LU83928A1 - AMINO-2 HALOGENOBENZOYL-3 METHYPHENYLACETIC ACIDS AND THEIR ESTERS AND SALTS USEFUL AS ANTI-INFLAMMATORY AND ANALGESIC DRUGS - Google Patents
AMINO-2 HALOGENOBENZOYL-3 METHYPHENYLACETIC ACIDS AND THEIR ESTERS AND SALTS USEFUL AS ANTI-INFLAMMATORY AND ANALGESIC DRUGS Download PDFInfo
- Publication number
- LU83928A1 LU83928A1 LU83928A LU83928A LU83928A1 LU 83928 A1 LU83928 A1 LU 83928A1 LU 83928 A LU83928 A LU 83928A LU 83928 A LU83928 A LU 83928A LU 83928 A1 LU83928 A1 LU 83928A1
- Authority
- LU
- Luxembourg
- Prior art keywords
- amino
- benzoyl
- compounds
- methyl
- acids
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims description 6
- 230000003110 anti-inflammatory effect Effects 0.000 title claims description 5
- 229940035676 analgesics Drugs 0.000 title claims description 4
- 239000000730 antalgic agent Substances 0.000 title claims description 4
- 150000007513 acids Chemical class 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 31
- -1 2-amino (4-fluoro-benzoyl) Chemical group 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 5
- 150000001768 cations Chemical class 0.000 claims description 3
- 230000001760 anti-analgesic effect Effects 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims 1
- 229940121363 anti-inflammatory agent Drugs 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000002547 new drug Substances 0.000 claims 1
- 229960003424 phenylacetic acid Drugs 0.000 claims 1
- 239000003279 phenylacetic acid Substances 0.000 claims 1
- DGPIGKCOQYBCJH-UHFFFAOYSA-M sodium;acetic acid;hydroxide Chemical compound O.[Na+].CC([O-])=O DGPIGKCOQYBCJH-UHFFFAOYSA-M 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 22
- 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 10
- 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
- 241001465754 Metazoa Species 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
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 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
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 229940049953 phenylacetate Drugs 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000008174 sterile solution Substances 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 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
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 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
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical class OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- YBNYPWAZNIKXNI-UHFFFAOYSA-N 1-(4-chlorobenzoyl)-6-methyl-3H-indol-2-one Chemical compound ClC1=CC=C(C(=O)N2C(CC3=CC=C(C=C23)C)=O)C=C1 YBNYPWAZNIKXNI-UHFFFAOYSA-N 0.000 description 1
- 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
- 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
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000001243 acetic acids Chemical class 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
- SOYCMDCMZDHQFP-UHFFFAOYSA-N amfenac Chemical compound NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=CC=C1 SOYCMDCMZDHQFP-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 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
- 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
- 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
- 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
- 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
- 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
- HZOREEUASZHZBI-UHFFFAOYSA-M sodium;2-phenylacetate Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1 HZOREEUASZHZBI-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
-
- 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
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- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
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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
- 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
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- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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- A—HUMAN NECESSITIES
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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
- 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
La présente invention concerne des acides araino-2 halogénobenzoyl-3 méthylphénylacétiques et leurs esters et sels utiles comme médicaments anti-inflammatoires et analgésiques.The present invention relates to araino-2 halobenzoyl-3 methylphenylacetic acids and their esters and salts useful as anti-inflammatory and analgesic drugs.
Certains acides amino-2 benzoyl-3 (-5 et -6) phényl-5 acétiques 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° 4 045 576. Les composés de cette référence ne sont pas des acides méthylphénylacétiques ni des dérivés de tels acides.Certain 2-amino-benzoyl-3 (-5 and -6) phenyl-5 acetic acids whose benzoyl and phenyl fragments carry various substituents, as well as processes for their preparation and their use, are described in the United States patent. 'America No. 4,045,576. The compounds of this reference are not methylphenylacetic acids or derivatives of such acids.
10 Le brevet des Etats-Unis d'Amérique n° 4 221 716 décrit . . un procédé de préparation d'acyl-7 indolinones-2 qui sont des intermédiaires utiles dans la préparation des composés de l'invention.US Patent No. 4,221,716 describes. . a process for the preparation of acyl-7 indolinones-2 which are intermediates useful in the preparation of the compounds of the invention.
L'invention concerne plus particulièrement des acides amino-2 halogénobenzoyl-3 méthylphénylacétiques ainsi que leurs 15 esters alkyliques et leurs sels métalliques répondant à la formule :The invention relates more particularly to 2-amino-3-halobenzoyl-methylphenylacetic acids as well as their alkyl esters and their metal salts corresponding to the formula:
CH COORCH COOR
C=0 XC = 0 X
& 20 (Y) · n * dans laquelle : ‘ R représente un atome d'hydrogène, un radical alkyle inférieur ou un cation métallique acceptable en pharmacie, ; Y représente un atome d'halogène, et 25 n est 1, 2 ou 3.& 20 (Y) · n * in which: ‘R represents a hydrogen atom, a lower alkyl radical or a metal cation acceptable in pharmacy,; Y represents a halogen atom, and 25 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 antiinflammatoire et analgésique chez les animaux à aang chaud avec une 30 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.
2 L'invention a donc pour objet : de nouveaux composés et de nouvelles compositions; et un nouveau procédé pour traiter des animaux, et en particulier des mammifères, afin de soulager l'inflammation et la 5 douleur avec un minimum d'effets gastro-intestinaux indésirables.2 The subject of the invention is therefore: new compounds and new compositions; and a new method for treating animals, and in particular mammals, to relieve inflammation and pain with minimal 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 précédem-10 ment indiqués avec les définitions correspondantes, des compositions pharmaceutiques contenant les composés de formule I et l'utilisation des composés de formule I chez des animaux en raison de leurs effets pharmacologiques comme indiqué précédemment et ci-après.The invention encompasses the compounds of formula I previously indicated with the corresponding definitions, pharmaceutical compositions containing the compounds of formula I and the use of the compounds of formula I in animals because of their pharmacological effects as indicated above and below.
Dans la définition des symboles des formules et partout 15 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 20 radicaux méthyle, éthyle, propyle, isopropyle, butyle, sec-butyle, tert-butyle, pentyle, isopentyle et hexyle.The term "lower alkyl" denotes 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, dry radicals -butyl, 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 25 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 cations and their hydrates.
On prépare de façon pratique les composés de l'invention à partir d'une benzoyl-7 méthylindolinone-2 de formule : ™3-ÎO] 1The compounds of the invention are prepared in practice from a 7-benzoyl-methylindolinone-2 of formula: ™ 3-ÎO] 1
0=C H0 = C H
(ï)„ 3° 3 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 n° 4 045 576 et n° 4 221 716 précités. On prépare les composés de l'invention par 5 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 correspondants, on transforme l'acide en un sel métallique que l'on fait ensuite réagir dans un solvant approprié avec un halo-10 génure d'alkyle pour former l'ester désiré.(ï) „3 ° 3 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 aforementioned US Pat. Nos. 4,045,576 and No. 4,221,716. The compounds of the invention are prepared by hydrolysis of the 7-benzoyl-2-methylindolinones 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 to 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 1EXAMPLE 1
Préparation de l'amino-2 (fluoro-4 benzoyl)-3 méthyl-5 phénylacétate 15 de sodium monohydraté.Preparation of 2-amino (4-fluoro benzoyl) -3 5-methyl-phenylacetate sodium monohydrate.
On chauffe à reflux pendant 16 h un mélange de 8,0 g (0,03 mole) de (fluoro-4 benzoyl)-7 méthyl-5 indolinone-2 dans 120 ml d'hydroxyde de sodium 3 N. Après dilution à 300 ml avec de l'eau, on ajoute à la solution à 50°C de l'acide chlorhydrique concentré 20 jusqu'à obtention d'un pH de 8,2. On filtre la solution orange obtenue 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.A mixture of 8.0 g (0.03 mole) of (4-fluoro-benzoyl) -7-methyl-indolinone-2 in 120 ml of 3 N sodium hydroxide is heated at 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 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.
On ajoute de l'eau et on ajoute au mélange une solution diluée de ' 25 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.Water is added and a dilute solution of sodium bicarbonate 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.
On laisse le mélange reposer pendant 3 jours puis on recueille le 30 solide jaune et on le sèche à 25°C sous un vide poussé pendant 2 jours pour obtenir 1,6 g (rendement 16,5%) du composé désiré sous forme d'une poudre jaune ayant un point de fusion de 140-160°C.The mixture is left to stand for 3 days, then the yellow solid is collected and dried at 25 ° C. under high vacuum for 2 days to obtain 1.6 g (yield 16.5%) of the desired compound as a yellow powder having a melting point of 140-160 ° C.
Analyse : Théorique pour C^gH^FNO^Na,Η^Ο : C 58,72 ; H 4,62 ; N 4,28 Trouvée : C 58,71 ; H 4,68 ; N 4,26 4 EXEMPLE 2Analysis: Theoretical for C ^ gH ^ FNO ^ Na, Η ^ Ο: C 58.72; H 4.62; N 4.28 Found: C 58.71; H 4.68; N 4.26 4 EXAMPLE 2
Préparation de l'amino-2 (chloro-4 benzoyl)-3 méthyl-5 phénylacétate de sodium.Preparation of 2-amino (4-chloro-benzoyl) -3 5-methyl-phenylacetate sodium.
Selon le mode opératoire de l'exemple 1} un mélange de 5 15,5 g (0,04 mole) de (chloro-4 benzoyl)-7 méthyl-5 indolinone-2 et 160 ml d'hydroxyde de sodium 3 N fournit, après recristallisation dans l'eau, 2,5 g (187=) du composé désiré sous forme d'aiguilles , oranges, F, 262°C.According to the procedure of Example 1} a mixture of 5 15.5 g (0.04 mole) of (4-chloro-benzoyl) -7 methyl-5 indolinone-2 and 160 ml of 3 N sodium hydroxide provides , after recrystallization from water, 2.5 g (187 =) of the desired compound in the form of needles, oranges, mp, 262 ° C.
, Analyse : Théorique pour C^gH^ClNO^Na ; C 59,00 ; H 4,02 ; N 4,30 10 Trouvée : C 58,82 ; H 4,09 ; N 4,32 EXEMPLE 3, Analysis: Theoretical for C ^ gH ^ ClNO ^ Na; C 59.00; H 4.02; N 4.30 10 Found: C 58.82; H 4.09; N 4.32 EXAMPLE 3
Préparation de l'amino-2 (dichloro-2,4 benzoyl)-3 méthyl-5 phénylacétate de sodium.Preparation of 2-amino (2,4-dichloro-benzoyl) -3 5-methyl-phenylacetate sodium.
Selon le mode opératoire de l'exemple 1, un mélange de 15 (dichloro-2,4 benzoyl)-7 méthyl-5 indolinone-2 et d'hydroxyde de sodium 3 N fournit le composé désiré, EXEMPLE 4According to the procedure of Example 1, a mixture of 15 (2,4-dichloro-benzoyl) -7-methyl-2 indolinone-2 and 3 N sodium hydroxide provides the desired compound, EXAMPLE 4
Préparation de l'amino-2 (trichloro-2,3,5 benzoyl)-3 méthyl-6 phénylacétate de sodium.Preparation of 2-amino (2,3,5-trichloro-benzoyl) -3 methyl-6 phenylacetate sodium.
20 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 3 N fournit le composé désiré.According to the procedure of Example 1, a mixture of (2,3,5-trichloro-benzoyl) -7-methyl-2-indolinone and 3 N sodium hydroxide provides the desired compound.
EXEMPLE 5EXAMPLE 5
Préparation de l'amino-2 (chloro-4 benzoyl)-3 méthyl-4 phénylacétate ' 25 de sodium.Preparation of sodium amino-2 (4-chloro-benzoyl) -3-methyl-4-phenylacetate.
Selon le mode opératoire de l'exemple 1, un mélange de chlorobenzoyl-4 méthyl-6 indolinone-2 et d'hydroxyde de sodium 3 N fournit le composé désiré.According to the procedure of Example 1, a mixture of 4-chlorobenzoyl-6 methyl-2 indolinone and 3 N sodium hydroxide provides the desired compound.
Généralement, dans le passé, les médicaments anti-30 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 5 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 efficace pour réduire l'inflammation, par rapport à 1'indométhacine et aux acides amino-2 benzoyl-3 phényl-5 acétiques et leurs dérivés décrits dans le brevet des Etats-Unis d'Amérique n° 4 045 576. 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 1'indométhacine et l'amino-2 benzoyl-3 phénylacétate de sodium en ne provoquant 10 qu'un quart de l'irritation de l'estomac que provoque 1'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 avoir environ la moitié de l'activité de l'amino-2 (chloro-4 benzoyl)-3 fluoro-5 phénylacétate de sodium, mais ne 15 provoquer qu'environ le quart de l'irritation de l'estomac que provoque ce composé.Generally, in the past, potent anti-inflammatory drugs have been shown to produce severe side effects of hemorrhages and gastric ulcers by oral administration to animals in an effective range. The compounds of the invention have been shown to have the advantage of reducing the frequency of gastric irritation observed when administered in the range effective to reduce inflammation, compared to indomethacin and 2-amino-3-benzoyl-5-phenylacetic acids and their derivatives described in US Pat. No. 4,045,576. For example, the compound of Example 2, amino-2 (chloro- Sodium benzoyl) -3 methyl-5 phenylacetate, has been shown to be approximately twice as active as indomethacin and sodium amino-2 benzoyl-3 phenylacetate, causing only a quarter of the irritation of the stomach caused by indomethacin and about half of the stomach irritation caused by 2-amino-3-benzoyl-phenylacetate. The compound of Example 2 was found to have about half the activity of sodium amino-2 (4-chloro-benzoyl) -5 fluoro-phenylacetate, but to cause only about a quarter of stomach irritation caused by 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 carragéénane de Sancilio, L.F., 20 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., 20 J. Pharmacol. Exp. Ther. 168: 199-204 (1969).
La toxicité gastrique a été déterminée selon une modification de la méthode de Tsukada et coli., 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 25 comme des analgésiques selon une modification de la méthode de Collier et coli., Brit. J. Pharmacol. Chemoter. 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. Jogging. 32: 295-310 (1968),
Formulation et administration L'invention concerne également de nouvelles compositions contenant les composés de l'invention comme ingrédients actifs. On 30 peut administrer à un animal vivant de diverses façons des quantités efficaces de l'un quelconque des composés à activité pharmacologique précédents, par exemple par voie orale sous forme de capsules ou de comprimés, par voie parentérale sous forme de solutions ou de suspensions stériles et dans certains cas par voie intraveineuse sous 35 forme de solutions stériles. Pour former les nouvelles compositions 6 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 5 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.Formulation and administration The invention also relates to new compositions containing the compounds of the invention as active ingredients. A living animal can be administered in various ways effective amounts of any of the foregoing pharmacologically active compounds, for example, orally in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions and in some cases intravenously as sterile solutions. To form the new compositions 6 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. similar.
10 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.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.
La posologie journalière peut varier entre 0,3 et 450 mg. Une dose 15 unitaire de 25 mg semble optimale.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 déter-20 minées 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 des tampons, antiacides et similaires, pour leur administration, et la proportion de 25 l'agent actif dans la composition peut varier beaucoup.The active agents of the invention can be combined with other pharmacologically active agents or 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. Capsules1. Capsules
On prépare des capsules contenant 5 mg, 25 mg ou 50 mg 30 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 5,0Active ingredient 5.0
Lactose 296,7 35 Amidon 129,0Lactose 296.7 35 Starch 129.0
Stéarate de magnésium 4,3Magnesium stearate 4.3
Total : 435,0 7Total: 435.0 7
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 5 Lactose 306,5Active ingredient 25.0 5 Lactose 306.5
Amidon 99,2Starch 99.2
Stéarate de magnésium 4,3Magnesium stearate 4.3
Total : 435,0Total: 435.0
Dans chaque cas, on mélange uniformément l'ingrédient 10 actif choisi avec le lactose, l'amidon et le stéarate de magnésium et on encapsule le mélange.In each case, the selected active ingredient is mixed uniformly with lactose, starch and magnesium stearate and the mixture is encapsulated.
2. Comprimés2. Tablets
Une composition typique pour obtenir un comprimé contenant 5,0 mg d'ingrédient actif par comprimé est la suivante. On peut utiliser 15 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 (1) Ingrédient actif 5,0 (2) Amidon de maïs 13,6 20 (3) Amidon de maïs (empois) 3,4 (4) Lactose 79,2 (5) Phosphate dicalcique 68,0 (6) Stéarate de calcium 0,9 170,1 * 25 Mélanger uniformément 1, 2, 4 et 5. Préparer 3 sous forme d'un empois à 10¾ 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 les fait passer à travers un tamis de 1,41 mm d'ouverture de maille.Per tablet, mg (1) Active ingredient 5.0 (2) Corn starch 13.6 20 (3) Corn starch (poison) 3.4 (4) Lactose 79.2 (5) Dicalcium phosphate 68.0 ( 6) Calcium stearate 0.9 170.1 * 25 Mix evenly 1, 2, 4 and 5. Prepare 3 in the form of a paste at 10¾ 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.
30 On mélange les granulés séchés avec le stéarate de calcium et on presse.The dried granules are mixed with the calcium stearate and pressed.
δ 3. Solutions inîectables stériles à 2% „ 3δ 3. Sterile 2% sterile solutions „3
Par cmPer cm
Ingrédient actif 20 mgActive ingredient 20 mg
Conservateur, par exemple chlorobutanol 0,5% p/v 5 Eau injectable q.s.Preservative, for example chlorobutanol 0.5% w / v 5 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.
»"
Bien entendu, divèrses modifications peuvent être apportées par l'homme de l'art aux dispositifs ou procédés qui viennent d'être 10 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 (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23453181A | 1981-02-17 | 1981-02-17 | |
| US23453181 | 1981-02-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| LU83928A1 true LU83928A1 (en) | 1983-06-07 |
Family
ID=22881752
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LU83928A LU83928A1 (en) | 1981-02-17 | 1982-02-09 | AMINO-2 HALOGENOBENZOYL-3 METHYPHENYLACETIC ACIDS AND THEIR ESTERS AND SALTS USEFUL AS ANTI-INFLAMMATORY AND ANALGESIC DRUGS |
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| AT (1) | AT387213B (en) |
| AU (1) | AU7950382A (en) |
| BE (1) | BE892156A (en) |
| CA (1) | CA1173852A (en) |
| CH (1) | CH651294A5 (en) |
| DE (1) | DE3204854C2 (en) |
| DK (1) | DK155936C (en) |
| EG (1) | EG15798A (en) |
| ES (1) | ES8301895A1 (en) |
| FI (1) | FI73970C (en) |
| FR (1) | FR2499981B1 (en) |
| GB (1) | GB2093027B (en) |
| GR (1) | GR76516B (en) |
| HK (1) | HK90384A (en) |
| HU (1) | HU187644B (en) |
| IE (1) | IE52289B1 (en) |
| IL (1) | IL64724A0 (en) |
| IT (1) | IT1157001B (en) |
| KE (1) | KE3454A (en) |
| LU (1) | LU83928A1 (en) |
| MY (1) | MY8500908A (en) |
| NL (1) | NL8200607A (en) |
| NO (1) | NO160133C (en) |
| NZ (1) | NZ199745A (en) |
| PL (1) | PL139815B1 (en) |
| PT (1) | PT74441B (en) |
| SE (1) | SE453387B (en) |
| SG (1) | SG68584G (en) |
| YU (1) | YU44333B (en) |
| ZA (1) | ZA82697B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4683242A (en) * | 1985-10-28 | 1987-07-28 | A. H. Robins Company, Incorporated | Transdermal treatment for pain and inflammation with 2-amino-3-aroylbenzeneacetic acids, salts and esters |
| US5475034A (en) * | 1994-06-06 | 1995-12-12 | Alcon Laboratories, Inc. | Topically administrable compositions containing 3-benzoylphenylacetic acid derivatives for treatment of ophthalmic inflammatory disorders |
| BR9600975A (en) * | 1996-03-11 | 1997-12-30 | Fundacao Oswaldo Cruz | Derivatives of gem-difluorphenylacetic acid and gem-difluorphenylacetamide process of their preparation and their pharmaceutical applications |
| US6034266A (en) * | 1996-03-11 | 2000-03-07 | Fundacao Oswaldo Cruz-Fiocruz | Gem-difluoro derivative of phenylacetamide and phenylacetic acid and their pharmaceutical uses |
| AR030345A1 (en) * | 2000-08-14 | 2003-08-20 | Alcon Inc | METHOD OF TREATMENT OF DISORDERS RELATED TO ANGIOGENESIS |
| AR030346A1 (en) | 2000-08-14 | 2003-08-20 | Alcon Inc | METHOD OF TREATMENT OF NEURODEGENERATIVE DISORDERS OF THE RETINA AND HEAD OF OPTICAL NERVE |
| 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 CH CH791/82A patent/CH651294A5/en not_active IP Right Cessation
- 1982-02-09 LU LU83928A patent/LU83928A1/en unknown
- 1982-02-10 IT IT67152/82A patent/IT1157001B/en active
- 1982-02-11 DE DE3204854A patent/DE3204854C2/en not_active Expired - Fee Related
- 1982-02-12 GB GB8204137A patent/GB2093027B/en not_active Expired
- 1982-02-15 IE IE310/82A patent/IE52289B1/en not_active IP Right Cessation
- 1982-02-15 YU YU325/82A patent/YU44333B/en unknown
- 1982-02-15 GR GR67320A patent/GR76516B/el unknown
- 1982-02-15 SE SE8200891A patent/SE453387B/en unknown
- 1982-02-16 KR KR8200673A patent/KR880002289B1/en active
- 1982-02-16 ES ES509622A patent/ES8301895A1/en not_active Expired
- 1982-02-16 BE BE0/207327A patent/BE892156A/en not_active IP Right Cessation
- 1982-02-16 FR FR8202507A patent/FR2499981B1/en not_active Expired
- 1982-02-16 PL PL1982235095A patent/PL139815B1/en unknown
- 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 NZ NZ199745A patent/NZ199745A/en unknown
- 1982-02-16 PT PT74441A patent/PT74441B/en not_active IP Right Cessation
- 1982-02-16 HU HU82464A patent/HU187644B/en unknown
- 1982-02-16 DK DK067382A patent/DK155936C/en not_active IP Right Cessation
- 1982-02-16 NO NO820468A patent/NO160133C/en unknown
-
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
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