CH651294A5 - AMINO-2-HALOGENOBENZOYL-3-METHYLPHENYLACETIC ACIDS AND THEIR ESTERS AND SALTS USEFUL AS ANTI-INFLAMMATORY AND ANALGESIC DRUGS. - Google Patents
AMINO-2-HALOGENOBENZOYL-3-METHYLPHENYLACETIC ACIDS AND THEIR ESTERS AND SALTS USEFUL AS ANTI-INFLAMMATORY AND ANALGESIC DRUGS. Download PDFInfo
- Publication number
- CH651294A5 CH651294A5 CH791/82A CH79182A CH651294A5 CH 651294 A5 CH651294 A5 CH 651294A5 CH 791/82 A CH791/82 A CH 791/82A CH 79182 A CH79182 A CH 79182A CH 651294 A5 CH651294 A5 CH 651294A5
- Authority
- CH
- Switzerland
- Prior art keywords
- amino
- benzoyl
- methyl
- compounds
- inflammatory
- Prior art date
Links
- 230000003110 anti-inflammatory effect Effects 0.000 title claims description 5
- 239000000730 antalgic agent Substances 0.000 title claims description 4
- 239000002253 acid Substances 0.000 title description 6
- 150000007513 acids Chemical class 0.000 title description 4
- 229940035676 analgesics Drugs 0.000 title description 3
- 229940124599 anti-inflammatory drug Drugs 0.000 title description 3
- 150000002148 esters Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 30
- 229940049953 phenylacetate Drugs 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 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 7
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 21
- 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 9
- 238000002360 preparation method Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000002775 capsule Substances 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
- 239000000243 solution Substances 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 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
- 239000003937 drug carrier Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 229960000905 indomethacin Drugs 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- -1 2,4-dichloro-benzoyl Chemical group 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
- 206010061218 Inflammation Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 2
- 229940038472 dicalcium phosphate Drugs 0.000 description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 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
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-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
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000032843 Hemorrhage Diseases 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
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 238000010533 azeotropic distillation 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
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 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
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 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
- 229960003699 evans blue Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical class OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000000543 intermediate 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
- 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
- 150000001457 metallic cations Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 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
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000008215 water for injection Substances 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
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—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
-
- 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
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
Description
La présente invention concerne des acides amino-2-halogénoben-zoyl-3-méthylphénylacétiques et leurs esters et sels utiles comme médicaments anti-inflammatoires et analgésiques. The present invention relates to amino-2-halogenoben-zoyl-3-methylphenylacetic acids and their esters and salts useful as anti-inflammatory and analgesic drugs.
Certains acides amino-2-benzoyl-3(-5 et -6)phénylacétiques dont les fragments benzoyle et phényle portent divers substituants, ainsi que des procédés de leur préparation et leur emploi, sont décrits dans le brevet des Etats-Unis d'Amérique N° 4045576. Les composés de cette référence ne sont pas des acides méthylphénylacétiques ni des dérivés de tels acides. Certain amino-2-benzoyl-3 (-5 and -6) phenylacetic acids whose benzoyl and phenyl fragments carry various substituents, as well as processes for their preparation and their use, are described in the patent of the United States of America No. 4045576. The compounds of this reference are not methylphenylacetic acids or derivatives of such acids.
Le brevet des Etats-Unis d'Amérique N° 4221716 décrit un procédé de préparation d'acyl-7-indolinones-2 qui sont des intermédiaires utiles dans la préparation des composés de l'invention. U.S. Patent No. 4,221,716 describes a process for the preparation of acyl-7-indolinones-2 which are useful intermediates in the preparation of the compounds of the invention.
L'invention concerne plus particulièrement des acides amino-2-halogénobenzoyl-3-méthylphénylacétiques ainsi que leurs esters al-kyliques et leurs sels métalliques répondant à la formule: The invention relates more particularly to amino-2-halogenobenzoyl-3-methylphenylacetic acids as well as their alkyl esters and their metal salts corresponding to the formula:
CH. CH.
NH, NH,
C=0 C = 0
(Y) (Y)
dans laquelle: in which:
R représente un atome d'hydrogène, un radical alkyle inférieur ou un cation métallique acceptable en pharmacie, R represents a hydrogen atom, a lower alkyl radical or a metallic cation acceptable in pharmacy,
Y représente un atome d'halogène, et n est 1, 2 ou 3. Y represents a halogen atom, and n is 1, 2 or 3.
Les nouveaux composés de l'invention possèdent des propriétés pharmacologiques intéressantes et sont utiles comme médicaments. Ces composés présentent une remarquable activité anti-inflammatoire et analgésique chez les animaux à sang chaud avec une toxicité gastro-intestinale minime. The new compounds of the invention have interesting pharmacological properties and are useful as medicaments. These compounds exhibit remarkable anti-inflammatory and analgesic activity in warm-blooded animals with minimal gastrointestinal toxicity.
L'invention a donc pour objet de nouveaux composés et de nouveaux médicaments utilisables chez les hommes et les animaux, en particulier des mammifères, pour soulager l'inflammation et la douleur avec un minimum d'effets gastro-intestinaux indésirables. The subject of the invention is therefore new compounds and new drugs which can be used in humans and animals, in particular mammals, to relieve inflammation and pain with a minimum of undesirable gastrointestinal effects.
D'autres caractéristiques et avantages de l'invention ressortiront de la description qui suit. Other characteristics and advantages of the invention will emerge from the description which follows.
L'invention va maintenant être décrite de façon détaillée. The invention will now be described in detail.
L'invention englobe les composés de formule I précédemment indiqués avec les définitions correspondantes et des compositions pharmaceutiques contenant les composés de formule I. The invention encompasses the compounds of formula I previously indicated with the corresponding definitions and pharmaceutical compositions containing the compounds of formula I.
Dans la définition des symboles des formules et partout ailleurs dans la présente description, certains termes ont les significations suivantes: In the definition of the symbols of the formulas and everywhere else in the present description, certain terms have the following meanings:
Le terme alkyle inférieur désigne des radicaux droits ou ramifiés comportant jusqu'à 6 atomes de carbone inclusivement, de préférence pas plus de 4 atomes de carbone, tels que par exemple les radicaux méthyle, éthyle, propyle, isopropyle, butyle, sec.-butyle, tert.-butyle, pentyle, isopentyle et hexyle. The term lower alkyl designates straight or branched radicals containing up to 6 carbon atoms inclusive, preferably not more than 4 carbon atoms, such as for example the methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl radicals , tert.-butyl, pentyl, isopentyl and hexyl.
Le terme halogéno désigne les radicaux chloro, fluoro, bromo et iodo. The term halo designates the chloro, fluoro, bromo and iodo radicals.
On peut citer comme exemples de cations métalliques acceptables en pharmacie les cations sodium, potassium, calcium, magnésium, zinc, aluminium et cuivre, et leurs hydrates. Examples of metal cations that are acceptable in pharmacies include sodium, potassium, calcium, magnesium, zinc, aluminum and copper, and their hydrates.
On prépare de façon pratique les composés de l'invention à partir d'une benzoyl-7-méthylindolinone-2 de formule: The compounds of the invention are prepared in practical terms from a benzoyl-7-methylindolinone-2 of formula:
CH. CH.
'3 '3
o=c o o = c o
où Y et n ont la même définition que ci-dessus. On peut préparer ces composés de départ selon des procédés classiques tels que ceux décrits dans les brevets des Etats-Unis d'Amérique Nos 4045576 et 4221716 précités. On prépare les composés de l'invention par hydrolyse des benzoyl-7-méthylindolinones-2 dans une solution basique aqueuse pour produire les sels correspondants que l'on peut ensuite acidifier pour obtenir l'acide. Pour obtenir les esters alkyliques inférieurs correpondants, on transforme l'acide en un sel métallique que l'on fait ensuite réagir dans un solvant approprié avec un halo-génure d'alkyle pour former l'ester désiré. where Y and n have the same definition as above. These starting compounds can be prepared according to conventional methods such as those described in the patents of the United States of America Nos 4045576 and 4221716 cited above. The compounds of the invention are prepared by hydrolysis of the benzoyl-7-methylindolinones-2 in an aqueous basic solution to produce the corresponding salts which can then be acidified to obtain the acid. To obtain the corresponding lower alkyl esters, the acid is converted into a metal salt which is then reacted in a suitable solvent with an alkyl halide to form the desired ester.
La préparation des composés de l'invention est illustrée plus particulièrement par les exemples suivants : The preparation of the compounds of the invention is illustrated more particularly by the following examples:
Exemple 1 : Example 1:
Préparation de l'amino-2-(fluoro-4 ben:oyl)-3-méthyl-5-phènylacétate de sodium monohydraté Preparation of amino-2- (fluoro-4 ben: oyl) -3-methyl-5-phenylacetate sodium monohydrate
On chauffe à reflux pendant 16 h un mélange de 8,0 g (0,03 mol) de (fluoro-4-benzoyl)-7-méthyl-5-indolinone-2 dans 120 ml d'hy-droxyde de sodium 3N. Après dilution à 300 ml avec de l'eau, on ajoute à la solution à 50e C de l'acide chlorhydrique concentré jusqu'à obtention d'un pH de 8,2. On filtre la solution orange obtenue A mixture of 8.0 g (0.03 mol) of (fluoro-4-benzoyl) -7-methyl-5-indolinone-2 in 120 ml of 3N sodium hydroxide is heated to reflux for 16 h. After dilution to 300 ml with water, concentrated hydrochloric acid is added to the solution at 50 ° C. until a pH of 8.2 is obtained. The orange solution obtained is filtered
2 2
5 5
10 10
15 15
20 20
25 25
30 30
35 35
40 40
45 45
50 50
55 55
60 60
65 65
3 3
651294 651294
et on refroidit le filtrat à 5 C puis on acidifie à pH 4,5 avec de l'acide acétique glacial. On recueille le solide jaune obtenu et on le lave à l'eau puis on le dissout dans le chlorure de méthylène. On ajoute de l'eau et on ajoute au mélange une solution diluée de bicarbonate de sodium jusqu'à obtention d'un pH de 7,0. On sépare la couche aqueuse puis on la concentre par distillation azéotrope de l'eau avec de l'alcool éthylique absolu. On dissout la poudre jaune obtenue dans l'alcool isopropylique et on ajoute 1 ml d'eau. On laisse le mélange reposer pendant 3 d puis on recueille le solide jaune et on le sèche à 25 : C sous un vide poussé pendant 2 d pour obtenir 1,6 g (rendement 16,5%) du composé désiré sous forme d'une poudre jaune ayant un p.f. de 140-160e C. and the filtrate is cooled to 5 ° C. and then acidified to pH 4.5 with glacial acetic acid. The yellow solid obtained is collected and washed with water and then dissolved in methylene chloride. Water is added and a dilute sodium bicarbonate solution is added to the mixture until a pH of 7.0 is obtained. The aqueous layer is separated and then concentrated by azeotropic distillation of water with absolute ethyl alcohol. The yellow powder obtained is dissolved in isopropyl alcohol and 1 ml of water is added. The mixture is left to stand for 3 d then the yellow solid is collected and dried at 25: C under high vacuum for 2 d to obtain 1.6 g (yield 16.5%) of the desired compound as a yellow powder having a pf 140-160th C.
Analyse pour C16H13FN03Na, H20: Analysis for C16H13FN03Na, H20:
Calculé: C 58,72 H 4,62 N4,28% Calculated: C 58.72 H 4.62 N 4.28%
Trouvé: C 58,71 H 4,68 N 4,26% Found: C 58.71 H 4.68 N 4.26%
Exemple 2: Example 2:
Préparation de l'amino-2-(chloro-4-benzoyl)-3-méthyl-5-phénylacé-tate de sodium Preparation of amino-2- (chloro-4-benzoyl) -3-methyl-5-phenylaceous-sodium tate
Selon le mode opératoire de l'exemple 1, un mélange de 15,5 g (0,04 mol) de (chloro-4-benzoyl)-7-méthyl-5-indolinone-2 et 160 ml d'hydroxyde de sodium 3N fournit, après recristallisation dans l'eau, 2,5 g (18%) du composé désiré sous forme d'aiguilles orange, t p.f. 262e C. " According to the procedure of Example 1, a mixture of 15.5 g (0.04 mol) of (chloro-4-benzoyl) -7-methyl-5-indolinone-2 and 160 ml of 3N sodium hydroxide provides, after recrystallization from water, 2.5 g (18%) of the desired compound in the form of orange needles, t pf 262nd C. "
Analyse pour C16H13ClN03Na: Analysis for C16H13ClN03Na:
Calculé: C 59,00 H 4,02 N4,30% Calculated: C 59.00 H 4.02 N 4.30%
Trouvé: C 58,82 H 4,09 N4,32% Found: C 58.82 H 4.09 N 4.32%
Exemple 3: Example 3:
Préparation de l'amino-2-(dichloro-2,4-benzoyl)-3-méthyl-5-phényl-acètate de sodium Preparation of amino-2- (2,4-dichloro-benzoyl) -3-methyl-5-phenyl-sodium acetate
Selon le mode opératoire de l'exemple 1, un mélange de (dichloro-2,4-benzoyl)-7-méthyl-5-indolinone-2 et d'hydroxyde de sodium 3N fournit le composé désiré. According to the procedure of Example 1, a mixture of (2,4-dichloro-2,4-benzoyl) -7-methyl-5-indolinone-2 and 3N sodium hydroxide provides the desired compound.
Exemple 4: Example 4:
Préparation de l'amino-2-(trichloro-2,3,5-benzoyl)-3-méthyl-6-phénylacétate de sodium Preparation of amino-2- (2,3,5-trichloro-benzoyl) -3-methyl-6-phenylacetate sodium
Selon le mode opératoire de l'exemple 1, un mélange de (trichloro-2, 3,5-benzoyl)-7-méthyl-4-indolinone-2 et d'hydroxyde de sodium 3N fournit le composé désiré. According to the procedure of Example 1, a mixture of (2,3-trichloro, 3,5-benzoyl) -7-methyl-4-indolinone-2 and 3N sodium hydroxide provides the desired compound.
Exemple 5: Example 5:
Préparation de l'amino-2-(chloro-4-benzoyl)-3-méthyl-4-phényl-acétate de sodium Preparation of amino-2- (chloro-4-benzoyl) -3-methyl-4-phenyl-sodium acetate
Selon le mode opératoire de l'exemple 1, un mélange de chloro-benzoyl-4-mêthyl-6-indolinone-2 et d'hydroxyde de sodium 3N fournit le composé désiré. According to the procedure of Example 1, a mixture of chloro-benzoyl-4-methyl-6-indolinone-2 and 3N sodium hydroxide provides the desired compound.
Généralement, dans le passé, les médicaments anti-inflammatoires puissants se sont révélés produire des effets secondaires graves d'hémorragies et d'ulcérations gastriques par administration orale aux animaux dans une gamme efficace. Les composés de l'invention se sont révélés avoir pour avantage de réduire la fréquence de l'irritation gastrique que l'on observe lorsqu'on les administre dans la gamme efficce pour réduire l'inflammation, par rapport à l'indomé-thacine et aux acides amino-2-benzoyl-3-phénylacétiques et leurs dérivés décrits dans le brevet des Etats-Unis d'Amérique N° 4045576. Par exemple, le composé de l'exemple 2, l'amino-2-(chloro-4-benzoyl)-3-méthyl-5-phénylacétate de sodium, s'est révélé être environ deux fois plus actif que l'indométhacine et l'amino-2-benzoyl-3-phénylacétate de sodium en ne provoquant qu'un quart de l'irritation de l'estomac que provoque l'indométhacine et environ la moitié de l'irritation de l'estomac que provoque l'amino-2-benzoyl-3-phénylacétate de sodium. Le composé de l'exemple 2 s'est révélé Generally, in the past, potent anti-inflammatory drugs have been shown to produce serious side effects of hemorrhages and gastric ulcers by oral administration to animals in an effective range. The compounds of the invention have been found to have the advantage of reducing the frequency of gastric irritation which is observed when administered in the effective range for reducing inflammation, compared to indomethacin and amino-2-benzoyl-3-phenylacetic acids and their derivatives described in United States patent No. 4045576. For example, the compound of Example 2, amino-2- (chloro-4 -benzoyl) -3-methyl-5-phenylacetate sodium, has been shown to be about twice as active as indomethacin and amino-2-benzoyl-3-phenylacetate sodium, causing only a quarter of stomach irritation caused by indomethacin and about half the stomach irritation caused by sodium amino-2-benzoyl-3-phenylacetate. The compound of Example 2 was found
avoir environ la moitié de l'activité de l'amino-2 (chloro-4-benzoyl)-3-fluoro-5-phénylacétate de sodium, mais ne provoquer qu'environ le quart de l'irritation de l'estomac que provoque ce composé. have about half the activity of sodium amino-2 (chloro-4-benzoyl) -3-fluoro-5-phenylacetate, but cause only about a quarter of the stomach irritation it causes this compound.
L'activité anti-inflammatoire a été mise en évidence sur l'animal de laboratoire selon une modification du test d'épanchement pleural au bleu Evans et au carragénane de Sancilio, L.F., « J. Pharmacol. Exp. Ther.», 168: 199-204 (1969). The anti-inflammatory activity was demonstrated on the laboratory animal according to a modification of the pleural effusion test with Evans blue and carrageenan by Sancilio, L.F., "J. Pharmacol. Exp. Ther. ", 168: 199-204 (1969).
La toxicité gastrique a été déterminée selon une modification de la méthode de Tsukada et coll., «Arzneim. Forsch.», 28: 428-438 (1978). Gastric toxicity was determined according to a modification of the method of Tsukada et al., "Arzneim. Forsch. ”, 28: 428-438 (1978).
Les composés de l'invention se comportent également comme des analgésiques selon une modification de la méthode de Collier et coll., «Brit. J. Pharmacol. Chemother.», 32: 295-310 (1968). The compounds of the invention also behave as analgesics according to a modification of the method of Collier et al., "Brit. J. Pharmacol. Chemother. ", 32: 295-310 (1968).
Formulation et administration Formulation and administration
L'invention concerne également de nouvelles compositions contenant les composés de l'invention comme ingrédients actifs. On peut administrer de diverses façons des quantités efficaces de l'un des composés à activité pharmacologique précédents, par exemple par voie orale sous forme de capsules ou de comprimés, par voie pa-rentérale sous forme de solutions ou de suspensions stériles et dans certains cas par voie intraveineuse sous forme de solutions stériles. Pour former les nouvelles compositions de l'invention, on incorpore l'ingrédient actif à un véhicule approprié, par exemple un véhicule pharmaceutique. Des véhicules pharmaceutiques appropriés utiles pour préparer les compositions de l'invention comprennent l'amidon, la gélatine, le glucose, le carbonate de magnésium, le lactose, le malt et similaires. Les compositions liquides entrent également dans le cadre de l'invention, et des véhicules pharmaceutiques liquides appropriés comprennent l'alcool éthylique, le propylèneglycol, la glycérine, le sirop de glucose et similaires. The invention also relates to new compositions containing the compounds of the invention as active ingredients. Effective amounts of any of the foregoing pharmacologically active compounds can be administered in various ways, for example, orally in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. To form the new compositions of the invention, the active ingredient is incorporated into an appropriate vehicle, for example a pharmaceutical vehicle. Suitable pharmaceutical vehicles useful for preparing the compositions of the invention include starch, gelatin, glucose, magnesium carbonate, lactose, malt and the like. Liquid compositions also fall within the scope of the invention, and suitable liquid pharmaceutical vehicles include ethyl alcohol, propylene glycol, glycerin, glucose syrup and the like.
On peut de façon avantageuse utiliser les composés à activité pharmacologique sous forme de doses unitaires contenant 0,1 à 150 mg de composé actif. On peut administrer les doses unitaires une fois par jour ou en prises journalières multiples ou divisées. La posologie journalière peut varier entre 0,3 et 450 mg. Une dose unitaire de 25 mg semble optimale. The compounds with pharmacological activity can advantageously be used in the form of unit doses containing 0.1 to 150 mg of active compound. Unit doses can be administered once a day or in multiple or divided daily doses. The daily dosage can vary between 0.3 and 450 mg. A unit dose of 25 mg seems optimal.
Il suffit que l'ingrédient actif constitue une quantité efficace, c'est-à-dire que l'on obtienne une posologie appropriée convenant à la forme d'administration. Les posologies individuelles exactes ainsi que les doses journalières doivent bien sûr être déterminées selon les principes médicaux classiques sous la direction d'un médecin ou d'un vétérinaire. It is sufficient that the active ingredient constitutes an effective amount, that is to say that one obtains an appropriate dosage suitable for the form of administration. The exact individual dosages as well as the daily doses should of course be determined according to conventional medical principles under the guidance of a doctor or veterinarian.
Les agents actifs de l'invention peuvent être combinés à d'autres agents à activité pharmacologique ou à des tampons, antiacides et similaires, pour leur adminsitration, et la proportion de l'agent actif dans la composition peut varier beaucoup. The active agents of the invention can be combined with other agents with pharmacological activity or with buffers, antacids and the like, for their administration, and the proportion of the active agent in the composition can vary widely.
Des exemples de compositions formées selon l'invention figurent ci-après. Examples of compositions formed according to the invention appear below.
1. Capsules 1. Capsules
On prépare des capsules contenant 5 mg, 25 mg ou 50 mg d'ingrédient actif par capsule. Pour les quantités supérieures à 5 mg d'ingrédient actif, on peut ajuster la quantité de lactose. Capsules containing 5 mg, 25 mg or 50 mg of active ingredient per capsule are prepared. For amounts greater than 5 mg of active ingredient, the amount of lactose can be adjusted.
Mélange typique pour l'encapsulation Par capsule (mg) Typical mixture for encapsulation Per capsule (mg)
Ingrédient actif 5,0 Active ingredient 5.0
Lactose 296,7 Lactose 296.7
Amidon 129,0 Starch 129.0
Stéarate de magnésium 4,3 Magnesium stearate 4.3
Total: 435,0 Total: 435.0
Une autre composition pour capsules contenant une quantité plus élevée d'ingrédient actif est la suivante: Another composition for capsules containing a higher amount of active ingredient is as follows:
Ingrédients Par capsule (mg) Ingredients Per capsule (mg)
Ingrédient actif 25,0 Active ingredient 25.0
Lactose 306,5 Lactose 306.5
Amidon 99,2 Starch 99.2
Stéarate de magnésium 4,3 Magnesium stearate 4.3
Total: 435,0 Total: 435.0
5 5
10 10
15 15
20 20
25 25
30 30
35 35
40 40
45 45
50 50
55 55
60 60
65 65
651 294 651,294
4 4
Dans chaque cas, on mélange uniformément l'ingrédient actif choisi avec le lactose, l'amidon et le stéarate de magnésium, et on encapsule le mélange. In each case, the active ingredient chosen is uniformly mixed with the lactose, starch and magnesium stearate, and the mixture is encapsulated.
2. Comprimés 2. Tablets
Une composition typique pour obtenir un comprimé contenant 5,0 mg d'ingrédient actif par comprimé est la suivante. On peut utiliser cette composition avec d'autres quantités d'ingrédient actif en ajustant le poids du phosphate dicalcique. A typical composition for obtaining a tablet containing 5.0 mg of active ingredient per tablet is as follows. This composition can be used with other amounts of active ingredient by adjusting the weight of the dicalcium phosphate.
Par comprimé (mg) Per tablet (mg)
1. Ingrédient actif 5,0 1. Active ingredient 5.0
2. Amidon de maïs 13,6 2. Corn starch 13.6
3. Amidon de maïs (empois) 3,4 3. Corn starch (poison) 3,4
4. Lactose 79,2 4. Lactose 79.2
5. Phosphate dicalcique 68,0 5. Dicalcium phosphate 68.0
6. Stéarate de calcium 0,9 6. Calcium stearate 0.9
Total: 170,1 Total: 170.1
Mélanger uniformément 1, 2, 4 et 5. Préparer 3 sous la forme d'un empois à 10% dans l'eau. Granuler le mélange avec l'empois d'amidon et faire passer la masse humide à travers un tamis de 2,38 mm d'ouverture de maille. On sèche les granulés humides et on 5 les fait passer à travers un tamis de 1,41 mm d'ouverture de maille. On mélange les granulés séchés avec le stéarate de calcium et on presse. Mix 1, 2, 4 and 5 evenly. Prepare 3 as a 10% paste in water. Granulate the mixture with the starch paste and pass the wet mass through a 2.38 mm mesh screen. The wet granules are dried and passed through a 1.41 mm mesh screen. The dried granules are mixed with the calcium stearate and pressed.
3. Solutions injectables stériles à 2% Par cm3 3. Sterile injectable solutions at 2% Per cm3
io Ingrédient actif 20 mg io Active ingredient 20 mg
Conservateur, par exemple chlorobutanol 0,5% p/v Preservative, for example chlorobutanol 0.5% w / v
Eau injectable q.s. Water for injection q.s.
Préparer la solution, clarifier par filtration, conditionner en flacons, boucher et autoclaver. Prepare the solution, clarify by filtration, condition in bottles, stopper and autoclave.
'5 Bien entendu, diverses modifications peuvent être apportées par l'homme de l'art aux dispositifs ou procédés qui viennent d'être décrits uniquement à titre d'exemples non limitatifs sans sortir du cadre de l'invention. Of course, various modifications can be made by those skilled in the art to the devices or methods which have just been described only by way of nonlimiting examples without departing from the scope of the invention.
Claims (7)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23453181A | 1981-02-17 | 1981-02-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH651294A5 true CH651294A5 (en) | 1985-09-13 |
Family
ID=22881752
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH791/82A CH651294A5 (en) | 1981-02-17 | 1982-02-09 | AMINO-2-HALOGENOBENZOYL-3-METHYLPHENYLACETIC ACIDS AND THEIR ESTERS AND SALTS USEFUL AS ANTI-INFLAMMATORY AND ANALGESIC DRUGS. |
Country Status (32)
| Country | Link |
|---|---|
| JP (1) | JPS57149256A (en) |
| KR (1) | KR880002289B1 (en) |
| AT (1) | AT387213B (en) |
| AU (1) | AU7950382A (en) |
| BE (1) | BE892156A (en) |
| CA (1) | CA1173852A (en) |
| CH (1) | CH651294A5 (en) |
| DE (1) | DE3204854C2 (en) |
| DK (1) | DK155936C (en) |
| EG (1) | EG15798A (en) |
| ES (1) | ES509622A0 (en) |
| FI (1) | FI73970C (en) |
| FR (1) | FR2499981B1 (en) |
| GB (1) | GB2093027B (en) |
| GR (1) | GR76516B (en) |
| HK (1) | HK90384A (en) |
| HU (1) | HU187644B (en) |
| IE (1) | IE52289B1 (en) |
| IL (1) | IL64724A0 (en) |
| IT (1) | IT1157001B (en) |
| KE (1) | KE3454A (en) |
| LU (1) | LU83928A1 (en) |
| MY (1) | MY8500908A (en) |
| NL (1) | NL8200607A (en) |
| NO (1) | NO160133C (en) |
| NZ (1) | NZ199745A (en) |
| PL (1) | PL139815B1 (en) |
| PT (1) | PT74441B (en) |
| SE (1) | SE453387B (en) |
| SG (1) | SG68584G (en) |
| YU (1) | YU44333B (en) |
| ZA (1) | ZA82697B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4683242A (en) * | 1985-10-28 | 1987-07-28 | A. H. Robins Company, Incorporated | Transdermal treatment for pain and inflammation with 2-amino-3-aroylbenzeneacetic acids, salts and esters |
| US5475034A (en) * | 1994-06-06 | 1995-12-12 | Alcon Laboratories, Inc. | Topically administrable compositions containing 3-benzoylphenylacetic acid derivatives for treatment of ophthalmic inflammatory disorders |
| 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 |
| 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 (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 GR GR67320A patent/GR76516B/el unknown
- 1982-02-15 SE SE8200891A patent/SE453387B/en unknown
- 1982-02-15 YU YU325/82A patent/YU44333B/en unknown
- 1982-02-16 NZ NZ199745A patent/NZ199745A/en unknown
- 1982-02-16 ES ES509622A patent/ES509622A0/en active Granted
- 1982-02-16 HU HU82464A patent/HU187644B/en unknown
- 1982-02-16 BE BE0/207327A patent/BE892156A/en not_active IP Right Cessation
- 1982-02-16 KR KR8200673A patent/KR880002289B1/en active
- 1982-02-16 NL NL8200607A patent/NL8200607A/en not_active Application Discontinuation
- 1982-02-16 CA CA000396392A patent/CA1173852A/en not_active Expired
- 1982-02-16 PL PL1982235095A patent/PL139815B1/en unknown
- 1982-02-16 NO NO820468A patent/NO160133C/en unknown
- 1982-02-16 DK DK067382A patent/DK155936C/en not_active IP Right Cessation
- 1982-02-16 FR FR8202507A patent/FR2499981B1/en not_active Expired
- 1982-02-16 PT PT74441A patent/PT74441B/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
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FR2493322A1 (en) | CRYSTALLINE HYDRATES OF DIOXO-1,1 PENICILLANOYLOXYMETHYL (D-A-AMINO A-PHENYLACETAMIDO) -6 PENICILLANATE USEFUL AS ANTIMICROBIAL MEDICAMENTS AND METHODS OF THEIR PREPARATION | |
| BE898570A (en) | New carboxylic amides and imides, processes for their preparation and pharmaceutical composition containing them. | |
| FR2532843A1 (en) | PHARMACEUTICAL COMPOSITION COMPRISING PHYTOL OR ISOPHYTOL AS ACTIVE INGREDIENT | |
| CH651294A5 (en) | AMINO-2-HALOGENOBENZOYL-3-METHYLPHENYLACETIC ACIDS AND THEIR ESTERS AND SALTS USEFUL AS ANTI-INFLAMMATORY AND ANALGESIC DRUGS. | |
| CH648285A5 (en) | BENZOYL-3-NITRO-2-PHENYLACETIC ACIDS AND METAL SALTS, AMIDES AND RELATED ESTERS USEFUL IN PARTICULAR AS ANTI-INFLAMMATORY DRUGS, PROCESS AND COMPOUNDS FOR THEIR PREPARATION. | |
| CA1216859A (en) | Process for preparing new 4-phenyl 4-oxo buten-2-oic acid derivatives | |
| FR2476071A1 (en) | NOVEL 2-AMINO-3- (A-HYDROXYBENZYL) -PHENYLACETIC ACIDS AND THEIR ESTERS AND AMIDES, PARTICULARLY USEFUL AS ANTI-INFLAMMATORY AGENTS, AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME | |
| CH655924A5 (en) | DERIVATIVES OF 4-PHENYL 4-OXO 2-BUTENOIC ACID, THEIR SALTS, THEIR PREPARATION, MEDICAMENTS AND COMPOSITIONS CONTAINING THEM. | |
| CH646138A5 (en) | AMINO-2-BENZOYL-3-PHENYLACETAMIDES AND THEIR CYCLIC APPROVALS USEFUL AS MEDICINAL PRODUCTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. | |
| FR2489318A1 (en) | ((1-BENZYL-1H-INDAZOL-3-YL) OXY) ACETIC ACID SALT WITH LYSINE | |
| CH658053A5 (en) | DERIVATIVE OF PYRAZOLO (1,5-A) PYRIDINE ITS PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING IT. | |
| BE1003692A4 (en) | COMPOUNDS AND PYRROLIDINONE piperidinone AND PHARMACEUTICAL COMPOSITIONS CONTAINING. | |
| EP0001947A1 (en) | 2-Amino-thiazoline derivatives, their preparation and their use in pharmaceutical preparations | |
| CH648295A5 (en) | 2-AMINO-3- (ALKYLTHIOBENZYL) -PHENYLACETIC ACIDS AND THEIR DERIVATIVES. | |
| LU82333A1 (en) | PREPARATION OF HYDROXYL DERIVATIVES OF ISOPROPYL-AMINO-PYRIMIDINE | |
| FR2651129A1 (en) | New cysteine derivatives; pharmaceutical or cosmetic compositions containing them | |
| BE882414A (en) | NOVEL 4-AMINO-3-QUINOLEINE-CARBOXYLIC ACIDS AND ESTERS, ESPECIALLY USEFUL AS ANTISECRETORY AND ANTI-ULCER AGENTS | |
| CH635319A5 (en) | THERAPEUTICALLY ACTIVE OXANILIC ACID DERIVATIVES. | |
| FR2487196A1 (en) | PHARMACEUTICAL COMPOSITION PRODUCING DIURETIC, HYPOTENSE AND ANTI-EDEMATOUS EFFECTS BASED ON QUINOLINE DERIVATIVE | |
| CA1189526A (en) | Process for preparing new aminated 4-phenyl 4-oxo 2-butenoic acid derivatives and their salts | |
| FR2573071A1 (en) | 2-[N-(2-Hydroxy-1,1-dimethylethyl)amino]-1-phenylethanol which is useful, in particular, as an anti-inflammatory, and process for preparing it | |
| LU84427A1 (en) | AS MEDICINES, CERTAIN MONO DERIVATIVES SUBSTITUTED FOR 4-PHENYL 4-OXO BUTEN-2-OIQUE, AND THE COMPOSITIONS CONTAINING THEM | |
| JPH0138085B2 (en) | ||
| DE2726210A1 (en) | Hypoglycaemic 2-phenylalkyl-hydrazono-propionic acid derivs. - with minimal mono:amine oxidase inhibitory activity | |
| FR2532847A1 (en) | Pharmaceutical composition comprising 3,7,11,15-tetramethyl-1-hexadecen-3-ol as active principle |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PFA | Name/firm changed |
Owner name: A. H. ROBINS COMPANY, INCORPORATED (A DELAWARE COR |
|
| PUE | Assignment |
Owner name: AHP SUBSIDIARY (9) CORPORATION |
|
| PL | Patent ceased |