NO871961L - TETRAHYDRONAFTALINDERIVATER. - Google Patents

TETRAHYDRONAFTALINDERIVATER.

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Publication number
NO871961L
NO871961L NO871961A NO871961A NO871961L NO 871961 L NO871961 L NO 871961L NO 871961 A NO871961 A NO 871961A NO 871961 A NO871961 A NO 871961A NO 871961 L NO871961 L NO 871961L
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NO
Norway
Prior art keywords
compounds
formula
tetrahydro
tetramethyl
naphthyl
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Application number
NO871961A
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Norwegian (no)
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NO871961D0 (en
Inventor
Michael Klaus
Peter Loeliger
Original Assignee
Hoffmann La Roche
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Publication date
Priority claimed from CH1938/86A external-priority patent/CH668962A5/en
Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of NO871961D0 publication Critical patent/NO871961D0/en
Publication of NO871961L publication Critical patent/NO871961L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)

Abstract

Terapeutisk aktive forbindelser med den generelle formel. I. hvori Rbetyr o-, m- eller p-hydroksyfenyl;. 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, eller 3,5-dihydroksyfenyl;. eller 2,3.4-, 2,3,5-, 2,4,5-, 2,4,6-, 3,4,5- eller 2,3,6-trlhydroksyfenyl.Fremgangsmåten ved fremstilling derav er beskrevet.Therapeutically active compounds of the general formula. I. wherein R represents o-, m- or p-hydroxyphenyl ;. 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-dihydroxyphenyl; or 2,3,4-, 2,3,5-, 2,4,5-, 2,4,6-, 3,4,5- or 2,3,6-trihydroxyphenyl. The process for their preparation is described.

Description

Foreliggende oppfinnelse vedrører nye tetrahydronaftalin-derivater med generell formel The present invention relates to new tetrahydronaphthalene derivatives with a general formula

hvori Ri betyr o-, m-eller p-hydroksyfenyl; 2,3-, 2,4-, 2,5-, 2,6-, 3,4- eller 3,5-dihydroksyfenyl; eller 2,3,4-, 2,3,5-, 2,4,5-, 2,4,6-, 3,4,5- eller 2,3,6-trihydroksy-fenyl. wherein R 1 means o-, m- or p-hydroxyphenyl; 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl; or 2,3,4-, 2,3,5-, 2,4,5-, 2,4,6-, 3,4,5- or 2,3,6-trihydroxy-phenyl.

Forbindelsene med formel I kan foreligge som trans- eller cis-isomere eller cis/trans-isomerblandinger. Generelt er transforbindelsene med formel I foretrukket, videre de i hvilke Ri betyr o-, m- eller p-hydroksyfenyl, særlig p-hydroksyfenyl. The compounds of formula I can exist as trans or cis isomers or cis/trans isomer mixtures. In general, the trans compounds of formula I are preferred, further those in which Ri means o-, m- or p-hydroxyphenyl, especially p-hydroxyphenyl.

Oppfinnelsen vedrører videre en fremgangsmåte ved fremstilling av forbindelsene med formel I, farmasøytiske preparater på basis av forbindelsene med formel I, forbindelsene med formel I ved behandling og profylakse av neoplasier og dermatoser samt anvendelsen av forbindelsene med formel I ved fremstilling av farmasøytiske preparater til behandling og profylakse av slike sykdommer The invention further relates to a method for the preparation of the compounds of formula I, pharmaceutical preparations based on the compounds of formula I, the compounds of formula I in the treatment and prophylaxis of neoplasias and dermatoses as well as the use of the compounds of formula I in the preparation of pharmaceutical preparations for treatment and prophylaxis of such diseases

Forbindelsene med formel I kan i henhold til oppfinnelsen fremstilles ved at man i en forbindelse med den generelle formel II, hvori R<1!>betyr en gruppe R<1>, i hvilken hydroksygruppen(e) er beskyttet, avspalter beskyttelsesgruppen. According to the invention, the compounds of formula I can be prepared by removing the protective group in a compound of the general formula II, in which R<1!> means a group R<1>, in which the hydroxy group(s) is protected.

Som beskyttelsesgruppe kommer alle konvensjonelle hydroksy-beskyttelsesgrupper i betraktning. Eksempler på slike be-skyttelsesgrupper er eter, særlig 2-tetrahydropyranyleter og silyleter, som trimetylsilyleter; videre alkyletere som metyletere; og estere, f.eks. lav-alkankarboksylsyreestere som acetater og karbonater. Avspaltning av beskyttelsesgruppen kan gjennomføres på i og for seg kjent måte ved behandling med syrer, baser eller reduksjonsmidler. Eterbeskyttelsesgrupper som tetrahydropyranyl og tri-metylsilyl kan avspaltes ved behandling med syrer, som p-toluensulfosyre eller Lewis-syrer som BF3eller BBr3. Eterbeskyttelsesgrupper som acetater eller karbonater fjernes ved behandling med baser, f.eks. alkoholisk eller vandig-alkoholisk alkalihydroksydoppløsning. As a protecting group, all conventional hydroxy protecting groups come into consideration. Examples of such protecting groups are ether, especially 2-tetrahydropyranyl ether and silyl ether, such as trimethylsilyl ether; further alkyl ethers such as methyl ethers; and esters, e.g. lower alkane carboxylic acid esters such as acetates and carbonates. Removal of the protecting group can be carried out in a manner known per se by treatment with acids, bases or reducing agents. Ether protecting groups such as tetrahydropyranyl and tri-methylsilyl can be removed by treatment with acids, such as p-toluenesulfonic acid or Lewis acids such as BF3 or BBr3. Ether protecting groups such as acetates or carbonates are removed by treatment with bases, e.g. alcoholic or aqueous-alcoholic alkali hydroxide solution.

Forbindelsene med den generelle formel II kan fremstilles ved at man omsetter en forbindelse med den generelle formel The compounds with the general formula II can be prepared by reacting a compound with the general formula

III III

med en forbindelse med den generelle formel IV with a compound of the general formula IV

hvorved enten whereby either

A utgjør en av gruppene -CH(CH3)P<+>(Q)3Y~ eller A constitutes one of the groups -CH(CH3)P<+>(Q)3Y~ or

-CH(CH3)P(0)(0Alk)2og B utgjør formyl,-CH(CH3)P(0)(OAlk)2 and B constitutes formyl,

elleror

A utgjør acetyl og B utgjør en av gruppene -CH2P<+>(Q)3Y<->A constitutes acetyl and B constitutes one of the groups -CH2P<+>(Q)3Y<->

eller CH2P(0)(Alk)2or CH 2 P(0)(Alk) 2

og and

Q betyr aryl, særlig fenyl,Q means aryl, especially phenyl,

Y" betyr anionet til en organisk eller uorganisk syre, f.eks. br-, og alk betyr lavere alkyl, f.eks. metyl, Y" means the anion of an organic or inorganic acid, e.g. br-, and alk means lower alkyl, e.g. methyl,

og and

R-L1 er det samme som nevnt ovenfor.R-L1 is the same as mentioned above.

Omsetningen av forbindelsene med formel III og IV kan gjennomføres i henhold til de kjente fremgangsmåter for Wittig- eller Hornerreaksjonen. The reaction of the compounds of formula III and IV can be carried out according to the known methods for the Wittig or Horner reaction.

Ved Wittig-reaksjonen, dvs. ved anvendelsen av en forbindelse med formel III med A = -CH(CH3)P<+>(Q)3Y" eller med formel IV med B = -CH2P<+>(Q)3Y~, omsettes komponentene med hverandre i nærvær av et syrebindende middel, f.eks. i nærvær av en sterk base som f.eks. butyllitium, natriumhydrid eller natriumsaltet til dimetylsulfoksyd, fortrinnsvis dog i nærvær av et eventuelt med lavere alkyl substituert etylen-oksyd, som 1,2-butylenoksyd, eventuelt i et løsningsmiddel, f.eks. i en eter som dietyleter eller tetrahydrofuran eller i en aromatisk hydrokarbon som benzen i et område som ligger mellom romtemperatur og kokepunktet til reaksjonsblandingen. In the Wittig reaction, i.e. using a compound of formula III with A = -CH(CH3)P<+>(Q)3Y" or of formula IV with B = -CH2P<+>(Q)3Y~, the components react with each other in the presence of an acid-binding agent, for example in the presence of a strong base such as butyllithium, sodium hydride or the sodium salt of dimethyl sulphoxide, preferably in the presence of an optionally lower alkyl substituted ethylene oxide, which 1,2-butylene oxide, optionally in a solvent, for example in an ether such as diethyl ether or tetrahydrofuran or in an aromatic hydrocarbon such as benzene in a range between room temperature and the boiling point of the reaction mixture.

Av de uorganiske syreanioner Y~ er klor- og bromionet eller hydrosulfationet foretrukket, og av de organiske syreanioner er tosyloksyionet foretrukket. Arylgruppen Q er fortrinnsvis en fenylrest eller en substituert fenylrest som p-tolyl. Of the inorganic acid anions Y~, the chlorine and bromine ion or the hydrosulfation are preferred, and of the organic acid anions the tosyloxy ion is preferred. The aryl group Q is preferably a phenyl radical or a substituted phenyl radical such as p-tolyl.

Ved Horner-reaksJonen, dvs. ved anvendelse av en forbindelse med formel III med A = -CH(CH3)-P(0)(OAlk)2eller med formel IV med B = -CH2-P(0)(Alk)2kondenseres kmponentene ved hjelp av en base og fortrinnsvis i nærvær av et inert organisk løsningsmiddel, f.eks. ved hjelp av natriumhydrid i benzen,toluen, dimetylformamid, tetrahydrofuran, dioksan eller 1,2-dimetoksyetan, eller også ved hjelp av et natrium-alkoholat i en alkohol, f.ek. natriummetylat i metanol, i et temperatur område som ligger mellom 0 °C og kokepunktet til In the Horner reaction, i.e. when using a compound of formula III with A = -CH(CH3)-P(0)(OAlk)2 or with formula IV with B = -CH2-P(0)(Alk)2, the components are condensed by means of a base and preferably in the presence of an inert organic solvent, e.g. using sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, or also using a sodium alcoholate in an alcohol, e.g. sodium methylate in methanol, in a temperature range between 0 °C and the boiling point of

reaksjonsblandingen.the reaction mixture.

Alkoksyrestene OAlk er fortrinnsvis lavere alkoksyrester med 1-6 karbonatomer som metoksy eller etoksy. Alkoxy residues OAlk are preferably lower alkoxy residues with 1-6 carbon atoms such as methoxy or ethoxy.

Forbindelsene med formel I kan foreligge i trans- eller cis-form. Ved fremstillingen dannes de overveiende i trans-formen. Eventuelt dannede cis-andeler kan på i og for seg kjent måte hvis ønsket, adskilles. The compounds of formula I can be present in trans or cis form. During production, they are predominantly formed in the trans form. Any cis-parts formed can, if desired, be separated in a manner known per se.

Utgangsforbindelsene med formler III og IV kan, såfremt deres fremstilling ikke er kjent eller i det etterfølgende beskrevet, fremstilles analogt til kjente fremgangsmåter eller til fremgangsmåter beskrevet i det følgende. The starting compounds with formulas III and IV can, provided their preparation is not known or described in the following, be prepared analogously to known methods or to methods described in the following.

Forbindelsene med formel I er terapeutisk virksomme. De har særlig anti-seborré, anti-keratiniserende, anti-neoplastisk og anti-allergisk/anti-inflammatorisk aktivitet, hvilket kan vises med forsøksanordningene beskrevet i det følgende: A) Virkningen ved forhindring av kjemisk induserte mamma-tumorer kan bestemmes ved følgende prosedyre. Hun-Sprague-Dawleyrotter holdes under temperatur- og lyskontrollerte betingelser ved fri tilgang til drikkevann og for. I en alder på 50 dager administreres til hver rotte 15 mg di-metylbenz(a)antrasen løst i arachisolje ved hjelp av en magesonde. Behandlingen med forsøksforbindelsene begynner en dag etter administreringen av carcinogenet. Kroppsvekten til forsøksdyrene ble nedtegnet og tumorene ble palpert ukentlig og målt ved hjelp av et tykkelsesmål. Volumene ble The compounds of formula I are therapeutically active. In particular, they have anti-seborrheic, anti-keratinizing, anti-neoplastic and anti-allergic/anti-inflammatory activity, which can be demonstrated with the experimental devices described in the following: A) The effect in preventing chemically induced mammary tumors can be determined by the following procedure . Female Sprague-Dawley rats are kept under temperature- and light-controlled conditions with free access to drinking water and feed. At the age of 50 days, 15 mg of dimethylbenz(a)anthracene dissolved in arachis oil is administered to each rat by gastric tube. Treatment with the test compounds begins one day after the administration of the carcinogen. The body weight of the experimental animals was recorded and the tumors were palpated weekly and measured using a thickness gauge. The volumes were

D9D9

beregnet etter formelen^• d^, hvorved D betegner den større og d den mindre diameter til tumorellipsoiden. For-søkene ble avsluttet etter 11 uker og vurdert. I dette for-søk ble det foruten 30 kontrolldyr, hvilke kun fikk normalt for, anvendt de følgende to grupper forsøksdyr: calculated according to the formula^• d^, whereby D denotes the larger and d the smaller diameter of the tumor ellipsoid. The pre-searches were concluded after 11 weeks and evaluated. In this experiment, in addition to 30 control animals, which were only fed normally, the following two groups of experimental animals were used:

1. 33 rotter som daglig fikk administrert 30 mg/kg av forsøksforbindelsen blandet saammen med foret. 2. 36 rotter som daglig fikk administrert 90 mg/kg for-søksf orbindel se blandet med foret. B) Virkningen på tumorer kan videre bestemmes på transplan-tabel kondrosarkom til rotten ved følgende fremgangsmåte. Den faste tumor fra et giverdyr oppdeles fint og suspenderes i fosfatpuffer/koksaltoppløsning. 0,5 ml av den 30$ ige tumorgrøt implanteres subkutant på albinorotter. 1. 33 rats who were daily administered 30 mg/kg of the test compound mixed with the feed. 2. 36 rats who were daily administered 90 mg/kg of the test compound mixed with the feed. B) The effect on tumors can further be determined on transplantable chondrosarcoma to the rat by the following method. The solid tumor from a donor animal is finely divided and suspended in phosphate buffer/coxal saline. 0.5 ml of the 30% tumor slurry is implanted subcutaneously into albino rats.

De transplanterte rotter fordeles i tre forsøksgrupper på hver 8 dyr. Forsøksforbindelsene suspenderes i arachisolje og administreres oralt i løpet av 24 dager 5 ganger uken ved hjelp av en spiserørssonde. Tumorene eksideres på den 24. dag og veies. Ressultåtene uttrykkes i kvotienten C/T, som beregnes som følger:C/T=gjennomsnittlig tumorvekt hos kontrolldyr gjennomsnittlig tumorvekt hos behandlede dyr. C) Den antimetaplastiske virkning kan også bestemmes hos rotter ved følgende fremgangsmåte. Hun-Holtzmannrotter med en vekt på ca. 100 g ovarektomeres etter en tilpasningstid på 8 dager under tiogenalnarkose og tas i forsøk etter ytterligere 14 dager. Dyrene plasseres to og to i bur med fri tilgang til for som inneholder ca. 2000 iE analytisk besstemt vitamin A. Før den orale administrering av for-søksforbindelsene blir dyrene behandlet subkutant i 6 på hverandre følgende dager, daglig med 1 pg Østradiolbenzoat og 250 jjg testosteronpropionat, løst i 0,1 ml sesamolje. Den parenterale hormonapplikasjon fører til dannelen av et rent skorpestadium (1 - 1) i vaginalområdet, dvs. en squamos metaplasi. 2 dager etter den orale administrering av for-søkssubstansen, avleses reaksjonsresultåtet igjen på vagi- nalepitelet. For beregning av den midlere virksomme dose anvendes flatemetoden i henhold til Behrens og Kårber. The transplanted rats are divided into three experimental groups of 8 animals each. The test compounds are suspended in arachis oil and administered orally during 24 days 5 times a week by means of an esophageal tube. The tumors are excised on the 24th day and weighed. The results are expressed in the quotient C/T, which is calculated as follows: C/T=average tumor weight in control animals average tumor weight in treated animals. C) The antimetaplastic effect can also be determined in rats by the following method. Female Holtzmann rats with a weight of approx. 100 g are ovariectomized after an adaptation period of 8 days under thiogenal anesthesia and are tested after a further 14 days. The animals are placed two by two in cages with free access to the lining, which contains approx. 2000 iE analytically determined vitamin A. Before the oral administration of the test compounds, the animals are treated subcutaneously for 6 consecutive days, daily with 1 pg of estradiol benzoate and 250 µg of testosterone propionate, dissolved in 0.1 ml of sesame oil. The parenteral hormone application leads to the formation of a pure crust stage (1 - 1) in the vaginal area, i.e. a squamosal metaplasia. 2 days after the oral administration of the test substance, the reaction result is read again on the vagi- the nal epithelium. For calculation of the average effective dose, the surface method according to Behrens and Kårber is used.

Resultatene av forsøkene A-C med forbindelsen med formel I, p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8,-tetrametyl-2-naftyl)propenyl]fenol er oppført i etterfølgende tabeller The results of experiments A-C with the compound of formula I, p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthyl)propenyl]phenol are listed in subsequent tables

I - III.I - III.

Forbindelsene med formel I kan anvendes til topisk og systemisk terapi av godartede og ondartede neoplasider, The compounds of formula I can be used for topical and systemic therapy of benign and malignant neoplasms,

av premaligne lesjoner, samt videre også til systemisk og topisk profylakse av de nevnte affeksjner. of premalignant lesions, as well as also for systemic and topical prophylaxis of the aforementioned affections.

De er videre også egnet for den topiske og systemiske terapi av acne, psoriasis og andre dermatoser som er forblindet med en forsterket eller patologisk endring av horndannelsen, og også av betennelses- og allergiske dermatologiske affeksjo-ner. Fremgangsmåteproduktene med formel I kan videre også anvendes ved bekjempelse av slimhinnesykdommer med betennelses- eller degenerasive, henholdsvis metaplastiske endrin-ger. Forbindelsene med formel I utmerker seg særlig ved en lav toksisitet, henholdsvis en bedre fordragelighet sammen-lignet med kjente retinoider. Furthermore, they are also suitable for the topical and systemic therapy of acne, psoriasis and other dermatoses that are blinded by an enhanced or pathological change in the horn formation, and also by inflammatory and allergic dermatological affections. The process products with formula I can also be used to combat mucosal diseases with inflammatory or degenerative, respectively metaplastic changes. The compounds of formula I are distinguished in particular by a low toxicity, respectively a better tolerability compared to known retinoids.

Midlene kan også administreres enteralt, parenteralt eller topisk i galeniske anvendelsesformer. For den enterale applikasjon egner seg f.eks. midler i form av tabletter, kapsler, dragéer, sirup, suspensjoner, oppløsninger og suppositorier. For den parenterale applikasjon er midler i form av infusjons- eller injeksjonsoppløsninger egnet. The agents can also be administered enterally, parenterally or topically in galenic application forms. For the enteral application, e.g. agents in the form of tablets, capsules, dragées, syrups, suspensions, solutions and suppositories. For the parenteral application, agents in the form of infusion or injection solutions are suitable.

Dosene i hvilke preparatene kan administreres kan avhenge av anvendelsesart og anvendelsesmåte, samt varieres avhengig av pasientens behov. Generelt kommer en daglig dose i betraktning for den voksne på ca. 0,1-50 mg/kg, fortrinnsvis 1-15 mg/kg. The doses in which the preparations can be administered may depend on the type of application and the method of application, as well as being varied depending on the patient's needs. In general, a daily dose for the adult of approx. 0.1-50 mg/kg, preferably 1-15 mg/kg.

Preparatene kan administreres i en eller flere doseringer. En foretrukket administreringsform er kapsler medet innhold på ca. 5-200 mg aktivstoff. The preparations can be administered in one or more doses. A preferred form of administration is capsules with a content of approx. 5-200 mg of active ingredient.

Preparatene kan inneholde inerte eller også farmakodynamiske aktive tilsetningsstoffer. Tabletter eller granuler f.eks, kan inneholde en rekke bindemidler og fyllstoffer, bæresubstanser eller fortynningsmidler. Flytende preparater kan eksempelvis foreligge i form av en steril, med vann blandbar oppløsning. Kapsler kan foruten aktivstoffet også inneholde et fyllmateriale eller et fortykningsmiddel. The preparations may contain inert or pharmacodynamically active additives. Tablets or granules, for example, can contain a number of binders and fillers, carrier substances or diluents. Liquid preparations can, for example, be in the form of a sterile, water-miscible solution. In addition to the active substance, capsules may also contain a filler or a thickening agent.

Videre kan smaksforbedrende tilsetningsstoffer, samt stoffer som vanligvis anvendes som konserverings-, stabiliserings-, fuktighetsholdende midler og emulgeringsmidler foreligge, og videre kan også salter til forandring av det osmotiske trykk, puffere og andre tilsetningsstoffer foreligge. Furthermore, taste-improving additives, as well as substances that are usually used as preservatives, stabilisers, moisture-retaining agents and emulsifiers, can also be present, and also salts for changing the osmotic pressure, buffers and other additives can also be present.

De forut nevnte bæresubstanser og fortynningsmidler kan bestå av organiske eller uorganiske stoffer, f.eks. av vann, gelatin, melkesukker, stivelse, magnesiumstearat, talkum, og gummi arabicum, polyalkylenglykoler o.l. Forutsetningen er at alle hjelpestoffer som anvendes ved fremstilling av preparatene er utoksiske. The aforementioned carrier substances and diluents can consist of organic or inorganic substances, e.g. of water, gelatin, milk sugar, starch, magnesium stearate, talc, and gum arabic, polyalkylene glycols, etc. The prerequisite is that all excipients used in the preparation of the preparations are non-toxic.

For topisk anvendelse anvendes de aktive stoffer hensiktsmessig i form av salver, tinkturer, kremer, oppløsninger, losjoner, spray, suspensjoner eller lignende. Foretukket er salver og kremer samt oppløsninger. Disse for den topiske anvendelse bestemte preparater kan fremstilles ved at man blander fremgangsmåteproduktene som virksom bestanddel til ikke-toksiske, inerte, for den topiske behandling egnede i og for seg vanlige faste eller flytende bærersubstanser for slike preparater. For topical application, the active substances are suitably used in the form of ointments, tinctures, creams, solutions, lotions, sprays, suspensions or the like. Ointments and creams as well as solutions are preferred. These preparations intended for topical use can be prepared by mixing the process products as active ingredients with non-toxic, inert, suitable for the topical treatment in and of themselves usual solid or liquid carrier substances for such preparations.

For den topiske anvendelse er det hensiktsmessig medFor the topical application, it is appropriate with

ca. 0,1-5 $ige, fortrinnsvis 0,3-2 #ige oppløsninger, samt ca. 0,1-5 #ige, fortrinnsvis 0,3-2 #ige salver eller kremer. about. 0.1-5 µg, preferably 0.3-2 µg solutions, as well as approx. 0.1-5 #ige, preferably 0.3-2 #ige ointments or creams.

Til preparatene kan det eventuelt blandes et antioksyda-sjonsmiddel, f.eks. tocoferol, N-metyl-Y -tocoferamin samt butylert hydroksyanisol eller butylert hydroksytoluen. An antioxidant can optionally be mixed with the preparations, e.g. tocopherol, N-methyl-Y-tocopheramine as well as butylated hydroxyanisole or butylated hydroxytoluene.

I de følgende eksempler belyses oppfinnelsen nærmere. Temperaturene er oppført i Celciusgrader. In the following examples, the invention is explained in more detail. The temperatures are listed in degrees Celsius.

Eksempel 1Example 1

82,3 g p-[2-(5,6,7,8-tetrahydro-5,5,8,8,-tetrametyl-2-naftyl)propenyl]fenylacetat suspenderes 12 1 etanol og en oppløsning av 130 g kaliumhydroksyd i 600 ml vann tilsettes. Etter 1 times omrøring ved romtemperatur surgjør man under isavkjøling med fortynnet saltsyre og ekstaherer flere ganger med eddikester. Den organiske fase vaskes fire ganger med vann, tørkes over natriumsulfat og fordampes. Den krystalline rest lar seg omkrystallisere av heksan/eddikester og gir 66 g p-[(E)-2-(5,6, 7,8-tetrahydro-5,5,8,8-tetrametyl-2-naftyl)propenyl]fenol. Smeltepunkt 140-142 °C. 82.3 g of p-[2-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthyl)propenyl]phenyl acetate are suspended in 12 l of ethanol and a solution of 130 g of potassium hydroxide in 600 ml of water is added. After stirring for 1 hour at room temperature, acidify under ice-cooling with dilute hydrochloric acid and extract several times with acetic acid. The organic phase is washed four times with water, dried over sodium sulphate and evaporated. The crystalline residue can be recrystallized from hexane/acetic ester and gives 66 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl] phenol. Melting point 140-142 °C.

Utgangsmaterialet kan fremstilles som følger:The starting material can be prepared as follows:

360 g [l-(5,6,7,8-tetrahydro-5,5,8,8-tetrametyl-2-naftyl) etyl]-trifentlfosfoniumbromid suspenderes i 500 ml tetrahydrofuran og ved 0 °C tilsettes 410 ml n-butyllitium (1,6 molar i heksan). Etter 1 times omrøring ved 0 °C tilsettes dråpevis en oppløsning av 94,5 g 4-acetoksy-benzaldehyd i 300 ml twtrahydrofuran og det røres ytterligere 2 timer ved romtemperatur. Deretter heller man reaksjonsblandingen i 2 1 metanol/vann (6:4) og ekstraherer flere ganger med heksan. Den organiske fase vaskes tre ganger med vann og fordampes etter tørking med natriumsulfat. Filtrering av resten over kiselgel (elueringsmiddel heksan/eddikester = 9:1) 360 g of [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]-triphentylphosphonium bromide are suspended in 500 ml of tetrahydrofuran and at 0 °C 410 ml of n-butyl lithium are added (1.6 molar in hexane). After stirring for 1 hour at 0 °C, a solution of 94.5 g of 4-acetoxybenzaldehyde in 300 ml of tetrahydrofuran is added dropwise and the mixture is stirred for a further 2 hours at room temperature. The reaction mixture is then poured into 2 1 methanol/water (6:4) and extracted several times with hexane. The organic phase is washed three times with water and evaporated after drying with sodium sulphate. Filtration of the residue over silica gel (eluent hexane/acetic ester = 9:1)

og krystallisering fra heksan får man 83 g p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetrametyl - 2-naftyl)propenyl]fenyl-acetat i farveløse krystaller, smeltepunkt 114-116 °C. and crystallization from hexane gives 83 g of p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl acetate in colorless crystals, melting point 114- 116 °C.

Eksempel 2Example 2

Analog til eksempel 1 ble m-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetrametyl -2-naftyl)propenyl]fenol fremstilt ved hydrolyse av m-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetrametyl -2-naftyl)-propenyl]fenylacetat, smeltepunkt 91-93 °C. Analogous to example 1, m-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenol was prepared by hydrolysis of m-[2 -(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]phenylacetate, melting point 91-93 °C.

Eksempel 3Example 3

Analog til eksempel 1 ble ved hydrolyse av o-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetrametyl -2-naftyl)-propenyl]fenyl-acetat fremstilt 0-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetrametyl -2-naftyl)propenyl]fenol, smp. 97-99 °C. Analogous to example 1, by hydrolysis of o-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]phenyl-acetate, 0-[(E )-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthyl)propenyl]phenol, m.p. 97-99 °C.

Fremstillingen av bruksformer av forbindelsene med formelThe preparation of forms of use of the compounds with formula

I kan skje på vanlig måte, f.eks. som i de etterfølgende eksempler. I can happen in the usual way, e.g. as in the following examples.

Eksempel AExample A

Hardgelatinkapsler kan fremstilles som følger:Hard gelatin capsules can be prepared as follows:

Det sprøytetørkede pulver som er basert på aktlvstoffet, gelatin og mikrokrystallin cellulose og som utviser en midlere kornstørrelse for aktivstoffet på <1 jj (målt ved hjelp av autokorrelasjonsspektroskopi) fuktes med en vandig oppløsning av natriumkarboksymetylcellulose og natriumdioktylsulfosuccinat og knas. Den resulterende masse granuleres, tørkes og siles, og det slik dannede granulat blandes med mikrokrystallin cellulose, talkum og magnesiumstearat. Pulveret fylles i kapsler med størrelse 0. The spray-dried powder which is based on the active substance, gelatin and microcrystalline cellulose and which exhibits an average grain size for the active substance of <1 jj (measured by means of autocorrelation spectroscopy) is moistened with an aqueous solution of sodium carboxymethyl cellulose and sodium dioctyl sulfosuccinate and crushed. The resulting mass is granulated, dried and sieved, and the granules thus formed are mixed with microcrystalline cellulose, talc and magnesium stearate. The powder is filled in size 0 capsules.

Eksempel BExample B

Den finmalte substans blandes med melkesukker og en del av maisstivelsen. Blandingen fuktes med en vandig oppløsning av povidone K30 og knas, og den resulterende masse granuleres, tørkes og siles. Granulatet blandes med den reste-rende maisstivelse, talkum og magnesiumstearat og presses til tabletter med egnet størrelse. The finely ground substance is mixed with milk sugar and part of the cornstarch. The mixture is moistened with an aqueous solution of povidone K30 and crushed, and the resulting mass is granulated, dried and sieved. The granulate is mixed with the remaining corn starch, talc and magnesium stearate and pressed into tablets of a suitable size.

Eksempel CExample C

Mykgelatinkapsler kan fremstilles som følger: 10 g av forbindelse I løses under omrøring, inert gasstil-førsel og lysbeskyttelse i 90 g mellomkjedetriglycrid. Denne oppløsning bearbeides som kapselfyllmasse til mykgelatinkapsler å 50 mg aktivstoff. Soft gelatin capsules can be prepared as follows: 10 g of compound I are dissolved under stirring, inert gas supply and light protection in 90 g of medium chain triglyceride. This solution is processed as a capsule filler for soft gelatin capsules containing 50 mg of active substance.

Eksempel DExample D

En lotion kan fremstilles som følger:A lotion can be prepared as follows:

BestanddelerConstituents

Aktivstoffet innarbeides under lysbeskyttelse i blandingen etanol, 94#ig/ vann. Carbopol 934 røres inn inntil full-stendig gelering og pH-verdien innstilles med natrium-hydroksyd. The active substance is incorporated under light protection into the mixture ethanol, 94#ig/ water. Carbopol 934 is stirred in until complete gelation and the pH value is adjusted with sodium hydroxide.

Claims (5)

1. Fremgangsmåte ved fremstilling av forbindelser med den generelle formel I 1. Procedure for the preparation of compounds of the general formula I hvori R <1> betyr o-,m- eller p-hydroksylfenyl; 2,3-, 2,4-, 2,5-, 2,6-, 3,4- eller 3,5-dihydroksyfenyl; eller 2,3,4-, 2,3,5-, 2,4,5-, 2,4,6-, 3,4,5- eller 2,3,6-trihydroksy-fenyl, karakterisert ved at man i en forbindelse med den generelle formel II, wherein R<1> means o-, m- or p-hydroxylphenyl; 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl; or 2,3,4-, 2,3,5-, 2,4,5-, 2,4,6-, 3,4,5- or 2,3,6-trihydroxy-phenyl, characterized in that in a connection with the general formula II, hvori rH betyr en gruppe R <1> , i hvilken hydroksygruppen(e) er beskyttet, avspalter beskyttelsesgruppen.wherein rH means a group R <1> , in which the hydroxy group(s) are protected, deprotecting group. 2. Fremgangsmåte i henhold til krav 1, karakterisert ved at man fremstiller forbindelser i hvilke den molefiniske dobbeltbinding har trans-konfigurasjon.2. Method according to claim 1, characterized in that compounds are prepared in which the molfinic double bond has a trans configuration. 3. Fremgangsmåte i henhold til krav 1 ved fremstilling av p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetrametyl-2-naftyl)-propenyl]fenol, karakterisert ved at man utgår fra tilsvarende substituerte utgangsforbindelser.3. Process according to claim 1 for the production of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]phenol, characterized by starting from correspondingly substituted starting compounds. 4. Fremgangsmåte i henhold til krav 1 ved fremstilling av m-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetrametyl-2-naftyl )-propenyl]fenol, karakterisert ved at man utgår fra tilsvarende substituerte utgangsforbindelser.4. Method according to claim 1 for the production of m-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]phenol, characterized in that starting from correspondingly substituted starting compounds. 5. Fremgangsmåte i henhold til krav 1 ved fremstilling av o-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetrametyl-2-naftyl) propenyl]fenol, karakterisert ved at man utgår fra tilsvarende substituerte utgangsforbindelser.5. Process according to claim 1 for the production of o-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenol, characterized by starting from correspondingly substituted starting compounds.
NO871961A 1986-05-13 1987-05-12 TETRAHYDRONAFTALINDERIVATER. NO871961L (en)

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CH1938/86A CH668962A5 (en) 1986-05-13 1986-05-13 New hydroxy:phenyl:propenyl substd. naphthalene cpds.
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