- MKNIBNQJIMDODU-UHFFFAOYSA-M NC1=C(C(=CC=C1C(C1=C(C(=CC(=C1)Cl)Cl)Cl)=O)C)CC(=O)[O-].[Na+] Chemical compound NC1=C(C(=CC=C1C(C1=C(C(=CC(=C1)Cl)Cl)Cl)=O)C)CC(=O)[O-].[Na+] MKNIBNQJIMDODU-UHFFFAOYSA-M 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
- 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
- 239000004411 aluminium Substances 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
- 230000000202 analgesic effect Effects 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
- 229940124599 anti-inflammatory drug Drugs 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
- 238000009835 boiling Methods 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
- 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
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005538 encapsulation Methods 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
- 230000002496 gastric effect Effects 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
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 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
- 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
- 239000008177 pharmaceutical agent Substances 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
- 230000003389 potentiating effect Effects 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
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 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
- 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
- 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
- 230000036269 ulceration Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- 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
- A61K31/13—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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- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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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Abstract
Novel 2-amino-3-(halobenzoyl)- methylphenylacetic acids, esters and salts having the formula: <IMAGE> wherein R represents a hydrogen atom, a lower alkyl group or a pharmaceutically acceptable metal cation, Y represents a halogen atom and n is an integer from 1 to 3 are provided. The compounds exhibit outstanding anti-inflammatory and analgesic activity in warm blooded animals with minimal gastro-intestinal toxicity.
Description
SPECIFICATION 2-amino-3-(halobenzoyl)-methylphenylacetic acids, esters and salts thereof
The present invention relates to certain 2-amino-3-(halobenzoyl)-methylphenylacetic acids, their alkylesters and metal salts, pharmaceutical compositions containing such compounds and pharmaceutical uses thereof.
Certain 2-amino-3-(5 and 6) benzoylphenylacetic acids having various substituents on the benzoyl and phenyl moieties and the methods of preparing and using the same are disclosed in
U.S. Patent 4,045,576. The compounds of this reference are not methylphenylacetic acids or their derivatives.
U.S. Patent 4,221,761 discloses a process for the preparation of 7-acylindolin-2-ones which are intermediates in the preparation of the compounds of this invention.
The invention is more especially concerned with 2-amino-3-(halobenzoyl)methylphenylacetic acids, alkylesters and metal salts having the formula:
Formula I wherein,
R. represents a hydrogen atom or a lower alkyl group or a pharmaceutically acceptable metal cation,
Y represents a halogen atom and
n is an integer from 1 to 3.
The novel compounds of this invention possess valuable pharmacological properties and are useful as pharmaceutical agents. The compounds exhibit outstanding anti-inflammatory and analgesic acitivity in warm blooded animals with minimal gasto-intestinal toxicity.
The present invention encompasses the compounds of Formula I set forth above with the accompanying definitions, pharmaceutical compositions comprising the compounds of Formula I and the compounds of Formula I for use in alleviating inflammation in living animals.
In the definition of symbols in the formulas hereof and where they appear elsewhere throughout this specification, the terms have the following meaning and significance.
The term "lower alkyl" as used herein includes straight and branched chain radicals of up to six carbon atoms inclusive, preferably no more than four carbon atoms and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, amyl, isoamyl and hexyl.
The term "halogen" when referred to herein includes chlorine, fluorine, bromine and iodine.
Illustrative of pharmaceutically acceptable metal cations are sodium, potassium, calcium, magnesium, zinc, aluminium, copper and hydrates thereof.
The compounds of this invention are conveniently prepared from a 7-benzoylmethylindolin-2one of the formula:
wherein Y and n are defined above. These starting compounds may be prepared by conventional methods, such as those disclosed in U.S. Patents 4,045,576 and 4,221,716 mentioned above.
The compounds of this invention are prepared by hydrolysis of the 7-benzoylmethylindolin-2ones in aqueous basic solution to provide salts thereof which may then be acidified to obtain the acid. To obtain the lower alkyl esters thereof, the acid is converted to a metal salt which is then reacted in a suitable solvent with an alkyl halide to provide the desired ester.
The invention may be put into practice in various ways and a number of specific embodiments will be described to illustrate the invention with reference to the accompanying examples.
Example 1
Preparation of Sodium 2-Amino-3-(4-Fluorobenzoyl)-5-Methylphenylacetate Monohydrate.
A mixture of 8.0 grams (0.03 mol) of 7-(4-fluorobenzoyl)-5-methylindolin-2-one in 120 ml of 3N sodium hydroxide was heated at reflux for 1 6 hours. After diluting with water to 300 ml, the solution at a temperature of 50"C was titrated with concentrated hydrochloric acid to a pH of 8.2. The resulting orange solution was filtered and the filtrate obtained was cooled at 5"C and acidified to a pH of 4.5 with glacial acetic acid. The resulting yellow solid was collected and washed with water, then dissolved in methylene chloride. Water was added and the mixture was titrated with dilute sodium bicarbonate solution until a pH of 7.0 was maintained. The aqueous layer was separated and concentrated by boiling with absolute ethyl alcohol so as to remove water as the azeotrope.The yellow powder obtained was dissolved in isopropyl alcohol and one ml of water was added. After allowing the mixture to stand for 3 days, the resulting yellow solid was collected and dried at 25"C under high vacuum for 2 days to yield 1.6 grams (16.5% yield) of the title compound as a yellow powder having a m.p. of 140-1 60 C.
Analysis : Calculated for C,6H13FNO3Na.H20 : C,58.72; H,4.62
N,4.28
Found : C,58.71; H,4.68
N,4.26
Example 2
Preparation of Sodium 2-Amino-3-(4-Chlorobenzoyl)-5-Methylphenylacetate.
Following the procedure of Example 1, a mixture of 11.5 grams (0.04 mol) of 7-(4chlorobenzoyl)-5-methylindolin-2-one and 1 60 ml of 3N sodium hydroxide gave, after recrystallisation from water, 2.5 grams (18%) of the title compound as orange needles, m.p. 262"C.
Analysis : Calculated for C'6H13CINO3Na : C,59.00; H,4.02;
N,4.30
Found C,58.82; H,4.09;
N,4.32
Example 3
Preparation of sodium 2-Amino-3-(2,4-dichlorobenzoyl)-5-Methylphen"lacetate.
Following the procedure of Example 1, a mixture of 7-(2,4-dichlorobenzoyl)-5-methylindolin-2- one and 3N sodium hydroxide produced the title compound.
Example 4
Preparation of Sodium 2-Amino-3-(2, 3, 5-Trichlorobenzoyl)-6-Methylphenylacetate.
Following the procedure of Example 1, a mixture of 7-(2,3,5-trichlorobenzoyl)-4-methylindolin- 2-one and 3N sodium hydroxide produced the title compound.
Example 5
Preparation of Sodium 2-Amino-3-(4-Chlorobenzoyl)-4-Methylphenylacetate.
Following the procedure of Example 1, a mixture of 4-chlorobenzoyl-6-methylindolin-2-one and 3N sodium hydroxide produced the title compound.
Generally, in the past, strong anti-inflammatory drugs have been found to produce serious side effects of gastric bleeding and ulceration when administered orally to animals in effective amounts. The compounds of the present invention have been found to have the advantage that lowered incidence of gastric irritation is observed when they are administered in effective amounts for reducing inflammation as compared to indomethacin and the 2-amino-3-benzoylphenyl-acetic acids and their derivatives diclosed in U.S. Patent 4,045,576.For example, the compound of Example 2, sodium 2-amino-3-(4-chlorobenzoyl)-5-methylphenylacetate, was found to be approximately twice as potent as indomethacin and sodium 2-amino-3-benzoylphenylacetate but exhibited about 1/4 as much irritation to the stomach as indomethacin and about 1/2 as much irritation to the stomach as sodium 2-amino-3-benzoylphenylacetate. The compound of
Example 2 was found to have about 1/2 the potency of sodium 2-amino-3-(4-chlorobenzoyl)-5fluorophenylacetate but surprisingly exhibited about 1/4 as much irritation to the stomach as that compound.
The anti-inflammatory activity was demonstrated in laboratory animals using a modification of the Evans Blue-Carrageenan Pleural Effusion Assay of Sancilio, L. F., J. Pharmacol. Exp. Ther.
168:199-204(1969).
Gastric toxicity was determined by a modification of the method of Tsukada et al., Arzneim.
Forsch. 28: 428-438 (1978).
The compounds of this invention also act as analgetics as determined by a modification of the method of Collier, et al., Brit. J. Pharmacol. Chemother. 32: 295-310 (1968).
The present invention also contemplates novel compositions containing the compounds of the invention as active ingredients. Effective quantities of any of the foregoing pharmacologically active compounds may be administered to a living animal body in any one of various ways, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. In forming the novel compositions of this invention, the active ingredient is incorporated in a suitable carrier, illustratively, a pharmaceutical carrier. Suitable pharmaceutical carriers which are useful in formulating the compositions of this invention include starch, gelatin, glucose, magnesium carbonate, lactose and malt.Liquid compositions are also within the purview of this invention and suitable liquid pharmaceutical carriers include ethyl alcohol, propylene glycol, glycerine and glucose syrup.
The pharmacologically active compounds may be advantageously employed in a unit dosage of from 0.1 to 1 50 milligrams. The unit dosage may be administered once daily or in multiple or divided daily doses. The daily dosage may vary from 0.3 to 450 milligrams. Five to 25 milligrams appears optimum per unit dose.
It is only necessary that the active ingredient constitute an effective amount i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. The exact individual dosages as well as daily dosages will, of course, be determined according to standard medical principles under the direction of a physician or veterinarian.
The active agents of the invention may be combined with other pharmacologically active agents, or with buffers, antacids or the like, for administration and the proportion of the active agent in the composition may be varied widely.
The following are examples of compositions formed in accordance with this invention.
Examples 6A to 6C
Capsules of 5 mg (Example 6A), 25 mg (Example 6B) and 50 mg (Example 6C) of active ingredient per capsule were prepared. With the higher amounts of active ingredient, adjustment may be made in the amount of lactose.
Example 6A
Typical blend for Per capsule, encapsulation mg
Active ingredient 5.0
Lactose 296.7
Starch 129.0
Magnesium stearate 4.3
Total 435.0 mg
Additional capsule formulations preferably contain a higher dosage of active ingredient and are as follows:
Example 6B
Per capsule
Ingredients mg
Active ingredient 25.0
Lactose 306.5
Starch 99.2
Magnesium stearate 4.3
Total 435.0 mg
In each case the selected active ingredient was uniformly blended with lactose, starch, and magnesium stearate and the blend then encapsulated.
Example 7
A typical formulation for a tablet containing 5.0 mg of active ingredient per tablet follows.
The formulation may be used for other strengths of active ingredient by adjustment of the weight of dicalcium phosphate.
Per tablet, mg (1) Active ingredient 5.0 (2) Corn starch 1 3.6 (3) Corn starch (paste) 3.4 (4) Lactose 79.2 (5) Dicalcium phosphate 68.0 (6) Calcium stearate 0.9 170.1 mg
Ingredients 1, 2, 4 and 5 were uniformly blended. Ingredient 3 was prepared as a 10 per cent paste in water. The blend was granulated with starch paste and the wet mass passed through an eight mesh (US sieve) screen (which has openings of 2.38 mms). The wet granulation was dried and sized through a twelve mesh (US sieve) screen (which has openings of 1.68 mms). The dried granules were blended with calcium stearate and pressed.
Example 8
Injectable - 2% sterile solutions may be made as follows:
Per cc
Active ingredient 20 mg
Preservative, e.g.
cholorobutanol 0.5% weight/volume
Water for injection q.s.
The solution was prepared, clarified by filtration and filled into vials which were then sealed and autoclaved.
Claims (10)
1. A compound having the formula:
wherein;
R represents a hydrogen atom, or a lower alkyl group or a pharmaceutically acceptable cation,
Y represents a halogen atom, and
n is an integer from 1 to 3.
2. 2-Amino-3-(4-fluorobenzoyl)-5-methylphenylacetic acid.
3. Sodium 2-amino-3-(4-fluorobenzoyl)-5-methyl-phenylacetate monohydrate.
4. 2-Amino-3-(4-chlorobenzoyl)-5-methylphenylacetic acid.
5. Sodium 2-am ino-3-(4chlorobenzoyl)-5-methyl-phenylacetate.
6. A compound as claimed in Claim 1 substantially as specifically described herein with reference to any one of Examples 1 to 5.
7. A pharmaceutical composition suitable for alleviating inflammation and pain in a living animal body comprising an effective amount of a compound as claimed in any one of Claims 1 to 6 and a pharmaceutically acceptable carrier or diluent thereof.
8. A composition as claimed in Claim 7 substantially as specifically described herein with reference to any one of Examples 6A to 8.
9. A compound as claimed in any one of Claims 1 to 6 or a composition as claimed in Claim 7 or Claim 8 for use in alleviating inflammation in a living animal body.
10. A compound as claimed in any one of Claims 1 to 6 or a composition as claimed in
Claim 7 or Claim 8 for use in alleviating pain in a living animal body,
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US23453181A | 1981-02-17 | 1981-02-17 |
Publications (2)
Publication Number | Publication Date |
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GB2093027A true GB2093027A (en) | 1982-08-25 |
GB2093027B GB2093027B (en) | 1984-07-04 |
Family
ID=22881752
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Application Number | Title | Priority Date | Filing Date |
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GB8204137A Expired GB2093027B (en) | 1981-02-17 | 1982-02-12 | 2-amino-3-(halobenzoyl)-methylphenylacetic acids esters and salts thereof |
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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) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0221753A2 (en) * | 1985-10-28 | 1987-05-13 | A.H. ROBINS COMPANY, INCORPORATED (a Delaware corporation) | 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 |
WO2002013805A2 (en) * | 2000-08-14 | 2002-02-21 | Alcon, Inc. | Method of treating neurodegenerative disorders of the retina and optic nerve head |
WO2002013804A2 (en) * | 2000-08-14 | 2002-02-21 | Alcon, Inc. | Method of treating angiogenesis-related disorders using benzoyl phenylacetic acid |
US6646003B2 (en) | 2001-04-02 | 2003-11-11 | Alcon, Inc. | Method of treating ocular inflammatory and angiogenesis-related disorders of the posterior segment of the eye using an amide derivative of flurbiprofen or ketorolac |
US7834059B2 (en) | 2004-12-02 | 2010-11-16 | Alcon, Inc. | Topical nepafenac formulations |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1226344A (en) * | 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 |
CH577461A5 (en) * | 1975-08-13 | 1976-07-15 | Robins Co Inc A H | |
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
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0221753A2 (en) * | 1985-10-28 | 1987-05-13 | A.H. ROBINS COMPANY, INCORPORATED (a Delaware corporation) | Transdermal treatment for pain and inflammation with 2-amino-3-aroylbenzeneacetic acids, salts and esters |
JPS62126124A (en) * | 1985-10-28 | 1987-06-08 | エイ・エイチ・ロビンス・カンパニー・インコーポレーテッド | Composition for percutaneous administration drug |
EP0221753A3 (en) * | 1985-10-28 | 1988-04-27 | A.H. Robins Company, Incorporated | Transdermal treatment for pain and inflammation with 2-amino-3-aroylbenzeneacetic acids, salts and esters |
JPH07116027B2 (en) | 1985-10-28 | 1995-12-13 | エイ・エイチ・ロビンス・カンパニー・インコーポレーテッド | Anti-inflammatory analgesic composition for transdermal administration |
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 |
WO2002013804A2 (en) * | 2000-08-14 | 2002-02-21 | Alcon, Inc. | Method of treating angiogenesis-related disorders using benzoyl phenylacetic acid |
WO2002013805A2 (en) * | 2000-08-14 | 2002-02-21 | Alcon, Inc. | Method of treating neurodegenerative disorders of the retina and optic nerve head |
WO2002013805A3 (en) * | 2000-08-14 | 2002-05-30 | Alcon Inc | Method of treating neurodegenerative disorders of the retina and optic nerve head |
WO2002013804A3 (en) * | 2000-08-14 | 2002-06-06 | Alcon Universal Ltd | Method of treating angiogenesis-related disorders using benzoyl phenylacetic acid |
US6638976B2 (en) | 2000-08-14 | 2003-10-28 | Alcon, Inc. | Method of treating neurodegenerative disorders of the retina and optic nerve head |
US6646003B2 (en) | 2001-04-02 | 2003-11-11 | Alcon, Inc. | Method of treating ocular inflammatory and angiogenesis-related disorders of the posterior segment of the eye using an amide derivative of flurbiprofen or ketorolac |
US7834059B2 (en) | 2004-12-02 | 2010-11-16 | Alcon, Inc. | Topical nepafenac formulations |
US8071648B2 (en) | 2004-12-02 | 2011-12-06 | Novartis Ag | Topical nepafenac formulations |
US8324281B2 (en) | 2004-12-02 | 2012-12-04 | Novartis Ag | Topical nepafenac formulations |
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Date | Code | Title | Description |
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732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19960212 |