NO800946L - PROCEDURE FOR PREPARING BENZOTHIAZOLD DERIVATIVES - Google Patents

PROCEDURE FOR PREPARING BENZOTHIAZOLD DERIVATIVES

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NO800946L
NO800946L NO800946A NO800946A NO800946L NO 800946 L NO800946 L NO 800946L NO 800946 A NO800946 A NO 800946A NO 800946 A NO800946 A NO 800946A NO 800946 L NO800946 L NO 800946L
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acid
formula
solution
phenyl
salt
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Marcel Lepant
Pierre Bessin
Jacqueline Bonnet
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Rolland Sa A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms

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  • Chemical & Material Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Description

Oppfinnelsen angår en fremgangsmåte ved fremstilling av de to stereoisomere og racematet av 2-(2-fenyl-6-benzo-thiazolyl)-propionsyre med formelen: The invention relates to a method for producing the two stereoisomers and the racemate of 2-(2-phenyl-6-benzo-thiazolyl)-propionic acid with the formula:

og deres salter med i fysiologisk henseende akseptable baser, alkalimetallkationer, jordalkalimetallkationer og aminer, foruten deres salter med uorganiske og organiske, i fysiologisk henseende akseptable syrer, deres alkylestere og de .forbindelser som metabolisk danner denne syre i det menneske-lige legeme. and their salts with physiologically acceptable bases, alkali metal cations, alkaline earth metal cations and amines, in addition to their salts with inorganic and organic, physiologically acceptable acids, their alkyl esters and the compounds which metabolically form this acid in the human body.

De racemiske syrer av formel (I) fremstilles ved omsetning av aminothiol av formelen (II) eller en med denne ekvivalent forbindelse, såsom disulfidet svarende til formel The racemic acids of formula (I) are prepared by reaction of aminothiol of formula (II) or an equivalent compound thereof, such as the disulfide corresponding to formula

(III) :(III) :

med benzoesyre eller et derivat av denne, såsom benzoylklorid, en benzoylester eller benzaldehyd, idet reaksjonen med benzoylklorid gir det beste utbytte. with benzoic acid or a derivative thereof, such as benzoyl chloride, a benzoyl ester or benzaldehyde, the reaction with benzoyl chloride giving the best yield.

Under reaksjonen mellom syrekloridet og aminothiolen av formel (II), som fortrinnsvis utføres i nærvær av en uorganisk eller organisk base, er det typisk at der." dannes mellomprodukter (IV) og (V): During the reaction between the acid chloride and the aminothiol of formula (II), which is preferably carried out in the presence of an inorganic or organic base, it is typical that intermediates (IV) and (V) are formed:

Disse forbindelser av formler (IV) og (V) isoleres ikke, men. blandingen av de to forbindelser underkastes ringslutning enten ved innvirkning av varme eller ved innvirkning av syrer eller baser. These compounds of formulas (IV) and (V) are not isolated, but. the mixture of the two compounds undergoes ring closure either by the action of heat or by the action of acids or bases.

Under reaksjonen mellom benzaldehydet og aminothiolenDuring the reaction between the benzaldehyde and the aminothiol

•av formel (II), som utføres enten i et inert oppløsningsmiddel, såsom nitrobenzen, benzen, og lignende, eller i et basisk oppløsningsmiddel, såsom pyridin eller kinolin, kan der som mellomprodukt dannes et benzothiazin av formelen (VI) • of formula (II), which is carried out either in an inert solvent, such as nitrobenzene, benzene, and the like, or in a basic solvent, such as pyridine or quinoline, where a benzothiazine of formula (VI) can be formed as an intermediate

som ved oxydasjon, f.eks. med FeCl^eller dimethylsulfoxyd, vil gi det ønskede benzothiazol. as in oxidation, e.g. with FeCl^ or dimethylsulfoxyd, will give the desired benzothiazole.

De to enantiomere av syren av formel (I) kan separeres ved anvendelse av et salt av den tilsvarende syre med et chiralamin. Dette gjelder spesielt hver av de to enantiomere av 2-fenyl-ethylamin. I henhold til en i og for seg kjent fremgangsmåte omkrystalliseres så disse salter for å skille de to diastereoisomere fra hverandre. The two enantiomers of the acid of formula (I) can be separated by using a salt of the corresponding acid with a chiralamine. This applies in particular to each of the two enantiomers of 2-phenylethylamine. According to a method known per se, these salts are then recrystallized to separate the two diastereoisomers from each other.

Saltene av syrene av formel (I) kan fremstilles ved at man lar en støkiometrisk mengde av den valgte syre eller base innvirke på syrene av formel (I) i oppløsning i en alkohol, et keton eller en alifatisk ether. The salts of the acids of formula (I) can be prepared by allowing a stoichiometric amount of the selected acid or base to act on the acids of formula (I) in solution in an alcohol, a ketone or an aliphatic ether.

Esterne av syrene av formel (I) kan fremstilles ved innvirkning av en alkohol eller et halogenalkan på syren av formel (I) eller et reaktivt derivat av denne, i.henhold til. i og for seg kjente metoder. The esters of the acids of formula (I) can be prepared by the action of an alcohol or a haloalkane on the acid of formula (I) or a reactive derivative thereof, according to per se known methods.

Aminothiolene av formel (II) kan fremstilles ved spaltning, i et basisk medium, i nærvær eller fravær av et reduk-sjonsmiddel, av en forbindelse med formelen: The aminothiols of formula (II) can be prepared by cleavage, in a basic medium, in the presence or absence of a reducing agent, of a compound of the formula:

De omtalte aminosyrer er nye forbindelser, som kan fremstilles ved innvirkning av brom og åmmoniumthiocyanat på en forbindelse av formelen: The mentioned amino acids are new compounds, which can be produced by the action of bromine and ammonium thiocyanate on a compound of the formula:

i eddiksyreoppløsning. in acetic acid solution.

De følgende eksempler illustrerer fremstillingen av forbindelsene med formel (I). The following examples illustrate the preparation of the compounds of formula (I).

Eksempel 1Example 1

a) Fremstilling av 2-( 2- amino- 6- benzothiazolyl)- propionsyre 24,7 g 2-(4-amino-fenyl)-propionsyre, fremstilt f.eks. a) Preparation of 2-(2-amino-6-benzothiazolyl)-propionic acid 24.7 g of 2-(4-amino-phenyl)-propionic acid, prepared e.g.

som beskrevet i Org. Prep. Proe. Int. sider 303-307 (1977)., oppløses i 300 ml eddiksyre, hvoretter det tilsettes 22,8 g åmmoniumthiocyanat. 24. g brom oppløst i 60 ml eddiksyre settes dråpevis til denne oppløsning ved 15°C, hvoretter blandingen tillates å oppvarmes til romtemperatur i løpet av flere timer., samtidig som den omrøres. Oppløsningsmidlet fjernes så under redusert trykk, og den gjenværende olje opp-slemmes i en sur vandig oppløsning. Den erholdte utfeining fjernes, og den vandige fases pH innstilles på 4,5 ved tilsetning av en natriumhydroxydoppløsning. Den erholdte utfelning frafiltreres og omkrystalliseres fra methanol eller ethanol, hvorved det fåes 26 g 2-(2-fenyl-6-benzothiazolyl)- as described in Org. Prep. Pro. Int. pages 303-307 (1977)., is dissolved in 300 ml of acetic acid, after which 22.8 g of ammonium thiocyanate is added. 24 g of bromine dissolved in 60 ml of acetic acid is added dropwise to this solution at 15°C, after which the mixture is allowed to warm to room temperature over the course of several hours, while stirring. The solvent is then removed under reduced pressure, and the remaining oil is slurried in an acidic aqueous solution. The resulting slurry is removed, and the pH of the aqueous phase is adjusted to 4.5 by adding a sodium hydroxide solution. The resulting precipitate is filtered off and recrystallized from methanol or ethanol, whereby 26 g of 2-(2-phenyl-6-benzothiazolyl)-

propionsyre (ren) med smeltepunkt 234°C.propionic acid (pure) with melting point 234°C.

b) Fremstilling av 2-(2-f enyl-6-benzothiazolyl)-propionsyreb) Preparation of 2-(2-phenyl-6-benzothiazolyl)-propionic acid

med benzoylkloridwith benzoyl chloride

En oppløsning av 45 g 2-(2-amino-6-benzothiazolyl^propionsyre i 200 ml 40%<1>ig vandig natriumhydroxydoppløsning, som, om ønskes, kan inneholde 40 g natriumsulfid-nonahydrat oppvarmes til tilbakeløpstemperaturen inntil utviklingen av ammoniakk er opphørt. Omtrent 500 ml vann tilsettes oppløs-ningen, hvoretter det ved en temperatur på 10°C langsomt tilsettes 70 g benzoylklorid i 10%'ig oppløsning i et med vann ikke blandbart oppløsningsmiddel, såsom benzen. Under denne tilsetning foretas kraftig omrøring. Etter fullført tilsetning tillates reaksjonsblandingen å oppvarmes til romtemperatur, A solution of 45 g of 2-(2-amino-6-benzothiazolyl^propionic acid in 200 ml of 40% aqueous sodium hydroxide solution, which, if desired, may contain 40 g of sodium sulfide nonahydrate is heated to the reflux temperature until the evolution of ammonia has ceased Approximately 500 ml of water is added to the solution, after which, at a temperature of 10°C, 70 g of benzoyl chloride in a 10% solution in a water-immiscible solvent, such as benzene, is slowly added. Vigorous stirring is carried out during this addition. After completion addition, the reaction mixture is allowed to warm to room temperature,

og omrøringen fortsettes i flere timer, hvoretter den organiske fase fraskilles og den vandige fase surgjøres til pH 4 ved tilsetning av en konsentrert vandig saltsyreoppløsning. Den erholdte utfeining består av benzoesyre, de ikke-ringsluttede derivater av typene (IV) og (V) og, enkelte ganger, en viss mengde av det som sluttproduktønskede benzothiazol. and the stirring is continued for several hours, after which the organic phase is separated and the aqueous phase is acidified to pH 4 by adding a concentrated aqueous hydrochloric acid solution. The resulting refinement consists of benzoic acid, the non-ring-closed derivatives of types (IV) and (V) and, occasionally, a certain amount of the desired end product benzothiazole.

Denne blanding underkastes ringslutningen, f.eks. ved at det gummiaktige faste stoff oppvarmes ved 120°C i flere timer eller i surt medium, på følgende måte: det faste stoff oppløses i 1 liter vann inneholdende 70 ml av en 40% Vig vandig natriumhydroxydoppløsning, hvoretter oppløsningen filtre-res gjennom avfargende trekull og så settes dråpevis til en ca. 2N vandig saltsyreoppløsning som holdes ved ca. 50°C. Den erholdte utfeining frafiltreres ved denne temperatur. This mixture is subjected to the cyclization, e.g. by heating the rubbery solid at 120°C for several hours or in an acidic medium, as follows: the solid is dissolved in 1 liter of water containing 70 ml of a 40% Vig aqueous sodium hydroxide solution, after which the solution is filtered through decolorizing charcoal and then add drop by drop to an approx. 2N aqueous hydrochloric acid solution which is kept at approx. 50°C. The obtained clarification is filtered off at this temperature.

Den som sluttprodukt ønskede syre, som herved fåes iThe desired acid as the final product, which is thereby obtained in

et utbytte på 45 g, omkrystalliseres fra en blanding av isopropanol og vann (2:1) eller en blanding av 2-butanon og cyclohexanon (1:2), hvorved det fåes 36 g rent produkt som smelter ved ca. 160°C. Varierende med omkrystalliseringsopp-løsningene og utfelningshastigheten vil syren fåes i/for-skjellige krystallinske former, som av og til kan ha meget like smeltepunkter men hvis spektere for den faste fase i det. infrarøde område ikke dekker hverandre når de legges over hverandre. a yield of 45 g is recrystallized from a mixture of isopropanol and water (2:1) or a mixture of 2-butanone and cyclohexanone (1:2), whereby 36 g of pure product is obtained which melts at approx. 160°C. Varying with the recrystallization solutions and the precipitation rate, the acid will be obtained in different crystalline forms, which may occasionally have very similar melting points but different spectra for the solid phase in it. infrared area do not cover each other when they are superimposed.

Ringslutningen kan også utføres i basisk medium: det erholdte faste stoff vaskes grundig med vann og oppløses i 350 ml av en 95%'ig vandig ethanoloppløsning inneholdende 25 g kaliumhydroxyd. Etter oppvarming i flere timer The cyclization can also be carried out in a basic medium: the solid obtained is washed thoroughly with water and dissolved in 350 ml of a 95% aqueous ethanol solution containing 25 g of potassium hydroxide. After heating for several hours

surgjøres reaksjonsmediet, hvoretter ethanolen fjernes og det erholdte materiale helles over i ca. 1 liter vann. Den erholdte utfelning av den som sluttprodukt ønskede syre isoleres og omkrystalliseres som ovenfor nevnt. the reaction medium is acidified, after which the ethanol is removed and the material obtained is poured into approx. 1 liter of water. The obtained precipitation of the acid desired as end product is isolated and recrystallized as mentioned above.

Eksempel 2 Fremstilling av 2-(2-fenyl-6-benzothiazolyl)-propionsyre med benzaldehyd 22 g 2-(2-amino-6-benzothiazolyl)-propionsyre oppløses i 100 ml av en konsentrert natriumhydroxydoppløsning, og blandingen oppvarmes i 1 time ved tilbakeløpstemperaturen (inntil det ikke lenger utvikles ammoniakk). Oppløsningens pH-verdi innstilles ved romtemperatur på 4,5 med en saltsyreopp-løsning. Den erholdte utfelning frafiltreres, hvorved det fåes 16 g materiale med et smeltepunkt på ca. 154°C. Example 2 Preparation of 2-(2-phenyl-6-benzothiazolyl)-propionic acid with benzaldehyde 22 g of 2-(2-amino-6-benzothiazolyl)-propionic acid are dissolved in 100 ml of a concentrated sodium hydroxide solution, and the mixture is heated for 1 hour at the reflux temperature (until no more ammonia is developed). The solution's pH value is set at room temperature to 4.5 with a hydrochloric acid solution. The precipitate obtained is filtered off, whereby 16 g of material with a melting point of approx. 154°C.

Dette faste materiale og 8 g benzaldehyd oppløses i 100 ml pyridin, og blandingen holdes ved tilbakeløpstempera-turen i 5 timer. Oppløsningsmidlet fjernes så under redusert, trykk. Residuet oppløses i 100 ml ethanol, det tilsettes 200 mg ferriklorid, og oppløsningen holdes i 2 timer ved tilbake-løpstemperaturen. Utfeiningen som kommer til syne ved kjøling, This solid material and 8 g of benzaldehyde are dissolved in 100 ml of pyridine, and the mixture is kept at the reflux temperature for 5 hours. The solvent is then removed under reduced pressure. The residue is dissolved in 100 ml of ethanol, 200 mg of ferric chloride is added, and the solution is kept for 2 hours at the reflux temperature. The blur that appears on cooling,

.renses ved å oppløses i en vandig, basisk oppløsning, før den omkrystalliseres fra en blanding av 2-butanon og cyclohexan .purified by dissolving in an aqueous basic solution, before being recrystallized from a mixture of 2-butanone and cyclohexane

(1:2). Det ønskede produkt fåes i ren form i et utbytte på 40%. (1:2). The desired product is obtained in pure form in a yield of 40%.

Eksempel 3Example 3

Det hygroskopiske natriumsalt av 2-(2-fenyl-6-benzo-thiazolyl)-propionsyre fremstilles ved innvirkning av 0,55 The hygroscopic sodium salt of 2-(2-phenyl-6-benzo-thiazolyl)-propionic acid is prepared by the action of 0.55

g natriumhydroxyd og 3,7 g syre oppløst i 100 ml methanol. • Smeltepunkt=270°C. Dette salt er vannoppløselig. g of sodium hydroxide and 3.7 g of acid dissolved in 100 ml of methanol. • Melting point=270°C. This salt is water soluble.

Eksempel 4 Example 4

Pyrrolidinsaltet av 2-(2-fenyl-6-benzothiazolyl)-propionsyre fremstilles ved innvirkning av 1 g amin på 4 g syre oppløst i methanol. Saltet smelter ved 142°C og er vannopp-løselig. The pyrrolidine salt of 2-(2-phenyl-6-benzothiazolyl)-propionic acid is prepared by the action of 1 g of amine on 4 g of acid dissolved in methanol. The salt melts at 142°C and is water-soluble.

Eksempel 5Example 5

Methansulfonatet av 2-(2-feny 1-6-benzothiazolyl)-pro- The methanesulfonate of 2-(2-phenyl 1-6-benzothiazolyl)-pro-

pionsyre fremstilles ved innvirkning av 0,1 mol sulfonsyre .pionic acid is produced by the action of 0.1 mol of sulphonic acid.

på 0,1 mol syre oppløst i 500 ml aceton. Sméltepunkt=182°C. of 0.1 mol of acid dissolved in 500 ml of acetone. Melting point=182°C.

Eksempel 6Example 6

Hydrokloridet av 2-(2-feny1-6-benzothiazolyl)-propionsyre fremstilles ved innvirkning av gassformig hydrogenklorid på syren i benzenoppløsning. Det smelter ved 150°C under spaltning. The hydrochloride of 2-(2-phenyl-6-benzothiazolyl)-propionic acid is prepared by the action of gaseous hydrogen chloride on the acid in benzene solution. It melts at 150°C during decomposition.

Eksempel 7Example 7

Fremstilling av methyl- 2-( 2- fenyl- 6- benzothiazolyr)- propionatPreparation of methyl-2-(2-phenyl-6-benzothiazolyl)-propionate

6 g 2-(2-fenyl-6-benzothiazolyl)-propionsyre oppløses6 g of 2-(2-phenyl-6-benzothiazolyl)-propionic acid are dissolved

i 100 ml vannfri methanol, og blandingen oppvarmes med tilbake-løpskjøling i 6 timer ved oppløsningsmidlets temperatur etter tilsetning av noen få dråper konsentrert svovelsyre. Oppløs-ningen konsentreres til det halve volum, og esteren utfelles ved tilsetning av 1 volumdel isvann, hvorved det fåes 5 g. ester som smelter ved 86°C. in 100 ml of anhydrous methanol, and the mixture is heated under reflux for 6 hours at the temperature of the solvent after the addition of a few drops of concentrated sulfuric acid. The solution is concentrated to half the volume, and the ester is precipitated by adding 1 part by volume of ice water, whereby 5 g of ester is obtained which melts at 86°C.

E ksempel 8 Separasjon av de to enantiomere av 2-(2-fenyl-6-benzothiazolyl)-propionsyre fra den racemiske blanding Example 8 Separation of the two enantiomers of 2-(2-phenyl-6-benzothiazolyl)-propionic acid from the racemic mixture

a) Høyredreiende enantiomer (i dimethylformamidoppløsning) Saltet av syren med venstredreiende a-fenylethylamin a) Dextrorotatory enantiomer (in dimethylformamide solution) Salt of the acid with dextrorotatory a-phenylethylamine

fremstilles i 2-butanon. Ved tilsetning av 19 g amin oppløst i 50 ml 2-butanon til en oppløsning av 50 g syre i 5.00 ml 2-butanon fåes 51 g av en saltutfeining. Denne utfelning omkrystalliseres 6 ganger fra en minst mulig mengde 2-butanon, is produced in 2-butanone. By adding 19 g of amine dissolved in 50 ml of 2-butanone to a solution of 50 g of acid in 5.00 ml of 2-butanone, 51 g of a salt solution is obtained. This precipitate is recrystallized 6 times from the smallest possible amount of 2-butanone,

22 hvorved det fåes 10 g salt med en spesifikk dreining [a]D = 22,5° i methanol (c = 2g/100 ml). 22 whereby 10 g of salt are obtained with a specific rotation [a]D = 22.5° in methanol (c = 2g/100 ml).

Den frie syre fåes ved tilsetning av saltsyre til den vandige oppløsning av dette aminsalt. Den erholdte utfelning isoleres og omkrystalliseres gjentatte ganger fra isopropanol-vann (2:1), hvorved den høyredreiende enantiomer fåes i et utbytte på 35%. Smeltepunkt=179°C. b) Venstredreiende enantiomer (i dimethylformamidoppløsning) Oppløsningsmidlene som ble benyttet ved omkrystalli-seringen av chiralsaltet i henhold til a) inndampes, og syren, blandet med en liten mengde venstredreiende enantiomer, fri-gjøres fra saltet, hvorved det fåes 25 g syre. Av disse 25 g syre fremstilles 28 g salt ved innvirkning på syren av 10,3 g høyredreiende a-fenylethylamin oppløst i 540 ml 2-butanon. The free acid is obtained by adding hydrochloric acid to the aqueous solution of this amine salt. The precipitate obtained is isolated and recrystallized repeatedly from isopropanol-water (2:1), whereby the dextrorotatory enantiomer is obtained in a yield of 35%. Melting point=179°C. b) Left-handed enantiomers (in dimethylformamide solution) The solvents used in the recrystallization of the chiral salt according to a) are evaporated, and the acid, mixed with a small amount of left-handed enantiomers, is released from the salt, whereby 25 g of acid is obtained. From these 25 g of acid, 28 g of salt are produced by the action on the acid of 10.3 g of dextrorotatory α-phenylethylamine dissolved in 540 ml of 2-butanone.

Etter tre omkrystalliseringer fra 2-butanon har detAfter three recrystallizations from 2-butanone it has

22 o . isolerte salt en spesifikk dreining [a]D=23 (c = 2g/100 ml, methanol). 22 isolated salt a specific rotation [a]D=23 (c = 2g/100 ml, methanol).

Syren frigjøres så fra saltet og omkrystalliseres gjentatte ganger fra først isopropanol-vann (2:1) og deretter 2-butanon/cyclohexan (1:2), hvorved den venstredreiende iso-mer med optisk renhet ca. 98% fåes i et utbytte på 25%. The acid is then released from the salt and recrystallized repeatedly from first isopropanol-water (2:1) and then 2-butanone/cyclohexane (1:2), whereby the left-handed isomer with optical purity approx. 98% is obtained in a yield of 25%.

[a]D = -81° (C = 0,1 g/ml, dimethylformamid. Smeltepunkt =179°c. [a]D = -81° (C = 0.1 g/ml, dimethylformamide. Melting point = 179°c.

Forbindelsene av formel (I) inhiberer biosyntesen av prostaglandinene og oppviser analgetiske egenskaper i de inhiberende doser. De virker også hemmende på blodplatéaggre-gering og beskytter mot de cardiovaskulære virkninger av endotoxin-frembragt sjokk. The compounds of formula (I) inhibit the biosynthesis of the prostaglandins and exhibit analgesic properties in the inhibitory doses. They also inhibit platelet aggregation and protect against the cardiovascular effects of endotoxin-induced shock.

De har lav toksisitet (for mus er den orale ^^cnhøyere enn 1000 mg/kg). Da de effektive doser som er blitt bestemt ved de forskjellige tester, er betydelig lavere, er forbindelsenes terapeutiske indeks utmerket, hvilket gjør dem nyttige i humanterapien. They have low toxicity (for mice the oral dose is higher than 1000 mg/kg). Since the effective doses determined by the various tests are considerably lower, the therapeutic index of the compounds is excellent, making them useful in human therapy.

Den analgetiske virkning av forbindelsene av formelThe analgesic effect of the compounds of formula

(I) ble vist ved den test hvor det frembringes kramper hos mus ved hjelp av fenylbenzokinon. Syren av formel (I) (racematet) ga ved denne test en oral ED^Q .på 3-6 mg/kg. Denne analgetiske virkning er langvarig, idet en dose på 12,5 mg/kg av denne forbindelse fortsatt gir en analgesi på 42% 24 (I) was shown by the test in which convulsions are produced in mice by means of phenylbenzoquinone. The acid of formula (I) (the racemate) gave in this test an oral ED₂Q of 3-6 mg/kg. This analgesic effect is long-lasting, as a dose of 12.5 mg/kg of this compound still provides an analgesia of 42% 24

timer etter at administreringen.hours after the administration.

På den annen side inhiberte forbindelsene av formelOn the other hand, the compounds of formula inhibited

(I) den blodplateaggregering som ble frembragt in vitro med ADP på blodplateanriket plasma fra rotter. Således er natrium-2-(2-fenyl-6-benzothiazolyl)-propionat aktivt i en konsentra-sjon som er 10 ganger lavere enn for acetylsalicylsyre. (I) the platelet aggregation produced in vitro by ADP on rat platelet-enriched plasma. Thus, sodium 2-(2-phenyl-6-benzothiazolyl)-propionate is active in a concentration that is 10 times lower than that of acetylsalicylic acid.

Aktiviteten av forbindelsene med formel (I) på biosyntesen av prostaglandinene vises ved en beskyttendé virkning mot den toksiske virkning av arachidonsyre, som er en forløper ved denne biosyntese.. Således vil forbindelsene av formel (I) ved oral administrering i en dose på 0,5 mg/kg nedsette døde-ligheten hos mus som er gitt en dødelig dose av arachidonsyre. Gitt intravenøst er de oppløselige salter av forbindelsene av formel (I), og spesielt natriumsaltet, aktive i de samme doser. Den høyredreiende enantiomer av syren (eksempel 8) har en virkning som er sammenlignbar med virkningen av racematet (eksempel 1) og som er høyere enn virkningen av den homologe venstredreiende forbindelse. The activity of the compounds of formula (I) on the biosynthesis of the prostaglandins is shown by a protective effect against the toxic effect of arachidonic acid, which is a precursor in this biosynthesis. Thus, the compounds of formula (I) when administered orally in a dose of 0, 5 mg/kg reduce mortality in mice given a lethal dose of arachidonic acid. Given intravenously, the soluble salts of the compounds of formula (I), and especially the sodium salt, are active in the same doses. The dextrorotatory enantiomer of the acid (Example 8) has an activity comparable to that of the racemate (Example 1) and higher than the activity of the homologous levorotatory compound.

Forbindelsene av formel (I) kan administreres på mennesker i forskjellige farmasøytiske former, oralt, rektalt eller parenteralt, i effektive, ikke-toksiske doser for smertestillelse, behandling av hyperthermia, dysmenorrhea og sjokktilstander og for behandling av sykdommer hvor en minsk-ning av blodplateaggregeringen er en viktig faktor. The compounds of formula (I) can be administered to humans in various pharmaceutical forms, orally, rectally or parenterally, in effective, non-toxic doses for analgesia, treatment of hyperthermia, dysmenorrhea and shock states and for the treatment of diseases in which a decrease in platelet aggregation is an important factor.

Enhetsdosen avhenger av administreringsmåten og av arten av forbindelsen som velges som aktiv bestanddel i det terapeutiske preparat. Oppløsningene for parenteral eller -intravenøs administrering tilberedes fortrinnsvis med vandige fortynningsmidler, idet den aktive bestanddel anvendes i en kjemisk form som er oppløselig i dette mediet, f.eks. i form av et alkalimetallsalt. For oral administrering kan forbindelsene av formel (I) anbringes i kapsler eller blandes med de vanlige eksipienter for dannelse av piller, tabletter eller kapsler som er oppløselige i magen eller tarmen. The unit dose depends on the method of administration and on the nature of the compound chosen as active ingredient in the therapeutic preparation. The solutions for parenteral or intravenous administration are preferably prepared with aqueous diluents, the active ingredient being used in a chemical form which is soluble in this medium, e.g. in the form of an alkali metal salt. For oral administration, the compounds of formula (I) may be placed in capsules or mixed with the usual excipients to form pills, tablets or capsules which dissolve in the stomach or intestine.

Når det bortsees fra spesielle tilfeller, er den dag-lige dose for voksne fra 20 mg til 1 g, tatt som én enkelt dose eller i flere doser. Apart from special cases, the daily dose for adults is from 20 mg to 1 g, taken as a single dose or in several doses.

Claims (2)

1. Fremgangsmåte ved fremstilling av de enantiomere og racematet av 2-(2-fenyl-6-benzothiazolyl)-propionsyre med formelen: 1. Procedure for the preparation of the enantiomers and the racemate of 2-(2-phenyl-6-benzothiazolyl)-propionic acid with the formula: deres salter med i fysiologisk henseende akseptable baser, uorganiske kationer og aminer, og deres salter med i fysiologisk henseende akseptable uorganiske eller organiske syrer, samt deres alkylestere, karakterisert ved at benzoesyre eller en reaktiv, med denne ekvivalent forbindelse, såsom det tilsvarende syreklorid, ester eller ald ehyd , omsettes med en forbindelse av formelen: their salts with physiologically acceptable bases, inorganic cations and amines, and their salts with physiologically acceptable inorganic or organic acids, as well as their alkyl esters, characterized in that benzoic acid or a reactive, with this equivalent compound, such as the corresponding acid chloride, ester or aldehyde, is reacted with a compound of the formula: eller en med denne ekvivalent forbindelse, såsom det tilsvarende disulfid, hvoretter den erholdte syre eventuelt overføres til et salt eller en ester.or one with this equivalent compound, such as the corresponding disulfide, after which the acid obtained is optionally transferred to a salt or an ester. 2. Fremgangsmåte ifølge krav 1, for separasjon av de to enantiomere av 2-(2-fenyl-6-benzothiazoly1)-propionsyre, karakterisert ved at man omkrystalliserer de diastereoisomere salter som fåes ved omsetning av racematet med et chiralamin.2. Method according to claim 1, for the separation of the two enantiomers of 2-(2-phenyl-6-benzothiazoly1)-propionic acid, characterized in that the diastereoisomeric salts obtained by reacting the racemate with a chiralamine are recrystallized.
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