SE453387B - 2-AMINO-3- (HALOGENEBENZOYL) -METHYLPHENYLETIC ACIDS, ESTARS AND SALTS THEREOF - Google Patents

2-AMINO-3- (HALOGENEBENZOYL) -METHYLPHENYLETIC ACIDS, ESTARS AND SALTS THEREOF

Info

Publication number
SE453387B
SE453387B SE8200891A SE8200891A SE453387B SE 453387 B SE453387 B SE 453387B SE 8200891 A SE8200891 A SE 8200891A SE 8200891 A SE8200891 A SE 8200891A SE 453387 B SE453387 B SE 453387B
Authority
SE
Sweden
Prior art keywords
amino
sodium
compounds
active ingredient
present
Prior art date
Application number
SE8200891A
Other languages
Swedish (sv)
Other versions
SE8200891L (en
Inventor
D A Walsh
D A Shamblee
Original Assignee
Robins Co Inc A H
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Robins Co Inc A H filed Critical Robins Co Inc A H
Publication of SE8200891L publication Critical patent/SE8200891L/en
Publication of SE453387B publication Critical patent/SE453387B/en

Links

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
    • A61K31/185—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
    • A61K31/12—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)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (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

15 20 25 30 35 40 'Exempel på farmaceutiskt acceptabla metallkatjoner är natrium, 453 387 2 där "R betecknar väte, lägre alkyl eller en farmaceutisk acceptabel katjon, ' betecknar halogen och n betecknar 1, 2 eller 3. Examples of pharmaceutically acceptable metal cations are sodium, where "R represents hydrogen, lower alkyl or a pharmaceutically acceptable cation," represents halogen and n represents 1, 2 or 3.

De nya föreningarna enligt föreliggande uppfinning besitter värde- fulla farmakologiska egenskaper användbara som farmaceutiska medel. Föreningarna visar en utomordenlig antiinflammatorisk och analgetisk aktivitet i varmblodiga djur med minimal gastro- intestinal mozácitet. Det är följaktligen ett ändamål enligt föreliggande uppfinning att tillhandahålla nya föreningar och kompositioner vilka kan användas för behandling av dxxlevande djurkroppen, speciellt däggdjurskroppen för att lindra inflamma- tioner och smärtor med ett minimum av bieffekter i gastriska och intestinala områden.The novel compounds of the present invention possess valuable pharmacological properties useful as pharmaceuticals. The compounds show an excellent anti-inflammatory and analgesic activity in warm-blooded animals with minimal gastrointestinal mucosity. Accordingly, it is an object of the present invention to provide novel compounds and compositions which can be used to treat the living animal body, especially the mammalian body to relieve inflammation and pain with a minimum of side effects in gastric and intestinal areas.

Föreliggande uppfinning innefattar föreningar med formeln I inom ramen för ovan angivna allmänna formel och farmaceutiska kompositioner bestående av föreningar med formeln I och lämpliga utspädningsmedel. vid definitionen av symbolerna i anslutning till formeln ovan och den i övrigt förekommande i beskrivningen har uttrycken följande mening: Uttrycket "lägre alkyl" avses innefatta raka och grenade grupper med upp till sex kolatomer, företrädesvis högst fyra kolatomer och exemplifieras av sådana grupper som metyl, etyl, propyl, isopropyl, butyl, sekundär butyl, tertiär butyl, amyl, isoamyl och hexyl.The present invention includes compounds of formula I within the scope of the above general formula and pharmaceutical compositions consisting of compounds of formula I and suitable diluents. in the definition of the symbols in connection with the above formula and the one otherwise used in the description, the terms have the following meaning: The term "lower alkyl" is intended to include straight and branched groups having up to six carbon atoms, preferably not more than four carbon atoms and exemplified by such groups as methyl. ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, amyl, isoamyl and hexyl.

Uttrycket "halogen" avses innefatta klor, fluor, brom, jod. kalium, kalcium, magnesium, zink, aluminium, koppar och hydrater -därav.The term "halogen" is intended to include chlorine, fluorine, bromine, iodine. potassium, calcium, magnesium, zinc, aluminum, copper and hydrates thereof.

Föreningarna enligt föreliggande uppfinning framställes lämp- ligen ur 7-bensoylmetylindolin-2-on med formeln _. ._.~»;=._-_,-;-\~,~,4-.«.-____¿ __ 10 15 20 25 30 35 40 3 453 ss? (Y)n ”där Y och n tidigare definierats. Utgångsföreningen kan fram- ställas på konventionellt sätt, exempelvis Qfiligt de metoder anges i amerikanska patentskriften 4 045 576 och 4 221 716, nämnda ovan. Föreningarna i föreliggande uppfinning framställs genom hydrolys av 7-bensoylmetylindolin-2-oner i basisk vatten- lösning för att erhålla salter därav,vilka kan surgöras varvid syran erhålles. För att erhålla lägre alkylestrar därav om- vandlas syran till ett metallsalt vilket sedan får reagera i ett lämpligt lösningsmedel med en alkylhalogenid för erhållande av den önskade estern.The compounds of the present invention are conveniently prepared from 7-benzoylmethylindolin-2-one of the formula _. ._. ~ »; = ._-_, -; - \ ~, ~, 4 -.«.-____ ¿__ 10 15 20 25 30 35 40 3 453 ss? (Y) n ”where Y and n were previously defined. The starting compound can be prepared in a conventional manner, for example, according to the methods disclosed in U.S. Patent Nos. 4,045,576 and 4,221,716, cited above. The compounds of the present invention are prepared by hydrolysis of 7-benzoylmethylindolin-2-ones in basic aqueous solution to obtain salts thereof, which can be acidified to give the acid. To obtain lower alkyl esters thereof, the acid is converted to a metal salt which is then reacted in a suitable solvent with an alkyl halide to give the desired ester.

Framställningar av föreningar enligt föreliggande uppfinning belyses närmare av följande exempel: Exempel 1 Framställning av natrium-2-amino-3-(4-fluorobensoyl)-5-metyl- fenylacetat-monohydrat.Preparations of compounds of the present invention are further illustrated by the following examples: Example 1 Preparation of sodium 2-amino-3- (4-fluorobenzoyl) -5-methylphenylacetate monohydrate.

En blandning av 8,0 g (0,03 mol) 7-(4-fluorobensoyl)-5-metyl- indolin-2-on i 120 ml 3N natriumhydrosid upphettades till åter- flödande 16 timmar. Efter utspädning med vatten till 300 ml titrerades lösningen vid en temperatur av 50°C med koncentrerad saltsyra till ett pH-värde på 8,2. Den resulterande orangefärgade lösningen filtrerades och det erhållna filtratet kyldes till 5°C surgjordes till pH-värde på 4,5 med isättiksyra. Den resul- terande gula lösningen uppsamlades och tvättades med vatten varefter den upplöstes i metylenklorid. Vattnet tillsattes och blandningen titrerades med utspädd natriumvätekarbonat- lösning till dess pH-värde 7,0 kunna upprätthållas.Vatten- fasen separerades och koncentrerades genom att azeotrop av- 10 15 20 25 30 e 35 40 453 387 4 destillation av vatten med absolut etylalkohol. Det erhållna gula pulvret upplöstes i isopropylalkohol och 1 ml vatten till- sattes. Sedan blandningen fått stå tre dagar uppsamlades det gula fasta materialet och torkades i 25°C i vacuum under tvâ dagar, varvid erhölls 1,6 g (16,5 % utbyte) av titelföreningen som ett gult pulver med en smältpunkt på 140-160°C.A mixture of 8.0 g (0.03 mol) of 7- (4-fluorobenzoyl) -5-methylindolin-2-one in 120 ml of 3N sodium hydroside was heated to reflux for 16 hours. After dilution with water to 300 ml, the solution was titrated at a temperature of 50 ° C with concentrated hydrochloric acid to a pH of 8.2. The resulting orange solution was filtered and the resulting filtrate was cooled to 5 ° C and acidified to pH 4.5 with glacial acetic acid. The resulting yellow solution was collected and washed with water, after which it was dissolved in methylene chloride. The water was added and the mixture was titrated with dilute sodium bicarbonate solution until a pH of 7.0 could be maintained. The aqueous phase was separated and concentrated by azeotroping distilling off water with absolute ethyl alcohol. The resulting yellow powder was dissolved in isopropyl alcohol and 1 ml of water was added. After allowing the mixture to stand for three days, the yellow solid was collected and dried at 25 ° C in vacuo for two days to give 1.6 g (16.5% yield) of the title compound as a yellow powder, m.p. 140-160 °. C.

Analys beräknad för C16H13FNO3Na'H2O: C,58.72; H,4.62; N,4.28 Erhållet : C,58.71; H,4.68; N,4.26 Exempel 2 Framställning av natrium-2-amino-3-(4Åklorobensoyl)-5-metyl- fenylacetat.Analysis calculated for C 16 H 13 FNO 3 Na 3 H 2 O: C, 58.72; H, 4.62; N, 4.28 Found: C, 58.71; H, 4.68; N, 4.26 Example 2 Preparation of sodium 2-amino-3- (4-chlorobenzoyl) -5-methylphenylacetate.

Förfarandet enligt exempel 1 följdes varvid en blandning av 11,59 (0,04 mol) 7~(4-klorobensyl)-5-metylindolin~2-on och 160 ml 3N natriumhydroxid gav efter omkristallisation vatten 2,5 g (18 % ) av titelföreningen som orange färgade nålar med en smältpunkt på 262°C.The procedure of Example 1 was followed to give a mixture of 11.59 (0.04 mol) of 7- (4-chlorobenzyl) -5-methylindolin-2-one and 160 ml of 3N sodium hydroxide after recrystallization of water 2.5 g (18%). of the title compound as orange colored needles with a melting point of 262 ° C.

Analys beräknad för C16H13ClNO3Na: C,59.00; H,4.02; N,4.30 Erhållet : C,58.82; H,4.09 ' N,4.32 Exempel°3 Framställning av natrium-2-amino-3-(2,4-diklorobensoyl)-5- -metylfenylacetat.Analysis calculated for C 16 H 13 ClNO 3 Na: C, 59.00; H, 4.02; N, 4.30 Found: C, 58.82; H, 4.09 'N, 4.32 Example 3 Preparation of sodium 2-amino-3- (2,4-dichlorobenzoyl) -5-methylphenylacetate.

Förfarande enligt exempel 1 följas varvid en blandning av 7-(2,4-diklorobensoyl)-5-metylindolin-2-on och 3N natrium- hydroxid gav titelföreningen.The procedure of Example 1 was followed to give a mixture of 7- (2,4-dichlorobenzoyl) -5-methylindolin-2-one and 3N sodium hydroxide to give the title compound.

Exempel 4 Framställning av natrium~2-amino-3-(2,3,5-triklorobensoyl)-6- -metylfenylacetat.Example 4 Preparation of sodium 2-amino-3- (2,3,5-trichlorobenzoyl) -6-methylphenyl acetate.

Förfarandet enligt exempel 1 följdes varvid en blandning avd 7-(2,3,5-triklorobensoyl)-4~metylindolin-2-on och 3N natrium- 10 15 20 25 30 35 H~yr,.,,,., "He". _. .. ._ _ ___, 453 387 hydroxid gav titelföreningen.The procedure of Example 1 was followed, substituting a mixture of 7- (2,3,5-trichlorobenzoyl) -4-methylindolin-2-one and 3N sodium H-yr,. ". _. .. ._ _ ___, 453 387 hydroxide gave the title compound.

Exempel 5 Framställning av natrium-2-amino-3-(4-klorobensoyl)-4-metyl- fenylacetat.Example 5 Preparation of sodium 2-amino-3- (4-chlorobenzoyl) -4-methylphenylacetate.

Förfarandet enligt exempel 1 följdes varvid en blandning av 4- -klorobensoyl-6-metylindolin-2-on och 3N natriumhydroxid gav titelföreningen.The procedure of Example 1 was followed to give a mixture of 4-chlorobenzoyl-6-methylindolin-2-one and 3N sodium hydroxide to give the title compound.

Allmänt har tidigare starka antiinflammatoriska läkemedel visat sig ge allvarliga bieffekter i form av gastriska blödningar och sårbildningar när de administreras oralt till djur i effektiv mängd. Föreningar i föreliggande uppfinning har visat sig ha den fördelen att man observerat en sänkning av den gastriska irritationen när de administreras i effektiva mängder för minskning av inflammatoriska tillstånd i jämförelse med indo- metacin och 2-amino-3-bensoylfenyl-ättiksyror och deras deri- vat, visar den amerikanska patentskriften 4 045 576. Exempelvis visade sig föreningen enligt exempel 2, natrium-2-amino-3-(4- -klorobensoyl)-5-metylfenylacetat vara omkring 2 gånger så verksam som indometazin och natrium-2-amino-3-bensoylfenyl- acetat men uppvisar omkring en fjärdedel av den irritation av magen som indometazin uppvisar och ungefär hälften av den irri- tation för magen som uppvisas av natrium-2-amino-bensoylfenyl- acetat. Föreningarna enligt exempel 2 visade sig ha halva ver- kan hos natrium-2-amino-3-(4-klorobensoyl)-5-klorofenylacetat men de uppvisade överraskande endast en fjärdedelsá hög irri- tation av magen som denna förening.In general, previously strong anti-inflammatory drugs have been shown to cause serious side effects in the form of gastric bleeding and ulceration when administered orally to animals in effective amounts. Compounds of the present invention have been found to have the advantage of observing a reduction in gastric irritation when administered in effective amounts to reduce inflammatory conditions compared to indomethacin and 2-amino-3-benzoylphenyl acetic acids and their derivatives. U.S. Patent No. 4,045,576. For example, the compound of Example 2, sodium 2-amino-3- (4-chlorobenzoyl) -5-methylphenylacetate was found to be about 2 times as effective as indomethazine and sodium 2-amino. -3-benzoylphenyl acetate but shows about a quarter of the stomach irritation that indomethazine shows and about half of the irritation of the stomach that is shown by sodium 2-amino-benzoylphenyl acetate. The compounds of Example 2 were found to have half the action of sodium 2-amino-3- (4-chlorobenzoyl) -5-chlorophenyl acetate but they surprisingly showed only a quarter as much irritation of the stomach as this compound.

Den antiinflammatoriska aktiviteten belyses på laboratoriedjur man använde av en modifikation av Evans Blue-Carrageenan Pleural Effusion Assay'0fSancilio, L.F, J.Pharmaco1.Exp,Ther. 168: 199-204 (1969).The anti-inflammatory activity is illustrated in laboratory animals used by a modification of Evans Blue-Carrageenan Pleural Effusion Assay'0fSancilio, L.F, J.Pharmaco1.Exp, Ther. 168: 199-204 (1969).

Gastrisk toxicitet bestämdes med modifikation av det förfarande som beskrevs av Tsukada och medarbetare, Arzneim.Forsch.28: 428-438 (1978). m. _i-aß-e-awfi-ea-s-am.fseww-e-Qa...M i i.. ... ._ .. ,_ . 10 15 20 25 30 35 40 __---nnIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII 453 587 6 Föreningar i föreliggande uppfinning verkar också som anal- getika och denna effekt bestämmes med modifikation av för- farandet enligt Collier och medarbetare, Brit J Pharmacol Chemoter 32:295-310 (1968).Gastric toxicity was determined by modification of the procedure described by Tsukada et al., Arzneim.Forsch.28: 428-438 (1978). m. _i-aß-e-aw fi- ea-s-am.fseww-e-Qa ... M i i .. ... ._ .., _. Compounds of the present invention also act as analgesics and this effect is determined by modification of the method of Collier and co-workers, Brit J Pharmacol Chemoter 32: 295-310 (10) 20 20 30 30 30 35 40 __--- nnIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII 453 587 6 1968).

Beredning och administration Föreliggande uppfinning innefattar även nya kompositioner innehållande föreningarna i föreliggande uppfinning som aktiv ingrediens. Effektiva mängder av någon av de förutnämnda farma- kologiskt aktiva föreningarna kan administreras till den le- vande kroppen på något av olika metoder, exempelvis oralt som kapslar, tabletter, ; parenteralt i form av sterila lösningar och suspensioner och i vissa fall intravenöst i form av sterila lösningar. Vid framställningen av dennya kompositionen i före- liggande uppfinning inkorporeras den aktiva ingrediensen i en lämplig bärare, exempelvis en farmaceutisk bärare. Lämpliga farmaceutiska bärare, vilka är användbara för beredning av kompositionen i föreliggande uppfinning, innefattar stärkelse, gelatin, glykos, magnesiumkarbonat, lactoa, malt och liknande.Preparation and Administration The present invention also encompasses novel compositions containing the compounds of the present invention as active ingredient. Effective amounts of any of the aforementioned pharmacologically active compounds may be administered to the living body by any of various methods, for example, orally as capsules, tablets,; parenterally in the form of sterile solutions and suspensions and in some cases intravenously in the form of sterile solutions. In the preparation of this new composition of the present invention, the active ingredient is incorporated into a suitable carrier, for example, a pharmaceutical carrier. Suitable pharmaceutical carriers which are useful for preparing the composition of the present invention include starch, gelatin, glucose, magnesium carbonate, lactoa, malt and the like.

Flytande kompositioner faller också inom ramen för föreliggande uppfinning och lämpliga flytande farmaceutiska bärare innefattar etylalkohol, propylenglykol, glycerin, glykossirap och liknande.Liquid compositions are also within the scope of the present invention and suitable liquid pharmaceutical carriers include ethyl alcohol, propylene glycol, glycerin, glucose syrup and the like.

De farmakologiskt aktiva föreningarna kan företrädesvis utnyttjas i form av enhetsdoser på 0,1-150 mg. Enhetsdoaerna kan administreras en gång dagligen eller i flera dagliga doser. De dagliga doserna kan variera från 0,3-450 mg. 5-25 mg förefaller vara en opti- mal mängd.The pharmacologically active compounds can preferably be used in unit doses of 0.1-150 mg. The unit doses can be administered once daily or in several daily doses. The daily doses can vary from 0.3-450 mg. 5-25 mg seems to be an optimal amount.

Den enda nödvändiga faktorn är att de aktiva ingredienten utgör en effektiv mängd, det vill säga en lämplig effektiv dos erhålles i föreningen med den använda dosformen. Den exakta individuella dosen likson den dagliga dosen kommer naturligtvis att bestämmas i enlighet med standardiserade medicinska principer under led- ning av en läkare eller veterinär. De aktiva medlen enligt upp- finningen kombineras med olika farmaceutiska aktiva medel, eller med buffertar antacida medel och liknande för administration och mängden aktivt medel i kompositionen kan variera inom stora gränser. 10 15 20 25 30 35 40 7 453 387 Följande exempel belyser kompositionen bildad enligt före- liggande uppfinning. 1. Kapslar Kapslar på 5, 25, 50 rm;aktiv ingrediens per kapsel framställ- des. Med den högre mängden aktiv ingrediens kan justeringar i mängden laktos göras.The only necessary factor is that the active ingredient constitutes an effective amount, i.e. a suitable effective dose is obtained in association with the dosage form used. The exact individual dose as well as the daily dose will of course be determined in accordance with standardized medical principles under the guidance of a physician or veterinarian. The active agents according to the invention are combined with various pharmaceutically active agents, or with buffers, antacids and the like for administration, and the amount of active agent in the composition can vary within wide limits. 10 15 20 25 30 35 40 7 453 387 The following examples illustrate the composition formed according to the present invention. Capsules Capsules of 5, 25, 50 rm; active ingredient per capsule were prepared. With the higher amount of active ingredient, adjustments in the amount of lactose can be made.

Typisk blandning Per kapsel, för inkapsling mg Aktiv ingrediens 5,0 Laktos 296,7 Stärkelse 129,0 Magnesiumstearat 4,3 Totalt 435,0 mg Ytterligare kapselberedningar företrädesvis innehållande högre dos aktiv ingrediens är följande: Ingrediens Per kapsel, mg Aktiv ingrediens 25,0 Laktoa 306,5 Stärkelse 99,2 Magnesiumstearat 4,3 Totalt 435,0 mg I varje fall blandas de utvalda aktiva ingredienserna med laktos, stärkelse och magnesiumstearat och blandningen in- kapslas. 2. Tabletter Typisk beredning för tabletter innehållande 5,0 mg aktiv in- grediens per tablett anges nedan. Beredningen kan användas för andra mängder aktiv ingrediens genom justering av mängden äikal* ciumfusfiat. 10 15 20 25 35 453 387 Per tablett, mg (1) Aktiv ingrediens 5,0 (2) Majsstärkelse 13,6 (3) Majsstärkelse (pasta) 3,4 (4) Laktos 79,2 (5) Dikalciumfosfat 68,0 (6) Kalciumstearat 0,9 170,1 mg 1, 2, 4, och 5 blandas jämnt. 3 framställes som en 10 %-ig pasta i vatten. Blandningen granulerades med stärkelsepasta och fördes som en våt massa genom en sikt med sikttalet åtta mesh. De våta granulaten torkades och fördes genom en sikt med sikttalet tolv mesh. De torkade granulerna blandades med kalciumstearat och pressades. 3. Injicerbar 2 %-lg lösning .lïfialll Aktiv ingrediens 20 mg Konserveringsmedel, t ex klorobutanol Vatten för injektion 0,5 vikt-% per volym till 1 ml Lösningen framställdes, gjordes klar genom filtrering och fyll- des på behållare och förseglades samt autoklaverades. Olika modifikationer och ekvivalenta metoder är för fackmannen uppen- bara vid framställning av föreningar och kompositioner och för- farandena afligt föreliggande uppfinning avses innefatta allt som ligger inom ramen för bifogade krav.Typical mixture Per capsule, for encapsulation mg Active ingredient 5.0 Lactose 296.7 Starch 129.0 Magnesium stearate 4.3 Total 435.0 mg Additional capsule preparations preferably containing higher dose active ingredient are as follows: Ingredient Per capsule, mg Active ingredient 25, Lactoa 306.5 Starch 99.2 Magnesium stearate 4.3 Total 435.0 mg In each case, the selected active ingredients are mixed with lactose, starch and magnesium stearate and the mixture is encapsulated. 2. Tablets Typical formulation for tablets containing 5.0 mg of active ingredient per tablet is given below. The preparation can be used for other amounts of active ingredient by adjusting the amount of eikal * ciumfus fi at. 10 15 20 25 35 453 387 Per tablet, mg (1) Active ingredient 5.0 (2) Corn starch 13.6 (3) Corn starch (paste) 3.4 (4) Lactose 79.2 (5) Dicalcium phosphate 68.0 (6) Calcium stearate 0.9 170.1 mg 1, 2, 4, and 5 are mixed evenly. 3 is prepared as a 10% paste in water. The mixture was granulated with starch paste and passed as a wet mass through a sieve with a sieve number of eight mesh. The wet granules were dried and passed through a sieve with a sieve number of twelve mesh. The dried granules were mixed with calcium stearate and pressed. 3. Injectable 2% solution .lïfialll Active ingredient 20 mg Preservatives, eg chlorobutanol Water for injections 0.5% by weight per volume to 1 ml The solution was prepared, prepared by filtration and filled into containers and sealed and autoclaved . Various modifications and equivalent methods will be apparent to those skilled in the art upon preparation of compounds and compositions, and the methods of the present invention are intended to encompass everything within the scope of the appended claims.

Claims (5)

191 9 1 453 :av Patentkrav191 9 1 453: of Patent Claims 1. ; Förening, k ä n n e t e c k n a d »av formeln: 5 cnzcoon 10 i f, där R betecknar väte, lägre alkyl eller en farmaceutisk accep- tabel katjcn, É 15 Y betecknar halogen och É n betecknar 1, 2 eller 3.1.; A compound of the formula: wherein R represents hydrogen, lower alkyl or a pharmaceutically acceptable cation, É represents halogen and É represents 1, 2 or 3. 2. Förening enligt krav 1, k ä n n e t e c k n a d av afizden :Ü göras av 2-amino-3-(4-fluorobensoyl)-5-metylfenylättikssyra. 20A compound according to claim 1, characterized in that azene: Ü is made of 2-amino-3- (4-fluorobenzoyl) -5-methylphenylacetic acid. 20 3. Förening enligt krav 1, k ti n n e t e c k n a d av att utgöres av natrium-2-amino-3-(4-fluorobensoyl)-5-metylfenylacetat-mcnohydrat.A compound according to claim 1, which comprises sodium 2-amino-3- (4-fluorobenzoyl) -5-methylphenylacetate monohydrate. 4. Förening enligt krav 1, k ä n n e t e c k n a d av attdenxm- 25 göres av 2-amino-3-(4-klorobenaoyl)-5-metylfenylättikssyra.4. A compound according to claim 1, characterized in that it is prepared from 2-amino-3- (4-chlorobenoyl) -5-methylphenylacetic acid. 5. Förening enligt krav 1, k ä n n e t e c k n a d av att äen utgöres av natrium-2-amino-3-(4-klorobensoyl)-5-metylfenylacetat. 305. A compound according to claim 1, characterized in that the acid is 2-amino-3- (4-chlorobenzoyl) -5-methylphenyl acetate. 30
SE8200891A 1981-02-17 1982-02-15 2-AMINO-3- (HALOGENEBENZOYL) -METHYLPHENYLETIC ACIDS, ESTARS AND SALTS THEREOF SE453387B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US23453181A 1981-02-17 1981-02-17

Publications (2)

Publication Number Publication Date
SE8200891L SE8200891L (en) 1982-08-18
SE453387B true SE453387B (en) 1988-02-01

Family

ID=22881752

Family Applications (1)

Application Number Title Priority Date Filing Date
SE8200891A SE453387B (en) 1981-02-17 1982-02-15 2-AMINO-3- (HALOGENEBENZOYL) -METHYLPHENYLETIC ACIDS, ESTARS AND SALTS THEREOF

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) 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)

* Cited by examiner, † Cited by third party
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
US6646003B2 (en) 2001-04-02 2003-11-11 Alcon, Inc. Method of treating ocular inflammatory and angiogenesis-related disorders of the posterior segment of the eye using an amide derivative of flurbiprofen or ketorolac
TWI358290B (en) 2004-12-02 2012-02-21 Alcon Inc Topical nepafenac formulations

Family Cites Families (5)

* Cited by examiner, † Cited by third party
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
SE400966B (en) * 1975-08-13 1978-04-17 Robins Co Inc A H PROCEDURE FOR PREPARING 2-AMINO-3- (OR 5-) BENZOYL-PHENYLETIC ACIDS
FR2366015A1 (en) * 1975-11-05 1978-04-28 Robins Co Inc A H Amino-benzoyl-phenylacetic acid derivs - antiinflammatory, hypocholesterolemic and blood platelet agglomeration inhibitory activity
IL61945A (en) * 1980-02-19 1984-09-30 Robins Co Inc A H 2-amino-3-(hydroxy(phenyl)methyl)phenylacetic acids,esters and amides and pharmaceutical compositions containing them

Also Published As

Publication number Publication date
FI820392L (en) 1982-08-18
MY8500908A (en) 1985-12-31
DK67382A (en) 1982-08-18
NL8200607A (en) 1982-09-16
NZ199745A (en) 1985-07-12
NO160133B (en) 1988-12-05
KR880002289B1 (en) 1988-10-22
DK155936B (en) 1989-06-05
IT1157001B (en) 1987-02-11
AU7950382A (en) 1982-08-26
ATA43382A (en) 1988-05-15
HK90384A (en) 1984-11-23
FI73970C (en) 1987-12-10
DE3204854A1 (en) 1982-09-09
PT74441A (en) 1982-03-01
GB2093027A (en) 1982-08-25
ES509622A0 (en) 1982-12-16
AT387213B (en) 1988-12-27
IE820310L (en) 1982-08-17
JPH0365338B2 (en) 1991-10-11
IT8267152A0 (en) 1982-02-10
BE892156A (en) 1982-06-16
FI73970B (en) 1987-08-31
DK155936C (en) 1989-11-06
FR2499981B1 (en) 1986-05-23
DE3204854C2 (en) 1994-06-16
JPS57149256A (en) 1982-09-14
LU83928A1 (en) 1983-06-07
PL235095A1 (en) 1982-11-08
SE8200891L (en) 1982-08-18
SG68584G (en) 1985-03-15
PL139815B1 (en) 1987-02-28
ES8301895A1 (en) 1982-12-16
CA1173852A (en) 1984-09-04
YU44333B (en) 1990-06-30
NO160133C (en) 1989-03-15
EG15798A (en) 1986-06-30
ZA82697B (en) 1983-01-26
GR76516B (en) 1984-08-10
IL64724A0 (en) 1982-03-31
NO820468L (en) 1982-08-18
HU187644B (en) 1986-02-28
PT74441B (en) 1983-08-24
KE3454A (en) 1984-10-12
KR830008990A (en) 1983-12-16
CH651294A5 (en) 1985-09-13
FR2499981A1 (en) 1982-08-20
IE52289B1 (en) 1987-09-02
YU32582A (en) 1985-06-30
GB2093027B (en) 1984-07-04

Similar Documents

Publication Publication Date Title
US4126635A (en) 2-amino-3-(5- and 6-)benzoylphenylacetic acids, esters and metal salts thereof
US7550507B2 (en) 2-(alpha-hydroxypentyl) benzoate and its preparation and use
SE452155B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE ARYLSULPHINYLACETOH HYDROXAMIC ACID DERIVATIVES
US4503073A (en) 2-Amino-3-(alkylthiobenzoyl)-phenylacetic acids
SE453387B (en) 2-AMINO-3- (HALOGENEBENZOYL) -METHYLPHENYLETIC ACIDS, ESTARS AND SALTS THEREOF
US4254146A (en) 3-Benzoyl-2-nitrophenylacetic acids, metal salts, amides and esters
KR100979077B1 (en) Solid salts benzazepine compounds and pharmaceutical compositions comprising them
US20110269838A1 (en) Novel processes and pure polymorphs
US5747521A (en) N-cinnamoyl-2-methyl-5-methoxy-3-indoleacetic acid ester, and pharmaceutical preparation containing the same
US4000297A (en) N-p-chlorobenzoyl tryptophane, salts and compositions thereof
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
US3377241A (en) Certain diacyl derivatives of phloroglucinol as anthelmintics
CA1147746A (en) 2-amino-3-(alkylthiobenzoyl)phenylacetic acids
US4562205A (en) Derivatives of 2-aminoacetic acid
US4148912A (en) Pharmaceutical compositions and methods of using the same
KR950008316B1 (en) 1-hydroxy-oxo-5h-pyrido(3,2-a)-phenoxazine-3-carboxylic acid esters
US4397862A (en) Gastrointestinal sparing thioester drugs
JPS5910563A (en) Alpha-(n-pyrrolyl)-phenylacetic acid derivative and manufacture
RU2305092C2 (en) Novel 2-(alpha-hydroxypentyl)benzoates, their preparing and using
KR0143994B1 (en) Phenylacetic derivative and process for thereof
IL23268A (en) Anti-inflammatory compositions containing 4-phenyl-alpha-methyl-phenylacetic acid
JPH0128743B2 (en)
JP3242975B2 (en) Gastrointestinal motility improver
US4076839A (en) Uricosuric composition and method of producing uricosuria and hypouricemia
JPS5843938A (en) Ascochlorin derivative

Legal Events

Date Code Title Description
NAL Patent in force

Ref document number: 8200891-3

Format of ref document f/p: F