NO160133B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AMINO-3- (HALOBENZOYL) -METHYLPHENYLEDIC ACETIC ACIDS, ESTERS AND SALTS THEREOF. - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AMINO-3- (HALOBENZOYL) -METHYLPHENYLEDIC ACETIC ACIDS, ESTERS AND SALTS THEREOF. Download PDFInfo
- Publication number
- NO160133B NO160133B NO820468A NO820468A NO160133B NO 160133 B NO160133 B NO 160133B NO 820468 A NO820468 A NO 820468A NO 820468 A NO820468 A NO 820468A NO 160133 B NO160133 B NO 160133B
- Authority
- NO
- Norway
- Prior art keywords
- amino
- preparation
- salts
- esters
- halobenzoyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 13
- 238000002360 preparation method Methods 0.000 title claims description 11
- 150000002148 esters Chemical class 0.000 title claims description 3
- 150000001243 acetic acids Chemical class 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 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 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 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 239000003637 basic solution Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000203 mixture Substances 0.000 description 7
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010053155 Epigastric discomfort Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-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
- 239000003937 drug carrier Substances 0.000 description 3
- 229960000905 indomethacin Drugs 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 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
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 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
- 239000008174 sterile solution Substances 0.000 description 2
- 210000002784 stomach Anatomy 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
- 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
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000295146 Gallionellaceae Species 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
- 206010061218 Inflammation Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 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
- 229920002472 Starch Polymers 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
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 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
- 238000010171 animal model Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000010533 azeotropic distillation Methods 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
- 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
- 239000002775 capsule 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
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000000694 effects Effects 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
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000001727 glucose 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
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 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
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 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
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 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
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux 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
- 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
- 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 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
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 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
- 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
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- A—HUMAN NECESSITIES
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
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- 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
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- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
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- 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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- 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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- A—HUMAN NECESSITIES
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- 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
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/40—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
- C07C57/32—Phenylacetic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/46—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid
Description
Foreliggende oppfinnelse angår fremstilling av nye, terapeutisk aktive 2-amino-3-(halobenzoyl)-methylfenyleddiksyrer, deres alkylestere og metallsalter. The present invention relates to the production of new, therapeutically active 2-amino-3-(halobenzoyl)-methylphenylacetic acids, their alkyl esters and metal salts.
Visse 2-amino-3-(5 og 6)-benzoylfenyleddiksyrer med forskjellige substituenter på benzoyl- og fenylgruppene og fremgangsmåter for fremstilling og bruk av disse er beskrevet i US patentskrift 4 045 576. Forbindelsene kjent fra denne publikasjon, er ikke methylfenyleddiksyrer eller derivater derav. Certain 2-amino-3-(5 and 6)-benzoylphenylacetic acids with different substituents on the benzoyl and phenyl groups and methods for their preparation and use are described in US Patent 4,045,576. The compounds known from this publication are not methylphenylacetic acids or derivatives hence.
US patentskrift 4 221 716 beskriver en fremgangsmåte for fremstilling av 7-acylindolin-2-oner som er mellom-produkter ved fremstilling av foreliggende nye forbindelser. US patent document 4,221,716 describes a method for the production of 7-acylindolin-2-ones which are intermediate products in the production of the present new compounds.
Oppfinnelsen angår således en analogifremgangsmåte for fremstilling av terapeutisk aktive forbindelser av formelen: The invention thus relates to an analogue method for the production of therapeutically active compounds of the formula:
hvori R betegner hydrogen, laverealkyl eller et farmasøytisk akseptabelt kation, wherein R represents hydrogen, lower alkyl or a pharmaceutically acceptable cation,
Y er halogen, og Y is halogen, and
n er et helt tall fra 1 til 3. n is an integer from 1 to 3.
De nye forbindelser utviser verdifulle farmakologiske egenskaper og er anvendbare som farmasøytiske midler. Forbindelsene utviser glimrende antiinflammatorisk og analgetisk aktivitet i varmblodige dyr med minimal gastro-intestinal toksisitet. The new compounds exhibit valuable pharmacological properties and are useful as pharmaceutical agents. The compounds exhibit excellent anti-inflammatory and analgesic activity in warm-blooded animals with minimal gastro-intestinal toxicity.
I definisjonen av symboler i de foregående formler og hvor de ellers fremkommer i foreliggende beskrivelse, har uttrykkene følgende betydning. In the definition of symbols in the preceding formulas and where they otherwise appear in the present description, the expressions have the following meaning.
Uttrykket "laverealkyl" som anvendt her, innbefatter rettkjedede og forgrenede radikaler med opptil 6 carbonatomer, fortrinnsvis ikke mere enn 4 carbonatomer, f.eks. _ grupper som methyl, ethyl, propyl, isopropyl, butyl, sek-butyl, t-butyl, amyl, isoamyl og hexyl. The term "lower alkyl" as used herein includes straight chain and branched radicals of up to 6 carbon atoms, preferably not more than 4 carbon atoms, e.g. _ groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, amyl, isoamyl and hexyl.
Uttrykket "halogen" innbefatter klor, fluor, brom og jod. The term "halogen" includes chlorine, fluorine, bromine and iodine.
Eksempler på farmasøytisk akseptable metallkationer er natrium, kalium, calcium, magnesium, sink, aluminium, kobber og hydrater derav. Examples of pharmaceutically acceptable metal cations are sodium, potassium, calcium, magnesium, zinc, aluminium, copper and hydrates thereof.
Analogifremgangsmåten ifølge oppfinnelsen er kjenne-tegnet ved at et 7-benzoylmethylindolin-2-on av formelen: The analog method according to the invention is characterized by the fact that a 7-benzoylmethylindolin-2-one of the formula:
hvori Y og n er som ovenfor angitt, hydrolyseres i vandig basisk løsning under dannelse av salter derav som deretter surgjøres under dannelse av syren, og for fremstilling av laverealkylestere derav omdannes syren til et metallsalt som deretter omsettes i et egnet løsningsmiddel med et alkyl-halogenid under dannelse av den ønskede ester. in which Y and n are as stated above, is hydrolyzed in aqueous basic solution to form salts thereof which are then acidified to form the acid, and for the production of lower alkyl esters thereof, the acid is converted to a metal salt which is then reacted in a suitable solvent with an alkyl halide while forming the desired ester.
Utgangsforbindelsene kan fremstilles etter konven-sjonelle metoder, slik som beskrevet i US patentskrifter 4 045 576 og 4 221 716. The starting compounds can be produced according to conventional methods, such as described in US patents 4,045,576 and 4,221,716.
Fremstilling av forbindelsene illustreres i de etter-følgende eksempler. Preparation of the compounds is illustrated in the following examples.
Eksempel 1 Example 1
Fremstilling av n3trium-2-amino-3-(4-fluorbenzoyl)-5-methyl-fenylacetat- monohydrat Preparation of sodium 2-amino-3-(4-fluorobenzoyl)-5-methyl-phenylacetate monohydrate
En blanding av 8,0 g (0,03 mol) 7-(4-fluorbenzoyl)-5-methylindolin-2-on i 120 ml 3N natriumhydroxyd ble oppvarmet til tilbakeløpskokning i 16 timer. Etter fortynning med vann til 300 ml ble løsningen ved 50°C titrert med konsen-trert saltsyre til pH 8,2. Den resulterende orange løsning ble filtrert, og filtratet ble avkjølt til 5°C og surgjort til pH 4,5 med iseddik. Det resulterende gule, faste materiale ble oppsamlet og vasket med vann, deretter løst i methylenklorid. Vann ble tilsatt, og blandingen ble titrert med fortynnet natriumbicarbonatløsning inntil en pH på 7,0 ble opprettholdt. Det vandige lag ble fraskilt og konsen-trert ved azeotrop destillasjon av vannet med absolutt ethylalkohol. Det erholdte gule pulver ble oppløst i isopropyl-alkohol, og 1 ml vann ble tilsatt. Etter at blandingen hadde stått i 3 dager, ble det resulterende gule, faste materiale oppsamlet og tørket ved 25°C under høyvakuum i 2 dager under dannelse av 1,6 g (16,5% utbytte) av tittelforbindelsen som et gult pulver med et smeltepunkt på 140-160°C. A mixture of 8.0 g (0.03 mol) 7-(4-fluorobenzoyl)-5-methylindolin-2-one in 120 ml 3N sodium hydroxide was heated to reflux for 16 hours. After dilution with water to 300 ml, the solution was titrated at 50°C with concentrated hydrochloric acid to pH 8.2. The resulting orange solution was filtered, and the filtrate was cooled to 5°C and acidified to pH 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 azeotropic distillation of the water with absolute ethyl alcohol. The yellow powder obtained was dissolved in isopropyl alcohol, and 1 ml of water was added. After the mixture stood for 3 days, the resulting yellow solid was collected and dried at 25°C under high vacuum for 2 days to give 1.6 g (16.5% yield) of the title compound as a yellow powder with a melting point of 140-160°C.
Analyse: Analysis:
Beregnet for C16H13<F>N03Na-H20: C 58,72; H 4,62; N 4,28 Funnet; C 58,71; H 4,68; N 4,26 Calculated for C 16 H 13 <F>NO 3 Na-H 2 O: C 58.72; H 4.62; N 4.28 Found; C 58.71; H 4.68; N 4.26
Eksempel 2 Example 2
Fremstilling av natrium-2-amino-3-(4-klorbenzoyl)-5-methyl-fenylacetat Preparation of sodium 2-amino-3-(4-chlorobenzoyl)-5-methyl-phenylacetate
Ved å følge prosedyren beskrevet i eksempel 1 ga en blanding av 11,5 g (0,04 mol) 7-(4-klorbenzoyl)-5-methyl-indolin-2-on og 160 ml 3 N natriumhydroxyd etter omkrystal-lisering fra vann, 2,5 g (18%) av tittelforbindelsen som orange nåler med smeltepunkt 262 oC. Following the procedure described in Example 1, a mixture of 11.5 g (0.04 mol) of 7-(4-chlorobenzoyl)-5-methyl-indolin-2-one and 160 ml of 3 N sodium hydroxide gave, after recrystallization from water, 2.5 g (18%) of the title compound as orange needles m.p. 262 oC.
Analyse: Analysis:
Beregnet for C16H13ClN03Na: C 59,00; H 4,02; N 4,30 Calculated for C16H13ClN03Na: C 59.00; H 4.02; N 4.30
Funnet: C 58,82; H 4,09; N 4,32 Found: C 58.82; H 4.09; N 4.32
Eksempel 3 Example 3
Fremstilling av natrium-2-amino-3-(2,4-diklorbenzoyl)-5~ methylf enylacetat Preparation of sodium 2-amino-3-(2,4-dichlorobenzoyl)-5-methylphenylacetate
Ved å følge prosedyren beskrevet i eksempel 1 ga en blanding av 7-(2,4-diklorbenzoyl)-5-methyllndolin-2-on og 3 N natriumhydroxyd tittelforbindelsen. Following the procedure described in Example 1, a mixture of 7-(2,4-dichlorobenzoyl)-5-methylindolin-2-one and 3 N sodium hydroxide gave the title compound.
Eksempel 4 Example 4
Fremstilling av natrium-2-amino-3-(2,3,5-triklorbenzoyl)-6-methylf enylacetat Preparation of sodium 2-amino-3-(2,3,5-trichlorobenzoyl)-6-methylphenylacetate
Ved å følge prosedyren beskrevet i eksempel 1, ble det ut fra en blanding av 7-(2,3,5-triklorbenzoyl)-4-methylindolin-2-on og 3 N natriumhydroxyd fremstilt tittelforbindelsen. By following the procedure described in example 1, the title compound was prepared from a mixture of 7-(2,3,5-trichlorobenzoyl)-4-methylindolin-2-one and 3 N sodium hydroxide.
Eksempel 5 Example 5
Fremstilling av natrium-2-amino-3-(4-klorbenzoyl)-4-methylf enylacetat Preparation of sodium 2-amino-3-(4-chlorobenzoyl)-4-methylphenylacetate
Ved å følge prosedyren beskrevet i eksempel 1, ble det ut fra en blanding av 4-klorbenzoyl-6-methylindolin-2-on og 3 N natriumhydroxyd fremstilt tittelforbindelsen. By following the procedure described in example 1, the title compound was prepared from a mixture of 4-chlorobenzoyl-6-methylindolin-2-one and 3 N sodium hydroxide.
I den siste tid har sterke antiinflammatoriske lege-midler generelt blitt funnet å gi alvorlige bivirkninger slik som mageblødning og sårdannelse når de administreres oralt til dyr i det effektive område. De nye forbindelser ble funnet å medføre den fordel at nedsatt hyppighet av mage-irritasjon er blitt observert når disse administreres innen det effektive område for å redusere inflammasjon sammen-lignet med indomethacin og 2-amino-3-benzoylfenyleddiksyrer og deres derivater som beskrevet i US patentskrift 4 045 576. Eksempelvis viste forbindelsen fremstilt ifølge eksempel 2, natrium-2-amino-3-(4-klorbenzoyl)-5-methylfenylacetat, seg å være ca. to ganger så kraftig som indomethacin og natrium-2-amino-3-benzoylfenylacetat, men utviste bare fjerdeparten av indomethacins irritasjon på magen og halvparten av den irritasjon på 'magen som utvises av natrium-2-amino-3-benzoyl-fenylacetat. Forbindelsen ifølge eksempel 2 ble funnet å In recent times, strong anti-inflammatory drugs have generally been found to produce serious side effects such as gastric bleeding and ulceration when administered orally to animals in the effective range. The new compounds were found to have the advantage that reduced frequency of gastric irritation has been observed when these are administered within the effective range for reducing inflammation compared to indomethacin and 2-amino-3-benzoylphenylacetic acids and their derivatives as described in US patent 4 045 576. For example, the compound prepared according to example 2, sodium 2-amino-3-(4-chlorobenzoyl)-5-methylphenylacetate, turned out to be approx. twice as potent as indomethacin and sodium 2-amino-3-benzoylphenylacetate, but exhibited only a quarter of the gastric irritation of indomethacin and half the gastric irritation of sodium 2-amino-3-benzoyl-phenylacetate. The compound according to Example 2 was found to
ha tilnærmet den halve styrke av natrium-2-amino-3-(4-klor- having approximately half the strength of sodium 2-amino-3-(4-chloro-
benzoyl)-5-fluorfenylacetat, men utviste overraskende bare en fjerdepart av den irritasjon som utvises på magen av denne forbindelse. benzoyl)-5-fluorophenylacetate, but surprisingly exhibited only a quarter of the irritation exhibited on the stomach by this compound.
Den antiinflammatoriske aktivitet ble demonstrert på laboratoriedyr under anvendelse av en modifikasjon av Evans Blue-Carrageenan Pleural Effusion Assay of Sancilio, L. F., J. Pharmacol. Exp. Ther. 168: 199-204 (1969) . 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).
Magetoksisitet ble bestemt ved en modifikasjon av metoden beskrevet av Tsukada et al., Arzneim. Forsch. 28: 428-438 (1978) . Stomach toxicity was determined by a modification of the method described by Tsukada et al., Arzneim. research 28: 428-438 (1978).
Forbindelsene virker også som analgetiske midler som bestemt ved en modifikasjon av metoden beskrevet av Collier, et al., Brit. J. Pharmacol. Chemother. '32: 295-310 (1968). The compounds also act as analgesic agents as determined by a modification of the method described by Collier, et al., Brit. J. Pharmacol. Chemother. '32: 295-310 (1968).
Effektive mengder av hvilke som helst av de foregående farmakologisk aktive forbindelser kan administreres til et levende dyr på hvilke som helst av forskjellige måter, slik som f.eks. oralt som i kapsler eller tabletter, parenteralt i form av sterile løsninger eller suspensjoner, og i enkelte tilfeller intra-venøst i form av sterile løsninger. Ved formulering av de nye preparater innarbeides den aktive bestanddel i en egnet bærer, illustrativt en farmasøytisk bærer. Egnede farma-søytiske bærere som er anvendbare ved formulering av pre-paratene, innbefatter stivelse, gelatin, glucose, magnesium-carbonat, lactose, malt .og lignende. Egnede væskeformige farmasøytiske bærere innbefatter ethylalkohol, propylen-glycol, glycerol, glucosesirup og lignende. Effective amounts of any of the foregoing pharmacologically active compounds may be administered to a live animal by any of a variety of means, such as e.g. 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. When formulating the new preparations, the active ingredient is incorporated into a suitable carrier, illustratively a pharmaceutical carrier. Suitable pharmaceutical carriers useful in formulating the preparations include starch, gelatin, glucose, magnesium carbonate, lactose, malt, and the like. Suitable liquid pharmaceutical carriers include ethyl alcohol, propylene glycol, glycerol, glucose syrup and the like.
De farmakologisk aktive forbindelser kan med fordel anvendes innen en enhetsdose på fra 0,1 til 150 mg. Enhets-dosen kan administreres en gang daglig eller i multiple eller oppdelte daglige doser. Den daglige dose kan variere fra 0,3 til 450 mg. 5 til 25 mg synes å være optimale pr. enhetsdose. The pharmacologically active compounds can advantageously be used within a unit dose of from 0.1 to 150 mg. The unit dose may be administered once daily or in multiple or divided daily doses. The daily dose can vary from 0.3 to 450 mg. 5 to 25 mg seems to be optimal per unit dose.
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23453181A | 1981-02-17 | 1981-02-17 |
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| Publication Number | Publication Date |
|---|---|
| NO820468L NO820468L (en) | 1982-08-18 |
| NO160133B true NO160133B (en) | 1988-12-05 |
| NO160133C NO160133C (en) | 1989-03-15 |
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| NO820468A NO160133C (en) | 1981-02-17 | 1982-02-16 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AMINO-3- (HALOBENZOYL) -METHYLPHENYLEDIC ACETIC ACIDS, ESTERS AND SALTS THEREOF. |
Country Status (32)
| Country | Link |
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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) | ES509622A0 (en) |
| FI (1) | FI73970C (en) |
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| GB (1) | GB2093027B (en) |
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| HK (1) | HK90384A (en) |
| HU (1) | HU187644B (en) |
| IE (1) | IE52289B1 (en) |
| IL (1) | IL64724A0 (en) |
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| KE (1) | KE3454A (en) |
| LU (1) | LU83928A1 (en) |
| MY (1) | MY8500908A (en) |
| NL (1) | NL8200607A (en) |
| NO (1) | NO160133C (en) |
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| PT (1) | PT74441B (en) |
| SE (1) | SE453387B (en) |
| SG (1) | SG68584G (en) |
| YU (1) | YU44333B (en) |
| ZA (1) | ZA82697B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 (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 |
| 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 |
| 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 |
| TWI358290B (en) | 2004-12-02 | 2012-02-21 | Alcon Inc | Topical nepafenac formulations |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| SE400966B (en) * | 1975-08-13 | 1978-04-17 | Robins Co Inc A H | PROCEDURE FOR PREPARING 2-AMINO-3- (OR 5-) BENZOYL-PHENYLETIC ACIDS |
| 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 |
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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 YU YU325/82A patent/YU44333B/en unknown
- 1982-02-15 GR GR67320A patent/GR76516B/el unknown
- 1982-02-15 IE IE310/82A patent/IE52289B1/en not_active IP Right Cessation
- 1982-02-15 SE SE8200891A patent/SE453387B/en unknown
- 1982-02-16 BE BE0/207327A patent/BE892156A/en not_active IP Right Cessation
- 1982-02-16 NO NO820468A patent/NO160133C/en unknown
- 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 ES ES509622A patent/ES509622A0/en active Granted
- 1982-02-16 NZ NZ199745A patent/NZ199745A/en unknown
- 1982-02-16 CA CA000396392A patent/CA1173852A/en not_active Expired
- 1982-02-16 KR KR8200673A patent/KR880002289B1/en active
- 1982-02-16 PL PL1982235095A patent/PL139815B1/en unknown
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1984
- 1984-09-17 KE KE3454A patent/KE3454A/en unknown
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1985
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