NO125971B

NO125971B -

Info

Publication number: NO125971B
Application number: NO210969A
Authority: NO
Inventors: J Fried; I Harrison
Original assignee: Syntex Corp
Priority date: 1969-05-22
Filing date: 1969-05-22
Publication date: 1972-12-04

Description

Analogifremgangsmåte til fremstilling av Analogy method for the production of

nye terapeutisk virksomme naftylalkanoler. new therapeutically active naphthylalkanols.

Foreliggende oppfinnelse vedrører en analogifremgangsmåte til fremstilling av nye naftylalkanoler, og mer spesielt 3-(2-naftyl) a-metyletanoler og derivater derav, som har anti-inflammatorisk, analgetisk, anti-pyretisk og anti-pruritisk aktivitet, og som har den generelle formel: The present invention relates to an analogous process for the production of new naphthyl alkanols, and more particularly 3-(2-naphthyl) α-methylethanols and derivatives thereof, which have anti-inflammatory, analgesic, anti-pyretic and anti-pruritic activity, and which have the general formula:

hvor R1 er hydroksy eller acetoksy og R^ er metoksy, metyl eller metyl-tio. where R 1 is hydroxy or acetoxy and R 1 is methoxy, methyl or methyl-thio.

Forbindelsene med formel I kan foreligge som enantiomorfe par. Hver av de optiske isomerene av de fremstilte naftylalkanoler omfattes av foreliggende oppfinnelse. I noen tilfeller utviser en enantiomorf forbindelse større anti-inflammatorisk, analgetisk, anti-pyretisk og/eller anti-pruritisk- aktivitet enn den andre enantiomorfe forbindelse. Den venstredreiende form, 1 eller (-)-formen, av 0-(6-metoksy-2-naftyl)-3-metyletanol, utviser f.eks. større anti-inflammatorisk aktivitet enn den tilsvarende høyredreiende form. The compounds of formula I can exist as enantiomorphic pairs. Each of the optical isomers of the produced naphthyl alkanols is covered by the present invention. In some cases, one enantiomorphic compound exhibits greater anti-inflammatory, analgesic, anti-pyretic and/or anti-pruritic activity than the other enantiomorphic compound. The levorotatory form, 1 or (-)-form, of 0-(6-methoxy-2-naphthyl)-3-methylethanol exhibits e.g. greater anti-inflammatory activity than the corresponding dextrorotatory form.

De ifølge oppfinnelsen fremstilte naftylalkanoler som foreligger som enantiomorfe forbindelser kan administreres som blandinger av enantiomorfe forbindelser eller som rene, adskilte enantiomorfer. The naphthyl alkanols produced according to the invention which are present as enantiomorphic compounds can be administered as mixtures of enantiomorphic compounds or as pure, separated enantiomorphs.

De adskilte eller optisk aktive forbindelser med formel I kan fremstilles fra de tilsvarende optisk aktive utgangsforbindelser som benyttes for fremstilling av forbindelsene med formel I. De adskilte eller optisk aktive forbindelser med formel I og deres respek-tive optisk aktive utgangsforbindelser behøver nødvendigvis ikke å ha den. samme optiske rotasjon selv om de har den samme absolutte konfigurasjon. 1-3-(6-metoksy-2-naftyl)-3-metyletanol fremstilles f.eks. fra d-6-metoksy-2-naftyl-a-metyledddiksyre. The separated or optically active compounds of formula I can be prepared from the corresponding optically active starting compounds used for the preparation of the compounds of formula I. The separated or optically active compounds of formula I and their respective optically active starting compounds do not necessarily have to have the . same optical rotation even though they have the same absolute configuration. 1-3-(6-methoxy-2-naphthyl)-3-methylethanol is prepared, e.g. from d-6-methoxy-2-naphthyl-α-methylacetic acid.

Forbindelsene med formel I utviser anti-inflammatorisk, analgetisk, anti-pyretisk og anti-pruritisk aktivitet hos pattedyr. The compounds of formula I exhibit anti-inflammatory, analgesic, anti-pyretic and anti-pruritic activity in mammals.

Disse forbindelser er nyttige ved behandling av betennelser i huden, åndedrettsystemet, muskel-skjelettsystemet, ledd, indre or-ganer og i vev. Forbindelsene er følgelig nyttige ved behandling av tilstander som er kjennetegnet ved inflammasjon, slik som kontakt der-matitis, allergiske tilstander, brannsår, reumatisme, kontusjon, ar-tritis, brudd, post-traumatiske tilstander og podagra. I de tilfeller hvor de ovennevnte tilstander omfatter smerte, pyrexia og pruritus sammen med inflammasjon, er de fremstilte forbindelser nyttige for helbredning av disse tilstander og inflammasjon. De fremstilte forbindelser er videre egnet for behandling av smerte i forbindelse med post-operative tilstander, post-traumatiske tilstander, post-partum tilstander, dysmenorrhea, brannsår, podagra, kontusjoner, neuralgia, neuritis, hodepine og reumatisk feber. Forbindelsene utviser som tidligere nevnt også anti-pyretisk aktivitet og de er derfor nyttige ved behandling av pyrexia hvor det antydes en opphevelse av feberen, f. eks. tilfeller hvor høy feber er forbundet med sykdommer slik som reu-matisk feber, bronkitt, pneumonia, tyfoidfeber og lymfogranulomatosis. These compounds are useful in the treatment of inflammation in the skin, respiratory system, musculoskeletal system, joints, internal organs and tissues. The compounds are consequently useful in the treatment of conditions characterized by inflammation, such as contact dermatitis, allergic conditions, burns, rheumatism, contusion, arthritis, fractures, post-traumatic conditions and gout. In those cases where the above conditions include pain, pyrexia and pruritus together with inflammation, the prepared compounds are useful for healing these conditions and inflammation. The prepared compounds are further suitable for the treatment of pain in connection with post-operative conditions, post-traumatic conditions, post-partum conditions, dysmenorrhea, burns, gout, contusions, neuralgia, neuritis, headaches and rheumatic fever. As previously mentioned, the compounds also exhibit anti-pyretic activity and are therefore useful in the treatment of pyrexia where a cessation of the fever is suggested, e.g. cases where high fever is associated with diseases such as rheumatic fever, bronchitis, pneumonia, typhoid fever and lymphogranulomatosis.

De fremstilte forbindelser er .også nyttige ved behandling av pruritus hvor denne tilstand forekommer sammen med inflammasjon, smerte og/eller høy feber. Forbindelsene er dessuten egnet for behandling av pruritus per se. The prepared compounds are also useful in the treatment of pruritus where this condition occurs together with inflammation, pain and/or high fever. The compounds are also suitable for the treatment of pruritus per se.

De ifølge oppfinnelsen fremstilte forbindelser utviser i alminnelighet større anti-inflammatorisk, analgetisk, anti-pyretisk og anti-pruritisk aktivitet enn de tidligere kjente konvensjonelle forbindelser med samme virkning. Bedømmelse av f.eks. den anti-inf lammatoriske aktivitet ifølge det carrageenin-induserte ødem for-søk (Winter et al., Proceedings of the Society for Experimental Biology and Fedicin 111, 5^4 (1962)) viser at 1 3-(6-metoksy-2-naftyl)-6-metyletanol har en aktivitet som er syv ganger større enn aktiviteten for fenylbutazon. Lignende standardprøver for måling av analgetiske og anti-pyretiske aktiviteter viser at g-(6-metoksy-2-naftyl)-g-metyletanol har en aktivitet som er tre og åtte ganger større enn aktivi-tetene for aspirin i de to nevnte kategorier, respektivt. The compounds produced according to the invention generally exhibit greater anti-inflammatory, analgesic, anti-pyretic and anti-pruritic activity than the previously known conventional compounds with the same effect. Assessment of e.g. the anti-inflammatory activity in the carrageenin-induced edema study (Winter et al., Proceedings of the Society for Experimental Biology and Dieticin 111, 5^4 (1962)) shows that 1 3-(6-methoxy-2 -naphthyl)-6-methylethanol has an activity that is seven times greater than the activity of phenylbutazone. Similar standard tests for measuring analgesic and anti-pyretic activities show that g-(6-methoxy-2-naphthyl)-g-methylethanol has an activity that is three and eight times greater than the activities of aspirin in the two categories mentioned, respectively.

Forbindelsene med formel I fremstilles ifølge oppfinnelsen fra de tilsvarende 2-naftyl a-metyleddiksyrer eller estere derav via en fremgangsmåte som kan illustreres som følger: The compounds of formula I are prepared according to the invention from the corresponding 2-naphthyl α-methylacetic acids or esters thereof via a method which can be illustrated as follows:

5 11 5 11

hvori R har den ovenfor angitte betydning og R er hydrogen eller lavere alkyl. wherein R has the meaning given above and R is hydrogen or lower alkyl.

Den ovenfor illustrerte fremgangsmåte foretas ved behandling av forbindelsene med formel VI med litiumaluminiumhydrid. Dersom den frie karboksylsyreformen av forbindelsen med formel VI (hvor R^1 er hydrogen) anvendes som utgangsmateriale, benyttes minst 0.75 molarekvivalenter litiumaluminiumhydrid og fortrinnsvis ca. 1.0 - 2.5 molarekvivalenter. Dersom esterformen av forbindelsen med formel VI (hvor R<11> er alkyl) benyttes som utgangsmateriale, anvendes 0.5 molarekvivalenter og fortrinnsvis ca. 0,6 - 2.0 molarekvivalenter litiumaluminiumhydrid. Fremgangsmåten utføres i en inert organisk ester, slik Bom dietyleter, dipropyleter, diisopropyleter, dibutyleter. og tetrahydrofuran. Reaksjonen utføres ved en temperatur mellom 0°C og kokepunktet for det benyttede oppløsningsmiddel, fortrinnsvis mellom 15° og 35°C. The process illustrated above is carried out by treating the compounds of formula VI with lithium aluminum hydride. If the free carboxylic acid form of the compound with formula VI (where R^1 is hydrogen) is used as starting material, at least 0.75 molar equivalents of lithium aluminum hydride and preferably approx. 1.0 - 2.5 molar equivalents. If the ester form of the compound with formula VI (where R<11> is alkyl) is used as starting material, 0.5 molar equivalents are used and preferably approx. 0.6 - 2.0 molar equivalents of lithium aluminum hydride. The process is carried out in an inert organic ester, such as Bom diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether. and tetrahydrofuran. The reaction is carried out at a temperature between 0°C and the boiling point of the solvent used, preferably between 15° and 35°C.

Forbindelsene med formel VII isoleres ved ødeleggelse av eventuelt tilstedeværende overskudd litiumaluminiumhydrid, f.eks. ved tilsetning av et overskudd etylacetat eller vandige oppløsninger av natriumhydroksyd eller ammoniumklorid. Blandingen fortynnes deretter med vann, filtreres og ekstraheres med et inert organisk oppløsnings-middel som ikke er blandbart med vann. Forbindelsene med formel VII kan ytterligere renses ved hjelp av standard teknikker slik som krystallisering og kromatografi.'The compounds of formula VII are isolated by destroying any excess lithium aluminum hydride, e.g. by adding an excess of ethyl acetate or aqueous solutions of sodium hydroxide or ammonium chloride. The mixture is then diluted with water, filtered and extracted with an inert organic solvent which is not miscible with water. The compounds of formula VII can be further purified using standard techniques such as crystallization and chromatography.

Forbindelsene med formel VI kan alternativt reduseres ved behandling med diboran i tetrahydrofuran ved en temperatur på mellom 0° og ca. 65°C. The compounds of formula VI can alternatively be reduced by treatment with diborane in tetrahydrofuran at a temperature of between 0° and approx. 65°C.

Forbindelsene med formel VII kan forestres ved hjelp av vanlige metoder. Forbindelsene kan f.eks. forestres ved behandling med et syreanhydrid slik som eddiksyreanhydrid i pyridin, eller ved behandling med et syreklorid slik som acetylklorid The compounds of formula VII can be esterified by conventional methods. The connections can e.g. esterified by treatment with an acid anhydride such as acetic anhydride in pyridine, or by treatment with an acid chloride such as acetyl chloride

i pyridin, eller ved behandling med en karboksylsyre i nærvær av en syrekatalysator slik som p-toluensulfonsyre. in pyridine, or by treatment with a carboxylic acid in the presence of an acid catalyst such as p-toluenesulfonic acid.

Når en optisk aktiv enantiomorf forbindelse med formel VI anvendes som utgangsmateriale i den ovenfor beskrevne fremgangsmåte, oppnåes den tilsvarende optisk aktive enantiomorfe forbindelse med formel VII. Selv om den absolutte konfigurasjon av 2-naftyl-a-metyl-eddiksyre-utgangsforbindelsen og det tilsvarende 3-(2-naftyl)-a-metyl-etanolprodukt som nevnt ovenfor vil være identisk, er den optiske rotasjon av utgangsforbindelsen og produktet motsatt. When an optically active enantiomorphic compound of formula VI is used as starting material in the method described above, the corresponding optically active enantiomorphic compound of formula VII is obtained. Although the absolute configuration of the 2-naphthyl-α-methyl-acetic acid starting compound and the corresponding 3-(2-naphthyl)-α-methyl-ethanol product as mentioned above will be identical, the optical rotation of the starting compound and the product is opposite.

Forbindelsene med formel VI kan fremstilles som følger. En metode er å behandle en tetralonforbindelse substituert i C-6-stilling med en metoksy- eller metyltiogruppe, fortløpende med (1) et alkyl-karbonat og et alkalimetallhydrid, (2) et alkalimetallhydrid og en a-halogeneddiksyre og (3) vandig mineralsyre for oppnåelse av tilsvarende 2-(karboksymetyl)-l-tetralon. Denne sistnevnte forbindelse reduseres med natriumborhydrid for dannelse av den tilsvarende 1,2,3,4-tetrahydro-l-hydroksy-2-naftyleddiksyre, og dette produkt hydrogenolyseres med hydrogen i nærvær av en hydrogeneringskatalysator, det resulterende produkt forestres og blir deretter dehydrogenert med palladium-trekull-katalysator ved ca. 180°C for å oppnå det tilsvarende 2-naftyleddiksyreesterderivat. The compounds of formula VI can be prepared as follows. One method is to treat a tetralone compound substituted at the C-6 position with a methoxy or methylthio group, successively with (1) an alkyl carbonate and an alkali metal hydride, (2) an alkali metal hydride and an α-haloacetic acid, and (3) aqueous mineral acid to obtain the corresponding 2-(carboxymethyl)-1-tetralone. This latter compound is reduced with sodium borohydride to form the corresponding 1,2,3,4-tetrahydro-1-hydroxy-2-naphthylacetic acid, and this product is hydrogenolyzed with hydrogen in the presence of a hydrogenation catalyst, the resulting product is esterified and then dehydrogenated with palladium-charcoal catalyst at approx. 180°C to obtain the corresponding 2-naphthylacetic acid ester derivative.

a-metylsubstituentene adderes til de a-usubstituerte forbindelser (dvs. 6-metoksy-2-naftyleddiksyre) ved forestring av sistnevnte forbindelser og behandling av disse med en molarekvivalent av et alkalimetallhydrid slik som natriumhydrid og deretter med et molart overskudd av et metylhalogenid slik som metyljodid. The α-methyl substituents are added to the α-unsubstituted compounds (ie 6-methoxy-2-naphthylacetic acid) by esterifying the latter compounds and treating these with a molar equivalent of an alkali metal hydride such as sodium hydride and then with a molar excess of a methyl halide such as methyl iodide.

Forbindelsene med formel VI kan adskilles ved fremstilling av deres alkaloidbase-salter, resolvering av de resulterende diastereo-isomersalter ved fraksjonert krystallisering og spalting av de resol-verte salter. Den optiske rotasjon av en spesiell enantiomorf forbindelse bestemmes ved hjelp av polarimetri. The compounds of formula VI can be separated by preparation of their alkaloid base salts, resolution of the resulting diastereoisomeric salts by fractional crystallization and cleavage of the resolved salts. The optical rotation of a particular enantiomorphic compound is determined by polarimetry.

Fremstilling av utgangsmaterialer: Preparation of starting materials:

Fremstilling 1 Production 1

En blanding av 3.6 g 6-metoksy-l-tetralon, 12 g dietylkarbo-nat, 0.5 g natriumhydrid og 40 ml toluen, oppvarmes til 60°C i 5 timer. Blandingen avkjøles, surgjøres ved tilsetning av 40 ml 1 N saltsyre A mixture of 3.6 g of 6-methoxy-1-tetralone, 12 g of diethyl carbonate, 0.5 g of sodium hydride and 40 ml of toluene is heated to 60° C. for 5 hours. The mixture is cooled, acidified by adding 40 ml of 1 N hydrochloric acid

og ekstraheres deretter med tre 75 ml porsjoner benzen. Ekstraktene kombineres, vaskes med vann til nøytralitet og tørkes over natriumsulfat. and then extracted with three 75 ml portions of benzene. The extracts are combined, washed with water to neutrality and dried over sodium sulfate.

Blandingen som inneholder 6-metoksy-2-etoksykarbonyl-l-tetralon, behandles med 0.5 g natriumhydrid ved romtemperatur under omrøring. Deretter tilsettes 20 g etyl-a-bromacetat og blandingen hensettes ved romtemperatur i 12 timer. Blandingen tilsettes til 500 ml vann og ekstraheres med metylenklorid. Ekstraktene kombineres, vaskes med vann til nøytralitet, tørkes over natriumsulfat og inndampes. Resten, inneholdende 6-metoksy-2-etoksykarbonyl-2-(etoksykar-bonylmetyl)-l-tetralon, kokes under tilbakeløp i 40 ml 6 N saltsyre i 24 timer hvoretter blandingen inndampes. The mixture containing 6-methoxy-2-ethoxycarbonyl-1-tetralone is treated with 0.5 g of sodium hydride at room temperature with stirring. 20 g of ethyl-α-bromoacetate are then added and the mixture is allowed to stand at room temperature for 12 hours. The mixture is added to 500 ml of water and extracted with methylene chloride. The extracts are combined, washed with water until neutral, dried over sodium sulfate and evaporated. The residue, containing 6-methoxy-2-ethoxycarbonyl-2-(ethoxycarbonylmethyl)-1-tetralone, is refluxed in 40 ml of 6 N hydrochloric acid for 24 hours, after which the mixture is evaporated.

Resten, som inneholder 6-metoksy-2-(karboksymetyl)-l-tetralon, reduseres ved behandling med 40 ml etanol inneholdende 1.6 g natriumborhydrid. Etter 1 time surgjøres blandingen ved tilsetning av 20 ml 3 N saltsyre og den resulterende blanding ekstraheres med flere porsjoner metylenklorid. Ekstraktene kombineres, vaskes med vann til nøytralitet, tørkes over natriumsulfat og inndampes. The residue, which contains 6-methoxy-2-(carboxymethyl)-1-tetralone, is reduced by treatment with 40 ml of ethanol containing 1.6 g of sodium borohydride. After 1 hour, the mixture is acidified by adding 20 ml of 3 N hydrochloric acid and the resulting mixture is extracted with several portions of methylene chloride. The extracts are combined, washed with water until neutral, dried over sodium sulfate and evaporated.

Resten, som inneholder 6-metoksy-l-hydroksy-l,2,3,4-tetra-hydro-2-naftyleddiksyre, hydrogenolyseres ved hydrogenering med en ekvivalent hydrogen i eddiksyre inneholdende 60 mg 5 % palladium-på-bariumsulfat. Hydrogeneringsblandingen filtreres og inndampes. Resten, som inneholder 6-metoksy-l,2,3,4-tetrahydro-2-naftyleddiksyre, oppløses i 40 ml dietyleter og blandingen tilsettes deretter til en 20 ml's oppløsning av dietyleter inneholdende 1.3 g diazometan. Blandingen inndampes deretter til tørrhet. Den forestrede rest dehydro-generes ved å tilsette den til 1 g 10 % palladium-på-trekull og opp-varmning av den resulterende blanding i 6 timer ved 200°C. Den av-kjølte blanding fortynnes med 4.0 ml kloroform, filtreres og inndampes hvilket gir metyl-6-metoksy-2-naftylacetat. The residue, containing 6-methoxy-1-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetic acid, is hydrogenolyzed by hydrogenation with one equivalent of hydrogen in acetic acid containing 60 mg of 5% palladium-on-barium sulfate. The hydrogenation mixture is filtered and evaporated. The residue, which contains 6-methoxy-1,2,3,4-tetrahydro-2-naphthylacetic acid, is dissolved in 40 ml of diethyl ether and the mixture is then added to a 20 ml solution of diethyl ether containing 1.3 g of diazomethane. The mixture is then evaporated to dryness. The esterified residue is dehydrogenated by adding it to 1 g of 10% palladium-on-charcoal and heating the resulting mixture for 6 hours at 200°C. The cooled mixture is diluted with 4.0 ml of chloroform, filtered and evaporated to give methyl 6-methoxy-2-naphthyl acetate.

Til en blanding av 22 g metyl-6-metoksy-2-naftylacetat, 0.25 g natriumhydrid og 15 ml 1,2-rdimetoksyetan, tilsettes 25 g metyljodid. Reaksjonsblandingen settes til side i flere timer, hvoretter den fortynnes med etanol og deretter vann og ekstraheres med metylenklorid. Ekstraktene kombineres, vaskes med vann til nøytralitet, tørkes over natriumsulfat, filtreres og inndampes og dette gir metyl-6-metoksy-2-naftyl-a-metylacetat. To a mixture of 22 g of methyl-6-methoxy-2-naphthyl acetate, 0.25 g of sodium hydride and 15 ml of 1,2-dimethoxyethane, 25 g of methyl iodide is added. The reaction mixture is set aside for several hours, after which it is diluted with ethanol and then water and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered and evaporated and this gives methyl-6-methoxy-2-naphthyl-α-methylacetate.

Metyl-6-metoksy-2-naftyl- ot-metylacetatet, 1.5 g natrium-karbonat, 200 ml metanol og 25 ml vann settes til side i 24 timer. Reaksjonsblandingen surgjøres deretter med 200 ml 2 N saltsyre og ekstraheres med metylenklorid. Ekstraktene kombineres, vaskes med vann, tørkes over natriumsulfat og inndampes og dette gir 6-metoksy-2-naftyl-a-metyleddiksyre, smeltepunkt 151°C. The methyl-6-methoxy-2-naphthyl-o-methylacetate, 1.5 g of sodium carbonate, 200 ml of methanol and 25 ml of water are set aside for 24 hours. The reaction mixture is then acidified with 200 ml of 2 N hydrochloric acid and extracted with methylene chloride. The extracts are combined, washed with water, dried over sodium sulfate and evaporated and this gives 6-methoxy-2-naphthyl-α-methylacetic acid, melting point 151°C.

Ved å gjenta den ovenfor beskrevne fremgangsmåte med 6-metyl-tio-l-tetralon oppnåes 6-metyltio-2-naftyl-a-metyleddiksyre, smeltepunkt 140°C By repeating the procedure described above with 6-methyl-thio-1-tetralone, 6-methylthio-2-naphthyl-α-methylacetic acid is obtained, melting point 140°C

Fremstilling 2 Manufacturing 2

En blanding av 1 g dl 6-metoksy-2-naftyl-a-metyleddiksyre, 1.26 g cinchonidin og 22 ml metanol omrøres i 2 timer hvoretter blandingen hensettes inntil krystalliseringen er fullstendig. Krystallene frafiltreres og vaskes med metanol. Deretter omkrystalliseres krystallene fra metanol, filtreres, vaskes og tørkes. De rene krystaller tilsettes til 60 ml 0.2 N saltsyre. Den resulterende blanding omrøres i 2 timer og ekstraheres deretter med dietyleter. Ekstraktene kombineres, vaskes med vann til nøytralitet, tørkes over natriumsulfat og inndampes og dette gir d 6-metoksy-2-naftyl-a-metyleddiksyre, smeltepunkt 153°C. A mixture of 1 g dl of 6-methoxy-2-naphthyl-α-methylacetic acid, 1.26 g of cinchonidine and 22 ml of methanol is stirred for 2 hours, after which the mixture is allowed to stand until crystallization is complete. The crystals are filtered off and washed with methanol. The crystals are then recrystallized from methanol, filtered, washed and dried. The pure crystals are added to 60 ml of 0.2 N hydrochloric acid. The resulting mixture is stirred for 2 hours and then extracted with diethyl ether. The extracts are combined, washed with water to neutrality, dried over sodium sulfate and evaporated and this gives d 6-methoxy-2-naphthyl-α-methylacetic acid, melting point 153°C.

Ved å gjenta denne fremgangsmåte ved gjentatt omkrystallisering med dl 6-metyl-2-naftyl-a-metyleddiksyre og dl 6-metyltio-2-naftyl-a-metyleddiksyre oppnås henholdsvis d 6-.metyl-2-nafty 1-a-metyl-eddiksyre, smeltepunkt 149°C, og d 6-metyltio-2-naftyl-a-metyleddik-syre, smeltepunkt 188° - 191°C. By repeating this procedure by repeated recrystallization with dl 6-methyl-2-naphthyl-a-methylacetic acid and dl 6-methylthio-2-naphthyl-a-methylacetic acid, d 6-.methyl-2-naphthy 1-a-methyl is obtained respectively -acetic acid, melting point 149°C, and d 6-methylthio-2-naphthyl-α-methylacetic acid, melting point 188° - 191°C.

■ Følgende eksempler illustrerer oppfinnelsen. ■ The following examples illustrate the invention.

Eksempel 1 Example 1

Til en blanding av 0.4 g litiumaluminiumhydrid og 100 ml etyleter, tilsettes en blanding av 2.3 g av en d 6-metoksy-2-naftyl-a-metyleddiksyre og 100 ml etyleter. Blandingen omrøres ved 0°C i 30 minutter hvoretter 10 ml etylacetat tilsettes, og 1 time senere tilsettes 4 ml vann. Den resulterende blanding filtreres og inndampes under redusert trykk og dette gir 1 3-(6-metoksy-2-naftyl)-3-metyletanol, smeltepunkt 88° - 89°C. To a mixture of 0.4 g of lithium aluminum hydride and 100 ml of ethyl ether, a mixture of 2.3 g of a d 6-methoxy-2-naphthyl-α-methylacetic acid and 100 ml of ethyl ether is added. The mixture is stirred at 0°C for 30 minutes, after which 10 ml of ethyl acetate is added, and 1 hour later, 4 ml of water is added. The resulting mixture is filtered and evaporated under reduced pressure to give 1 3-(6-methoxy-2-naphthyl)-3-methylethanol, melting point 88°-89°C.

Ved å gjenta den ovenfor angitte metode med dl 6-metoksy-2-naftyl-a-metyleddiksyre, dl 6-metyltio-2-naftyl-a-metyleddiksyre, d 6-metyltio-2-naftyl-a-metyleddiksyre, dl 6-metyl-2-naftyl-a-metyleddik-syre og d 6-metyl-2-naftyl-a-metyleddiksyre oppnås dl 3-(6-metoksy-2-naftyl)-3-metyletanol, smeltepunkt 88.6°C og dl 3-(6-metyltio-2-naftyl)-3-metyletanol, smeltepunkt 82° - 83°C, 1 3-(6-metyltio-2-naftyl)-3-metyletanol, smeltepunkt 102° - 103°C, dl 3-(6-metyl-2-naftyl)-3-metyletanol, smeltepunkt 99° - 100°C, og 1 3-(6-metyl-2-naftyl)-3-metyletanol, smeltepunkt 93° - 94°C. o By repeating the above method with dl 6-methoxy-2-naphthyl-α-methylacetic acid, dl 6-methylthio-2-naphthyl-α-methylacetic acid, d 6-methylthio-2-naphthyl-α-methylacetic acid, dl 6- methyl-2-naphthyl-α-methylacetic acid and d 6-methyl-2-naphthyl-α-methylacetic acid are obtained dl 3-(6-methoxy-2-naphthyl)-3-methylethanol, melting point 88.6°C and dl 3- (6-methylthio-2-naphthyl)-3-methylethanol, melting point 82° - 83°C, 1 3-(6-methylthio-2-naphthyl)-3-methylethanol, melting point 102° - 103°C, dl 3- (6-methyl-2-naphthyl)-3-methylethanol, melting point 99° - 100°C, and 1 3-(6-methyl-2-naphthyl)-3-methylethanol, melting point 93° - 94°C. o

Ved å gjenta den ovenfor angitte metode, men ved å erstatte karboksylsyrene med de tilsvarende laverealky1-estrene oppnåes, i hvert tilfelle, den tilsvarende propanol, f.eks.: By repeating the method stated above, but by replacing the carboxylic acids with the corresponding lower alkyl esters, the corresponding propanol is obtained, in each case, e.g.:

metyl 2-.(6-metoksy-2-naft<y>l)-a-metylacetat, methyl 2-(6-methoxy-2-naphth<y>1)-α-methylacetate,

etyl 2-(6-metoksy-2-naftyl)-a-metylacetat, ethyl 2-(6-methoxy-2-naphthyl)-α-methylacetate,

isobutyl 2-(6-metoksy-2-naftyl)-a-metylacetat, isobutyl 2-(6-methoxy-2-naphthyl)-α-methylacetate,

n-pentyl 2- (6-metoksy-.2-naf tyl )-a-metylacetat, n-pentyl 2-(6-methoxy-.2-naphthyl)-α-methylacetate,

isopentyl 2-(6-metoksy-2-naftyl)-a-metylacetat, isopentyl 2-(6-methoxy-2-naphthyl)-α-methylacetate,

gir i hvert tilfelle, 2-(6-metoksy-2-naftyl)-3-metyletanol; gives in each case, 2-(6-methoxy-2-naphthyl)-3-methylethanol;

metyl 2-(6-metyltio-2-naftyl)-a-metylacetat, methyl 2-(6-methylthio-2-naphthyl)-α-methylacetate,

etyl 2-(6-metyltio-2-naftyl)-a-metylacetat, isobutyl 2-(6-metyltio-2-naftyl)-a-metylacetat, n-pentyl 2-(6-metyltio-2-naftyl)-a-metylacetat, ethyl 2-(6-methylthio-2-naphthyl)-α-methylacetate, isobutyl 2-(6-methylthio-2-naphthyl)-α-methylacetate, n-pentyl 2-(6-methylthio-2-naphthyl)-α -methyl acetate,

isopentyl 2-(6-metyltio-2-naftyl)-a-metylacetat, isopentyl 2-(6-methylthio-2-naphthyl)-α-methylacetate,

gir i hvert tilfelle 2- (6-metyltio-2-naftyl)-3-metyletanol, og gives in each case 2-(6-methylthio-2-naphthyl)-3-methylethanol, and

metyl 2-(6-metyl-2-naftyl)-a-metylacetat, methyl 2-(6-methyl-2-naphthyl)-α-methylacetate,

etyl 2-(6-metyl-2-naftyl)-a-metylacetat, ethyl 2-(6-methyl-2-naphthyl)-α-methylacetate,

isobutyl 2- (6-metyl-2-naftyl)-a-metylacetat, isobutyl 2-(6-methyl-2-naphthyl)-α-methylacetate,

n-pentyl 2-(6-metyl-2-naftyl)-a-metylacetat, n-pentyl 2-(6-methyl-2-naphthyl)-α-methylacetate,

isopentyl 2-(6-metyl-2-naftyl)-a-metylacetat, isopentyl 2-(6-methyl-2-naphthyl)-α-methylacetate,

gir i hvert tilfelle 2-(6-metyl-2-naftyl)-3-metyletanol. gives in each case 2-(6-methyl-2-naphthyl)-3-methylethanol.

Eksempel 2 Example 2

En blanding av 46 g 6-metoksy-2-naftyl-a-metyleddiksyre, A mixture of 46 g of 6-methoxy-2-naphthyl-α-methylacetic acid,

6 g diboran og 220 ml tetrahydrofuran omrøres i" 8 timer ved romtemperatur (ca. 23°C). Blandingen settes til side i 1 time etter å ha blitt fortynnet med 50 ml vandig aceton, hvoretter 300 ml dietyleter tilsettes. Den resulterende blanding vaskes med vann, tørkes over natriumsulfat og inndampes hvilket gir 3-(6-metoksy-2-naftyl)-3-metyletanol. 6 g of diborane and 220 ml of tetrahydrofuran are stirred for 8 hours at room temperature (about 23°C). The mixture is set aside for 1 hour after being diluted with 50 ml of aqueous acetone, after which 300 ml of diethyl ether is added. The resulting mixture is washed with water, dried over sodium sulfate and evaporated to give 3-(6-methoxy-2-naphthyl)-3-methylethanol.

Ved å gjenta den ovenfor beskrevne metode med 6-metyltio-2-naftyl-a-metyleddiksyre oppnåes 3-(6-metyltio-2-naftyl)-3-metyletanol. By repeating the method described above with 6-methylthio-2-naphthyl-α-methylacetic acid, 3-(6-methylthio-2-naphthyl)-3-methylethanol is obtained.

Eksempel 3 Example 3

En blanding av 1 g 3-(6-metyltio-2-naftyl)-3-metyletanol, A mixture of 1 g of 3-(6-methylthio-2-naphthyl)-3-methylethanol,

4 ml pyridin og 2 ml' eddiksyreanhydrid hensettes ved romtemperatur i 15 timer. Blandingen helles deretter i isvann og det dannede faste stoff oppsamles ved filtrering, vaskes med vann og tørkes til acetat-esteren av 3-(6-metoksy~2-naftyl)-3-metyletanol som kan renses ytterligere ved omkrystallisering fra aceton:heksan, smeltepunkt 49°-50°C. 4 ml of pyridine and 2 ml of acetic anhydride are allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid formed is collected by filtration, washed with water and dried to the acetate ester of 3-(6-methoxy~2-naphthyl)-3-methylethanol which can be further purified by recrystallization from acetone:hexane, melting point 49°-50°C.

Eksempel 4 Example 4

Den anti-inflammatoriske aktivitet av -3-(6-metoksy-2-naftyl)~ 3-metyletanol ble sammenlignet med den til fenylbutazon ved hjelp av The anti-inflammatory activity of -3-(6-methoxy-2-naphthyl)~ 3-methylethanol was compared with that of phenylbutazone using

0 0

et forsøk med carrageenin-indusert betennelse i en rottepote som be-skrevet av CA. Winter et al., Proceedings in Experimental Biology & M-dicine 111, 544-547 (1962). an experiment with carrageenin-induced inflammation in a rat paw as described by CA. Winter et al., Proceedings in Experimental Biology & Medicine 111, 544-547 (1962).

Forsøket ble modifisert idet det ble benyttet hunrotter med en vekt på 80 - 90 g og betennelsesgraden ble målt i enheter av vekten av bakre pote snarere enn i enheter av volumet av bakre pote. Resultatene er vist i den nedenstående tabell. The experiment was modified in that female rats with a weight of 80 - 90 g were used and the degree of inflammation was measured in units of the weight of the hind paw rather than in units of the volume of the hind paw. The results are shown in the table below.

Eksempel 5 Example 5

Den anti-pyretiske aktivitet for 3-(6-metoksy-2-naftyl)-3-metyletanol ble sammenlignet med den anti-pyretiske aktivitet for aspirin. The anti-pyretic activity of 3-(6-methoxy-2-naphthyl)-3-methylethanol was compared with the anti-pyretic activity of aspirin.

Anti- pyretisk aktivitet - Det ble benyttet hunrotter med en vekt på 90 - 100 g. Den "normale" rektale temperatur hos rottene ble målt ved tid 0, fulgt av subkutan injeksjon (1 ml dorsalt, 1 ml ven-tralt) av 2 ml av en gjærsuspensjon (gjærsuspensjonen fremstilles ved suspendering av en kake av Fleischman's gjær i 22 ml 0.9 % NaCl). In-jeksjonsstedene masseres for å fordele suspensjonen under huden. Gjær-injeksjonen forårsaker forhøyet legemstemperatur. Ved tid 17 ble rottene igjen massert for å stimulere' en ytterligere økning i legemstemperatur. (Det ble funnet at behandling av rottene på det tidspunkt den andre temperaturen ble notert, resulterte i en stigning i legemstemperatur). Ved tid 18 ble den andre rektale temperatur notert hvoretter forsøksforbindelsen ble administrert oralt ved gavage i 1 ml vandig bærer. (Den vandige bæreren besto av 0.9 % NaCl, 0.4 % "poly-sorbat 80", 0.5 % karboksymetylcellulose, 0.9 % benzylalkohol og vann). Den tredje rektale temperatur ble notert 2 timer etter administrering av forsøksforbindelsen. Antipyretic activity - Female rats weighing 90 - 100 g were used. The "normal" rectal temperature of the rats was measured at time 0, followed by subcutaneous injection (1 ml dorsal, 1 ml ventral) of 2 ml of a yeast suspension (the yeast suspension is prepared by suspending a cake of Fleischman's yeast in 22 ml of 0.9% NaCl). The injection sites are massaged to distribute the suspension under the skin. The yeast injection causes an elevated body temperature. At time 17, the rats were again massaged to stimulate a further increase in body temperature. (It was found that treating the rats at the time the second temperature was noted resulted in a rise in body temperature). At time 18, the second rectal temperature was noted after which the test compound was administered orally by gavage in 1 ml aqueous vehicle. (The aqueous vehicle consisted of 0.9% NaCl, 0.4% "poly-sorbate 80", 0.5% carboxymethylcellulose, 0.9% benzyl alcohol and water). The third rectal temperature was noted 2 hours after administration of the test compound.

Graden av anti-pyretisk aktivitet ble målt som en senkning The degree of anti-pyretic activity was measured as a lowering

i temperatur (°F) fra den andre til den tredje temperaturavlesning (temperatur ved tid 18 - temperatur ved tid 20) i forhold til en kon-trollprøve. Resultatene er vist i nedenstående tabell. in temperature (°F) from the second to the third temperature reading (temperature at time 18 - temperature at time 20) relative to a control sample. The results are shown in the table below.

Claims

1. Analogy method for the preparation of therapeutically active compounds with the formula: where R 1 is hydroxy or acetoxy and R 5 is methoxy,' methyl or methyl-thio, and where the compounds exist either in the dl, d, or 1 form, characterized in that the corresponding compound as in the 2-position in the naphthalene ring has the group: where R1"'' is hydrogen or lower alkyl, is reduced with a reducing agent, and when R"1" is acetoxy, any hydroxy group is acetylated, and the product is optionally split into its optical antipodes.

2. Process according to claim 1 for the production of 1-(3-(6-methoxy-2-naphthyl)-3-methylethanol, characterized in that d 3-(6-methoxy-2-naphthyl)-3-methylacetic acid or esters thereof , is reduced.