NO150080B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AMINO-3- (ALKYLTHIOBENZOYL) -PHENYLEDOIC ACID DERIVATIVES - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AMINO-3- (ALKYLTHIOBENZOYL) -PHENYLEDOIC ACID DERIVATIVES Download PDF

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NO150080B
NO150080B NO802306A NO802306A NO150080B NO 150080 B NO150080 B NO 150080B NO 802306 A NO802306 A NO 802306A NO 802306 A NO802306 A NO 802306A NO 150080 B NO150080 B NO 150080B
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alkylthiobenzoyl
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David Allan Walsh
Dwight Allen Shamblee
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Robins Co Inc A H
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00Preparation of thiols, sulfides, hydropolysulfides or polysulfides
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    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/30Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00Thiols, sulfides, hydropolysulfides or polysulfides
    • C07C321/24Thiols, sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
    • C07C321/28Sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings

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Description

Foreliggende oppfinnelse angår en analogifremgangsmåte ved fremstilling av visse nye terapeutisk aktive 2-amino-3-benzoylfenyleddiksyrer med alkylthiosubstitusjon på benzoyl-gruppen, og deres metallsalter, som er egnet for anvendelse i farmasøytiske preparater. The present invention relates to an analogous process for the production of certain new therapeutically active 2-amino-3-benzoylphenylacetic acids with alkylthio substitution on the benzoyl group, and their metal salts, which are suitable for use in pharmaceutical preparations.

Visse 2-amino-3-(5- og 6-)-benzoylfenyleddiksyrer hvis benzoylgruppe er substituert med lavere alkyl, halogen, nitro og trifluormethyl og fremgangsmåter for fremstilling og anvendelse av disse, er angitt i U.S. patent 4 045 576. Forbindelsene som fremstilles ifølge foreliggende oppfinnelse, kan ikke fremstilles ved de der angitte metoder. Certain 2-amino-3-(5- and 6-)-benzoylphenylacetic acids whose benzoyl group is substituted with lower alkyl, halogen, nitro and trifluoromethyl and methods for their preparation and use are disclosed in U.S. Pat. patent 4 045 576. The compounds produced according to the present invention cannot be produced by the methods specified there.

Foreliggende oppfinnelse angår mere spesielt fremstill-. ingen av 2-amino-3- (alkylthiobenzoyl)-fenyleddiksyrer The present invention relates more specifically to manufacturing. none of 2-amino-3-(alkylthiobenzoyl)-phenylacetic acids

og metallsalter derav, med formelen: and metal salts thereof, with the formula:

hvor where

R er hydrogen eller et farmasøytisk godtagbart metallkation, og R is hydrogen or a pharmaceutically acceptable metal cation, and

R 2er hydrogen, halogen eller lavere alkyl. R 2 is hydrogen, halogen or lower alkyl.

De nye fremgangsmåteforbindelser med formel I har verdi-fulle farmakologiske egenskaper og er nyttige som farmasøytiske midler. Forbindelsene oppviser anti-inflammatorisk og analgetisk aktivitet og inhiberer blodplateaggregering i varm-blodige dyr. The novel process compounds of formula I have valuable pharmacological properties and are useful as pharmaceutical agents. The compounds exhibit anti-inflammatory and analgesic activity and inhibit platelet aggregation in warm-blooded animals.

Visse nye mellomprodukter, 7-(S-laverealkylthiobenzoyl)-indolin-2-onene, har formelen: Certain new intermediates, the 7-(S-lower alkylthiobenzoyl)-indolin-2-ones, have the formula:

hvor R 2er som ovenfor angitt. where R 2 is as stated above.

Den anti-inflammatoriske aktivitet ble demonstrert i laboratoriedyr under anvendelse av en modifikasjon av Evans Blue Carrageenan Pleural Effusion Assay of Sancilio, The anti-inflammatory activity was demonstrated in laboratory animals using a modification of the Evans Blue Carrageenan Pleural Effusion Assay of Sancilio,

L. F., J. Pharmacol. Exp. Ther. 168, 199-204 (1969). Forbindelsene med formel I som inhibitorer for blodplateaggregering viser denne egenskap ved reduksjon av plateaggregering som beskrevet av Born, J. of Phys. 162, 67-68 (1962) og Evans et al, J. of Expt. Med. 128, 877-894 (1968). Rotter ble administrert oralt med forsøksdroger, og efter 2 timer ble rottene blodlatt, og et platerikt plasma ble er-holdt. Collagen ble tilsatt til det platerike plasma for å indusere plateaggregering, og sammenligninger ble gjort mellom kontrollprøver og behandlede prøver. LF, J. Pharmacol. Exp. Ther. 168, 199-204 (1969). The compounds of formula I as inhibitors of platelet aggregation show this property by reducing platelet aggregation as described by Born, J. of Phys. 162, 67-68 (1962) and Evans et al, J. of Expt. With. 128, 877-894 (1968). Rats were administered orally with experimental drugs, and after 2 hours the rats were bled, and a platelet-rich plasma was retained. Collagen was added to the platelet-rich plasma to induce platelet aggregation, and comparisons were made between control and treated samples.

Forbindelsene med formel I virker også som analgetika bestemt ved Bradykinin Analgetic Test-metode ifølge Dickerson et al, Life Sei. 4, 2063-2069 (1965) som modifisert av Sancilio og Cheung, Fed. Proe. 35, 774 (1976). The compounds of formula I also act as analgesics as determined by the Bradykinin Analgesic Test method according to Dickerson et al, Life Sci. 4, 2063-2069 (1965) as modified by Sancilio and Cheung, Fed. Pro. 35, 774 (1976).

Det er derfor et mål ved foreliggende oppfinnelse å frem-skaffe nye terapeutisk aktive forbindelser for behandling av levende dyrelegemer, og særlig pattedyrlegemer for å lindre inflammasjon og smerte, og inhibere blodplateaggregering med et minimum av uønskede bivirkninger. It is therefore an aim of the present invention to provide new therapeutically active compounds for the treatment of living animal bodies, and in particular mammalian bodies to alleviate inflammation and pain, and inhibit platelet aggregation with a minimum of unwanted side effects.

Fremgangsmåteforbindelsene omfatter forbindelsene med formel I. The method compounds include the compounds of formula I.

I definisjonen av symbolene i formlene har uttrykkene følgende betydning. In the definition of the symbols in the formulas, the expressions have the following meaning.

Uttrykket "lavere alkyl" er anvendt for å omfatte rett-kjedede og forgrenede grupper med inntil 6 carbonatomer, for-trinnsvis ikke mere enn 4 carbonatomer, og eksemplifisert ved slike grupper som methyl, ethyl, propyl, isopropyl, butyl, sek-butyl, t-butyl, amyl, isoamyl og hexyl. The term "lower alkyl" is used to include straight-chain and branched groups with up to 6 carbon atoms, preferably no more than 4 carbon atoms, and exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, amyl, isoamyl and hexyl.

Uttrykket "halogen" er brukt for å betegne klor, fluor, brom og jod. The term "halogen" is used to denote chlorine, fluorine, bromine and iodine.

Eksempler på farmasøytisk godtagbare salter er natrium-, kalium-, calcium-, magnesium-, zink- og kobber-saltene, og hydratene derav. Examples of pharmaceutically acceptable salts are the sodium, potassium, calcium, magnesium, zinc and copper salts, and the hydrates thereof.

Fluorbenzoylindolin-2-onene anvendt som utgangsmaterialer ved foreliggende fremgangsmåte, kan fremstilles ved én eller flere av fremgangsmåtene beskrevet i US patent 4 045 576. En fremgangsmåte angitt der, begynner med omsetning av 2-amino-4'-halogenbenzoylbenzofenon med ethyl-methylthioacetat, t-BuOCl og Et^N for å få 7-(halogenbenzoyl)-3-methylthioindolin-2-oner som så reduseres med Raney-nikkel for å danne 7- (halogenbenzoyl)-3-indolin-2-onene. En modifikasjon av denne fremgangsmåte ble anvendt hvori Raney-nikkel ble er-stattet med tinnpulver i alkohol og konsentrert saltsyre. Den følgende ligning illustrerer fremstillingen av 7-(fluorbenzoyl)-indolin-2-oner anvendt for fremstilling av fremgangsmåteforbindelsene: The fluorobenzoylindolin-2-ones used as starting materials in the present method can be prepared by one or more of the methods described in US patent 4,045,576. A method indicated there begins with the reaction of 2-amino-4'-halobenzoylbenzophenone with ethyl-methylthioacetate, t-BuOCl and Et^N to give 7-(halobenzoyl)-3-methylthioindolin-2-ones which are then reduced with Raney nickel to form the 7-(halobenzoyl)-3-indolin-2-ones. A modification of this method was used in which Raney nickel was replaced by tin powder in alcohol and concentrated hydrochloric acid. The following equation illustrates the preparation of 7-(fluorobenzoyl)-indolin-2-ones used to prepare the process compounds:

Fremstillingen av fremgangsmåteforbindelsene skjer ved å omsette fluorbenzoyl-indolin-2-oner med alkalimetall-alkylsulfid, fulgt av syrehydrolyse for å få 7-(alkylthio-benzoyl)-indolin-2-onene som hydrolyseres med alkalimetall-base for å få alkalimetallsaltene av 2-amino-3-(alkylthio-benzoyl)-fenyleddiksyrene. Det følgende reaksjonsskjerna illustrerer fremstillingen av alkalimetallsaltene av forbindelsene med formel I: The preparation of the process compounds is by reacting fluorobenzoyl-indolin-2-ones with alkali metal alkyl sulfide, followed by acid hydrolysis to obtain the 7-(alkylthio-benzoyl)-indolin-2-ones which are hydrolyzed with alkali metal base to obtain the alkali metal salts of 2 -amino-3-(alkylthio-benzoyl)-phenylacetic acids. The following reaction scheme illustrates the preparation of the alkali metal salts of the compounds of formula I:

For å få den frie syre (R<1> = H) fra alkalimetallsaltet, tilsettes eddiksyre forsiktig til en vandig oppløsning av saltet, hvilket bringer den frie syre til å felles. Den frie syre fraskilles så ved filtrering, vaskes med vann og tørres. Eksempel 1 Natrium-2-amino-3- (4-methylthiobenzoyl)-fenyleddiksyre-monohydrat To obtain the free acid (R<1> = H) from the alkali metal salt, acetic acid is carefully added to an aqueous solution of the salt, causing the free acid to precipitate. The free acid is then separated by filtration, washed with water and dried. Example 1 Sodium 2-amino-3-(4-methylthiobenzoyl)-phenylacetic acid monohydrate

En blanding av 5,2 g (0,018 mol) 7-(4-methylthiobenzoyl)-indolin-2-on i 75 ml 3N natriumhydroxyd ble oppvarmet under til-bakeløp i 20 timer. Den røde oppløsning ble avkjølt, og et gult bunnfall ble dannet. Bunnfallet ble oppsamlet ved filtrering og vasket med en liten mengde koldt vann og derpå tri-turert med tetrahydrofuran. Bunnfallet ble igjen fraskilt ved filtrering, tørret og omkrystallisert fra 95%-ig ethanol, hvorved man fikk 4,9 g (83%) skarpt gule nåler med smp. 244-247 C. Analyse: Beregnet for C16<H1>6N04SNa: C 56,30; H 4,72; N 4,10 A mixture of 5.2 g (0.018 mol) of 7-(4-methylthiobenzoyl)-indolin-2-one in 75 ml of 3N sodium hydroxide was heated under reflux for 20 hours. The red solution was cooled and a yellow precipitate formed. The precipitate was collected by filtration and washed with a small amount of cold water and then triturated with tetrahydrofuran. The precipitate was again separated by filtration, dried and recrystallized from 95% ethanol, whereby 4.9 g (83%) of bright yellow needles with m.p. 244-247 C. Analysis: Calculated for C16<H1>6N04SNa: C 56.30; H 4.72; N 4.10

Funnet: C 56,38; H 4,62; N 4,17 Found: C 56.38; H 4.62; N 4.17

Eksempel 2 Example 2

Ved å anvende fremgangsmåten i eksempel 1 , men ved å erstatte 7-(4-methylthiobenzoyl)-indolin-2-on med en ekvimolar mengde av de følgende forbindelser: 7- (4-methylthiobenzoyl)-5-methylindolin-2-on/ 7-(4-methylthiobenzoyl)-5-klorindolin-2-on, By using the method in example 1, but by replacing 7-(4-methylthiobenzoyl)-indolin-2-one with an equimolar amount of the following compounds: 7-(4-methylthiobenzoyl)-5-methylindolin-2-one/ 7-(4-methylthiobenzoyl)-5-chloroindolin-2-one,

7-(4-methylthiobenzoyl)-5-fluorindolin-2-on, 7-(4-methylthiobenzoyl)-5-fluoroindolin-2-one,

fåes henholdsvis: natrium-2-amino-3-(4-methylthiobenzoyl)-5-methylfenyl-eddiksyre, smp. 225-260°C, obtained respectively: sodium 2-amino-3-(4-methylthiobenzoyl)-5-methylphenyl-acetic acid, m.p. 225-260°C,

natrium-2-amino-3-(4-methylthiobenzoyl)-5-klorfenyl-eddiksyre, smp. 259-260°C, sodium 2-amino-3-(4-methylthiobenzoyl)-5-chlorophenyl-acetic acid, m.p. 259-260°C,

natrium-2-amino-3-(4-methylthiobenzoyl)-5-fluorfenyl-eddiksyre, smp. 241-244°C. sodium 2-amino-3-(4-methylthiobenzoyl)-5-fluorophenyl-acetic acid, m.p. 241-244°C.

Reaksjonsbetingelsene anvendt for fremstilling av fluor-benzoylindolin-2-on-utgangsmaterialene, illustreres mere spesielt i de følgende fremstillingsmetoder. The reaction conditions used for the preparation of the fluoro-benzoylindolin-2-one starting materials are illustrated more particularly in the following preparation methods.

Fremstilling av utgangsmaterialer Production of starting materials

Metode 1 Method 1

7-( 4- methylthiobenzoyl)- indolin- 2- on 7-(4-methylthiobenzoyl)-indolin-2-one

En oppløsning av natrium-methylmercaptid, fremstilt fra 400 ml 3N natriumhydroxyd og 24 g (0,5 mol) methylsulfid, ble blandet med 25,5 g (0,1 mol) 7-(4-fluorbenzoyl)-indolin-2-on. Blandingen ble kokt under tilbakeløp i 1,5 timer, avkjølt og surgjort (forsiktighet, meget methylsulfid utvikles hurtig). Det dannede bunnfall ble oppsamlet og omkrystallisert to ganger fra benzen, hvorved man fikk 17,8 g (70%) som gule krystaller med smp. 167,0-169,0°C. A solution of sodium methyl mercaptide, prepared from 400 ml of 3N sodium hydroxide and 24 g (0.5 mol) of methyl sulfide, was mixed with 25.5 g (0.1 mol) of 7-(4-fluorobenzoyl)-indolin-2-one . The mixture was refluxed for 1.5 hours, cooled and acidified (caution, much methyl sulphide is rapidly developed). The precipitate formed was collected and recrystallized twice from benzene to give 17.8 g (70%) as yellow crystals, m.p. 167.0-169.0°C.

Analyse: Beregnet for C16H13<N>02S: C 67,82; H 4,63; N 4,94 Analysis: Calculated for C16H13<N>02S: C 67.82; H 4.63; N 4.94

Funnet: C 67,65; H 4,63; N 4,91. Found: C 67.65; H 4.63; N 4.91.

Metode 2 Method 2

7-( 4- fluorbenzoyl)- 3- methylthioindolin- 2- on 7-(4-fluorobenzoyl)-3-methylthioindolin-2-one

En oppløsning av 42,2 g (0,196 mol) 2-amino-4'-fluor-benzofenon i 2 1 methylenklorid ble avkjølt til -65°C, og A solution of 42.2 g (0.196 mol) of 2-amino-4'-fluoro-benzophenone in 2 L of methylene chloride was cooled to -65°C, and

26,5 g (0,198 mol) ethyl-methylthioacetat ble tilsatt. En opp-løsning av 23,0 g (0,21 mol) 95%-ig t-butoxyklorid i 50 ml methylenklorid ble tilsatt dråpevis idet temperaturen ble holdt under -65°C. 1 time efter at tilsetningen var avsluttet, ble 22,2 g (0,22 mol) triethylamin tilsatt dråpevis, og blandingen fikk lov til å oppvarmes til værelsetemperatur. Oppløsningen ble inndampet til 700 ml og derpå vasket med vann. Den organiske oppløsning ble konsentrert og residuet oppløst i 400 ml methanol inneholdende 30 ml konsentrert saltsyre. Blandingen ble oppvarmet under tilbakeløp i 1 time fulgt av avkjøling. Blandingen ble hensatt over natten, krystallene ble oppsamlet og vasket med methanol, hvorved man fikk 31,4. g (53%) som et skarpt gult, fast stoff med smp. 165-167,5°C. 26.5 g (0.198 mol) of ethyl methyl thioacetate was added. A solution of 23.0 g (0.21 mol) of 95% t-butoxychloride in 50 ml of methylene chloride was added dropwise, keeping the temperature below -65°C. 1 hour after the addition was complete, 22.2 g (0.22 mol) of triethylamine was added dropwise, and the mixture was allowed to warm to room temperature. The solution was evaporated to 700 ml and then washed with water. The organic solution was concentrated and the residue dissolved in 400 ml of methanol containing 30 ml of concentrated hydrochloric acid. The mixture was heated under reflux for 1 hour followed by cooling. The mixture was allowed to stand overnight, the crystals were collected and washed with methanol to give 31.4. g (53%) as a bright yellow solid with m.p. 165-167.5°C.

Analyse: Beregnet for C^H N02FS: C 63,77; H 4,01; N 4,65 Analysis: Calculated for C 2 H NO 2 FS: C 63.77; H 4.01; N 4.65

Funnet: C 63,58; H 4,11; N 4,67 Found: C 63.58; H 4.11; N 4.67

Metode 3 Method 3

7-( 2- fluorbenzoyl)- 3- methylthioindolin- 2- on 7-(2-fluorobenzoyl)-3-methylthioindolin-2-one

En oppløsning av 86 g (0,4 mol) 2-amino-2'-fluorbenzo-fenon i 3 1 methylenklorid ble avkjølt til -65°C, og 54. g (0,4 mol) ethyl-methylthioacetat ble tilsatt. En oppløsning av 46 g (0,42 mol) 95%-ig t-butoxyklorid i 100 ml methylenklorid ble tilsatt dråpevis idet temperaturen ble holdt under A solution of 86 g (0.4 mol) of 2-amino-2'-fluorobenzophenone in 3 L of methylene chloride was cooled to -65°C, and 54 g (0.4 mol) of ethyl methylthioacetate was added. A solution of 46 g (0.42 mol) of 95% t-butoxychloride in 100 ml of methylene chloride was added dropwise while maintaining the temperature below

-65°C. 1 time efter at tilsetningen var avsluttet, ble 41 g (0,4 mol) triethylamin tilsatt dråpevis, og blandingen fikk lov til å oppvarmes til værelsetemperatur. Oppløsningen ble -65°C. 1 hour after the addition was finished, 41 g (0.4 mol) of triethylamine was added dropwise, and the mixture was allowed to warm to room temperature. The resolution was

inndampet til ca. 1400 ml og derpå vasket med vann. Den organiske oppløsning ble inndampet, og residuet ble oppløst i 800 ml methanol inneholdende 60 ml konsentrert saltsyre. Blandingen ble oppvarmet under tilbakeløp i 1 time fulgt av avkjøling. Blandingen hensto over natten, derpå ble krystallene oppsamlet og omkrystallisert fra 20%-ig vandig ethanol, hvorved man fikk 66 g (55%) blekt gule nåler med smp. 147,0-148,5°C. evaporated to approx. 1400 ml and then washed with water. The organic solution was evaporated, and the residue was dissolved in 800 ml of methanol containing 60 ml of concentrated hydrochloric acid. The mixture was heated under reflux for 1 hour followed by cooling. The mixture stood overnight, then the crystals were collected and recrystallized from 20% aqueous ethanol, whereby 66 g (55%) pale yellow needles with m.p. 147.0-148.5°C.

Analyse: Beregnet for C16<H>12<N0>2FS: C 63,77; H 4,01; N 4,65 Analysis: Calculated for C16<H>12<N0>2FS: C 63.77; H 4.01; N 4.65

Funnet: C 63,97; H 4,19; N 4,66 Found: C 63.97; H 4.19; N 4.66

Metode 4 Method 4

7- ( 4- fluorbenzoyl)- indolin- 2- on 7-(4-fluorobenzoyl)-indolin-2-one

En blanding av 40,0 g (0,133 mol) 7-(4-fluorbenzoyl)-3-methylthioindolin-2-on og 40,0 g (0,34 mol) tinnpulver i 1 liter 95%-ig ethanol ble oppvarmet under tilbakeløp, og 100 ml konsentrert saltsyre ble tilsatt. Blandingen ble oppvarmet i 6 timer og derpå filtrert mens varm. Filtratet ble avkjølt, og bunnfallet ble oppsamlet og omkrystallisert fra isopropylalkohol, hvorved man fikk 24,5 g (72%) av gråhvite nåler med smp. 185-187,0°C. A mixture of 40.0 g (0.133 mol) 7-(4-fluorobenzoyl)-3-methylthioindolin-2-one and 40.0 g (0.34 mol) tin powder in 1 liter of 95% ethanol was heated under reflux , and 100 ml of concentrated hydrochloric acid was added. The mixture was heated for 6 hours and then filtered while hot. The filtrate was cooled, and the precipitate was collected and recrystallized from isopropyl alcohol, whereby 24.5 g (72%) of off-white needles with m.p. 185-187.0°C.

Analyse: Beregnet for C15<H>10N02F: C 70,58; H 3,95; N 5,49 Analysis: Calculated for C15<H>10N02F: C 70.58; H 3.95; N 5.49

Funnet: C 70,80; H 4,12; N 5,51 Found: C 70.80; H 4.12; N 5.51

Metode 5 7- ( 2- fluorbenzoyl)- indolin- 2- on Method 5 7-(2-fluorobenzoyl)-indolin-2-one

En blanding av 60 g (0,2 mol) 7-(2-fluorbenzoyl)-3-methylthioindolin-2-on pg 60 g (0,5 mol) tinnpulver i 1 liter 95%-ig ethanol, ble oppvarmet under tilbakeløp, og 150 ml konsentrert saltsyre ble tilsatt. Oppvarmningen ble fortsatt i 18 timer, og derpå ble blandingen avkjølt, og bunnfallet ble oppsamlet ved å dekantere oppslemningen fra det gjenværende tinn og filtrere oppslemningen. Filterkaken ble omkrystallisert to ganger fra absolutt ethanol, hvorved man fikk 31 g (60%) hvite nåler med smp. 209-210°C. A mixture of 60 g (0.2 mol) 7-(2-fluorobenzoyl)-3-methylthioindolin-2-one and 60 g (0.5 mol) tin powder in 1 liter 95% ethanol was heated under reflux, and 150 ml of concentrated hydrochloric acid was added. Heating was continued for 18 hours, then the mixture was cooled and the precipitate was collected by decanting the slurry from the remaining tin and filtering the slurry. The filter cake was recrystallized twice from absolute ethanol, whereby 31 g (60%) of white needles with m.p. 209-210°C.

Analyse: Beregnet for C15H10N02F: C 70,58; H 3,95; N 5,49 Analysis: Calculated for C15H10N02F: C 70.58; H 3.95; N 5.49

Funnet: C 70,31; H 4,08; N 5,56 Found: C 70.31; H 4.08; N 5.56

Charles River albino hannrotter som hadde fastet og veide over 250 g, ble anvendt. Hver kontroll- og forsøks-gruppe besto av 6 dyr. Gruppene og dyrene ble valgt ved til-feldige metoder. Forbindelsene ble administrert ved intra-gastrisk intubasjon (10 ml/kg) som en oppløsning eller en suspensjon i 0,5% Tween^80. Kontrollgruppen fikk mediet. 1 time efter administrasjon av forbindelsene ble rottene be-handlet med ether og 5 ml av en mild irriterende oppløsning (0,075% Evans Blue og 0,5% carageenan) ble administrert intra-pleuralt. 5 timer senere ble dyrene avlivet med kloroform eller carbondioxyd. Pleuralvæskene ble oppsamlet og målt i kalibrerte sentrifugerør. Fasted male Charles River albino rats weighing over 250 g were used. Each control and experimental group consisted of 6 animals. The groups and animals were selected by random methods. The compounds were administered by intra-gastric intubation (10 ml/kg) as a solution or a suspension in 0.5% Tween^80. The control group received the medium. 1 hour after administration of the compounds, the rats were treated with ether and 5 ml of a mild irritant solution (0.075% Evans Blue and 0.5% carrageenan) was administered intra-pleurally. 5 hours later, the animals were euthanized with chloroform or carbon dioxide. The pleural fluids were collected and measured in calibrated centrifuge tubes.

Resultatene er vist i den følgende tabell og er uttrykt som den gjennomsnittlige prosentvise nedsettelse i volumet av pleuralvæske i forhold til den i kontrollgruppen. "Pleural Effusion Tests" (anti-inflammatoriske) ved metoden angitt på side 2, linjer 10-13 i beskrivelsen, ga følgende resultater: The results are shown in the following table and are expressed as the average percentage reduction in the volume of pleural fluid compared to that in the control group. "Pleural Effusion Tests" (anti-inflammatory) by the method indicated on page 2, lines 10-13 of the description, gave the following results:

Effektive mengder av de farmakologisk aktive fremgangsmåteforbindelser kan administreres til et levende dyrelegeme på en rekke forskjellige måter, f.eks. oralt som i kapsler eller tabletter, parenteralt i form av sterile oppløsninger eller suspensjoner, og i noen tilfelle intravenøst i form av sterile oppløsninger. Ved fremstilling av preparater inkor-poreres den aktive bestanddel i en passende bærer, f.eks. en farmasøytisk bærer. Passende farmasøytiske bærere som er nyttige ved fremstilling av preparatene inneholdende fremgangsmåteforbindelsene, omfatter stivelse, gelatin, glucose, magnesiumcarbonat, lactose, malt og lignende. For flytende preparater anvendes passende flytende, farmasøytiske bærere innbefattende ethylalkohol, propylenglycol, glycerol, glucose-sirup og lignende. Effective amounts of the pharmacologically active method compounds can be administered to a living animal body in a number of different ways, e.g. orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. When preparing preparations, the active ingredient is incorporated into a suitable carrier, e.g. a pharmaceutical carrier. Suitable pharmaceutical carriers useful in the preparation of the preparations containing the process compounds include starch, gelatin, glucose, magnesium carbonate, lactose, malt and the like. For liquid preparations, suitable liquid pharmaceutical carriers including ethyl alcohol, propylene glycol, glycerol, glucose syrup and the like are used.

De farmakologisk aktive forbindelser som fremstilles ifølge oppfinnelsen, kan med fordel anvendes i en enhetsdose på fra 0,1 til 150 mg. Enhetsdosen kan administreres en gang daglig eller i flere eller oppdelte daglige doser. Den daglige dose kan variere fra 0,3 til 450 mg. 5 - 25 mg synes å The pharmacologically active compounds produced according to the invention can advantageously be used in a unit dose of from 0.1 to 150 mg. The unit dose may be administered once daily or in multiple or divided daily doses. The daily dose can vary from 0.3 to 450 mg. 5 - 25 mg seems to

være optimum pr. enhetsdose. be optimal per unit dose.

Det er bare nødvendig at den aktive bestanddel utgjør en effektiv mengde, dvs. slik at en passende effektiv dose fåes jevnt ved den anvendte doseform. Den nøyaktige individuelle dose såvel som dagsdosene vil selvsagt måtte bestemmes i hen-hold til vanlige medisinske prinsipper under rettledning av en lege eller veterinær. It is only necessary that the active ingredient constitutes an effective amount, i.e. so that a suitable effective dose is obtained uniformly in the dosage form used. The exact individual dose as well as the daily doses will of course have to be determined according to normal medical principles under the guidance of a doctor or veterinarian.

De aktive fremgangsmåteforbindelser kan kombineres med andre farmakologisk aktive midler, eller med puffere, antisyrer og lignende, for administrasjon, og mengden av det aktive middel i preparatet kan variere sterkt. The active process compounds can be combined with other pharmacologically active agents, or with buffers, antacids and the like, for administration, and the amount of the active agent in the preparation can vary greatly.

Claims (1)

Analogifremgangsmåte ved fremstilling av terapeutisk aktive forbindelser med den generelle formel:Analogous procedure in the preparation of therapeutically active compounds with the general formula: hvor R"<*>" er hydrogen eller et farmasøytisk godtagbart metallkation, ogwherein R"<*>" is hydrogen or a pharmaceutically acceptable metal cation, and R 2 er hydrogen, halogen eller lavere alkyl, karakterisert ved at en forbindelse med formelen:R 2 is hydrogen, halogen or lower alkyl, characterized in that a compound with the formula: hvor R 2 er som ovenfor angitt, hydrolyseres med en alkali-metallbase, og hvis den frie syre ønskes, nøytraliseres det erholdte metallsalt med formel I med en syre for å overføre R"*" til hydrogen.where R 2 is as indicated above, is hydrolyzed with an alkali metal base, and if the free acid is desired, the obtained metal salt of formula I is neutralized with an acid to transfer R"*" to hydrogen.
NO802306A 1979-08-01 1980-07-31 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AMINO-3- (ALKYLTHIOBENZOYL) -PHENYLEDOIC ACID DERIVATIVES NO150080C (en)

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