NO130643B - - Google Patents

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Publication number
NO130643B
NO130643B NO03647/72A NO364772A NO130643B NO 130643 B NO130643 B NO 130643B NO 03647/72 A NO03647/72 A NO 03647/72A NO 364772 A NO364772 A NO 364772A NO 130643 B NO130643 B NO 130643B
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general formula
group
compound
hydroxy
yloxy
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NO03647/72A
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Norwegian (no)
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NO130643C (en
Inventor
F Lauria
V Vecchietti
M Bergamaschi
R Tommasini
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Erba Carlo Spa
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/34—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/38—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/52—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

.Analogifremgangsmåter for fremstilling av terapeutisk aktive 1,4-metan- og 1,4-etan-tetrahydronaftyloksy-propanoler. .Analogous methods for the preparation of therapeutically active 1,4-methane- and 1,4-ethane-tetrahydronaphthyloxy-propanols.

Nærværende oppfinnelse vedrorer fremgangsmåter for å frem-:.stille aminoforbindelser som har (3-adrenerg reseptor-blokkerende 'Virkning. The present invention relates to methods for producing amino compounds which have β-adrenergic receptor-blocking action.

I norsk utlegningsskrift nr. 129 042 er det beskrevet aminoforbindelser av den generelle formel (i) In Norwegian explanatory document no. 129 042, amino compounds of the general formula (i) are described

hvor R betegner en rétt eller forgrenet alkylgruppe where R denotes a straight or branched alkyl group

med 1-4 karbonatomer, with 1-4 carbon atoms,

eller et farmakologisk aksepterbart syreaddisjonssalt av denne. or a pharmacologically acceptable acid addition salt thereof.

3-amino-2-hydroksy-propoksygruppen er foretrukket i 5-stilling. The 3-amino-2-hydroxy-propoxy group is preferred in the 5-position.

Disse forbindelser har (3-adrenerg reseptor-blokkerende virkning. These compounds have (3-adrenergic receptor-blocking action.

Det er nå funnet at forbindelser med formel II It has now been found that compounds of formula II

hvor X er 1 eller 2, where X is 1 or 2,

R"*" er en hydroksy-, lavere alkanoyloksy- eller benzoyloksygruppe, og R"*" is a hydroxy, lower alkanoyloxy or benzoyloxy group, and

R 2er en alkylgruppe med 1-4 karbonatomer, R 2 is an alkyl group with 1-4 carbon atoms,

eller et farmakologisk aksepterbart salt derav, også har or a pharmacologically acceptable salt thereof, also has

(3-adrenerg reseptor-blokkerende virkning, men er i besittelse av ennå fordelaktigere terapeutisk indeks. Det skal bemerkes at foranstående definisjon for forbindelsene som fremstilles etter oppfinnelsen omfatter alle mulige stereoisomerer såvel som deres blanding. (3-adrenergic receptor-blocking effect, but is in possession of an even more advantageous therapeutic index. It should be noted that the above definition for the compounds produced according to the invention includes all possible stereoisomers as well as their mixture.

Alkylgruppen kan være en rettkjedet eller forgrenet alkylgruppe. R"*" er fortrinnsvis en acetoksy-, propionyloksy- eller benzoyloksygruppe. The alkyl group can be a straight-chain or branched alkyl group. R"*" is preferably an acetoxy, propionyloxy or benzoyloxy group.

De foretrukne forbindelser er de hvor R^" er en hydroksygruppe og The preferred compounds are those where R 1 is a hydroxy group and

R 2er en alkylgruppe med 3 eller 4 karbonatomer (særlig en isopropyl- eller t-butylgruppe). R^" er fortrinnsvis i R 2 is an alkyl group with 3 or 4 carbon atoms (especially an isopropyl or t-butyl group). R^" is preferably i

Bestillingen, mens etersidekjeden fortrinnsvis er i 5-stilling. The order, while the ether side chain is preferably in the 5-position.

Eksempler på egnede salter er de av uorganiske syrer (f.eks. saltsyre) og organiske syrer (f.eks. fumarsyre og sitronsyre). Examples of suitable salts are those of inorganic acids (eg hydrochloric acid) and organic acids (eg fumaric acid and citric acid).

Oppfinnelsen fremskaffer fremgangsmåter for fremstilling av The invention provides methods for the production of

. en forbindelse med den generelle formel (II) ved at . a compound of the general formula (II) in that

a) gruppen R^ i en forbindelse med den generelle formel (III) a) the group R^ in a compound of the general formula (III)

hvor x og R er som foran definert, og where x and R are as defined above, and

R 4 er en alkyl- eller aralkylgruppe, R 4 is an alkyl or aralkyl group,

avspaltes, og når en forbindelse med den generelle formel (II) , hvori R<1> er en lavere alkanoyloksy- eller benzoyloksygruppe, er onsket, forestres avetringsproduktet på kjent måte, eller is cleaved off, and when a compound of the general formula (II), in which R<1> is a lower alkanoyloxy or benzoyloxy group, is desired, the esterification product is esterified in a known manner, or

b) en forbindelse med generell formel (IV) eller (V) b) a compound of general formula (IV) or (V)

hvor x er som foran definert, where x is as defined above,

Z er et halogenatom, og Z is a halogen atom, and

R 5 er en lavere alkanoyl- eller benzoylgruppe, omsettes med et amin med den generelle formel R 5 is a lower alkanoyl or benzoyl group, is reacted with an amine of the general formula

2 2

hvor R er som foran definert, hvoretter hvis onsket, forsåpes reaksjonsproduktet på kjent måte til en forbindelse med den generelle formel (II), hvor R"<*>" er en hydroksygruppe, where R is as defined above, after which, if desired, the reaction product is saponified in a known manner to a compound of the general formula (II), where R"<*>" is a hydroxy group,

og derpå hvis onsket, omsettes forbindelsen med den generelle formel (II) oppnådd ifolge a) eller b) med en syre for å gi et farmakologisk aksepterbart salt og/eller hvis onsket, spaltes en oppnådd blanding av optiske isomere i de isomere. and then, if desired, the compound of general formula (II) obtained according to a) or b) is reacted with an acid to give a pharmacologically acceptable salt and/or if desired, an obtained mixture of optical isomers is resolved into the isomers.

Det eventuelle saltdannelsestrinn eller den eventuelle opp-spalting av isomerene kan utfores etter vanlige metoder, slik som det er kjent for fagmannen på området. The possible salt formation step or the possible splitting of the isomers can be carried out according to usual methods, as is known to the person skilled in the field.

Forbindelsene med generell formel (III) kan oppnås slik som beskrevet i norsk utlegningsskrift nr. 129 042. Egnede avetringsmidler omfatter Lewis-syrer (f.eks. bortribromid og aluminiumtriklorid) eller pyridinhydroklorid. Nar R 4 er en benzylgruppe, kan katalytisk hydrogenering anvendes0 The compounds of general formula (III) can be obtained as described in Norwegian explanatory document no. 129 042. Suitable stripping agents include Lewis acids (e.g. boron tribromide and aluminum trichloride) or pyridine hydrochloride. When R 4 is a benzyl group, catalytic hydrogenation can be used0

Reaksjon (b) kan eventuelt utfores i nærvær av et opplosnings-middel. Egnede opplosningsmidler er toluen eller dioksan. Reaction (b) can optionally be carried out in the presence of a solvent. Suitable solvents are toluene or dioxane.

Forbindelsene med generell formel (IV) kan fremstilles ved å omsette en forbindelse med den generelle formel (VI) The compounds of general formula (IV) can be prepared by reacting a compound of general formula (VI)

hvor x og R-<>> er som foran definert, where x and R-<>> are as defined above,

med en forbindelse med den generelle formel (VII) with a compound of the general formula (VII)

hvor Z er som foran definert. where Z is as defined above.

Forbindelsene med den generelle formel (V) kan oppnås fra forbindelsene med generell formel (IV) ved behandling med en base, f.eKs. natriumhydroksyd, -bikarbonat eller -metoksyd. The compounds of general formula (V) can be obtained from the compounds of general formula (IV) by treatment with a base, e.g. sodium hydroxide, bicarbonate or methoxide.

De folgende virkninger for forbindelsene med generell formel (II) ble påvist: (a) Virkning som antagonist for tachycardia indusert ved injeksjon av isoproterenol ((3-adrenerg reseptor-blokkerende stimulerende middel) hos reserpinisert og vagotomisert katt under vanlig anestesi. (b) Virkning som antagonist ved bkning av hjertehastig-heten indusert av isoproterenol hos den beviste hund. The following actions for the compounds of general formula (II) were demonstrated: (a) Action as an antagonist of tachycardia induced by injection of isoproterenol ((3-adrenergic receptor-blocking stimulant) in reserpinized and vagotomized cats under general anesthesia. (b) Effect as an antagonist in lowering the heart rate induced by isoproterenol in the proven dog.

(c) Virkning på kontraksjonen av isolert myocardium. (c) Effect on the contraction of isolated myocardium.

(d) Lokal anestetisk virkning. (d) Local anesthetic action.

(e) Virkning på isolert bronkial glattmuskel. (e) Effect on isolated bronchial smooth muscle.

Aktiviteten for forbindelsene i å antagonisere forandringene som fremkalles ved stimulering av de adrenerge (3-reseptorer såvel som virkningen på den myokardiale kontraksjon ble sam-menlignet med den for propranolol og med den for en forbindelse som beskrives i norsk utlegningsskrift nr. 129 042. Resultatene er gjengitt i tabellen nedenfor. l-t-butylamino-3-(8'-hydroksy-11,4'-etan-11, 2 ' , 3 ' , 4'-tetra-hydronaft-51-yloksy)-2-propanol har en markert virkning på hjerte-(3-adrenerge reseptorer, mens uonskede virkninger felles for allé ^-blokkerende midler (slik som undertrykkelse av den myokardiale kontraksjon og den toniske virkning på den bronki-ale muskel) er markert lavere, og dessuten har denne forbindelse en terapeutisk indeks som er ennå bedre enn den for det kjente l-isopropylamino-3-(1'14'-etan-1<1>,2<1>,3<1>,4'-tetra-hydronaft-5'-yloksy)-2-propanol. The activity of the compounds in antagonizing the changes induced by stimulation of the adrenergic (3) receptors as well as the effect on the myocardial contraction was compared with that of propranolol and with that of a compound described in Norwegian publication no. 129 042. The results is reproduced in the table below. 1-t-Butylamino-3-(8'-hydroxy-11,4'-ethan-11,2',3',4'-tetrahydronaphth-51-yloxy)-2-propanol has a marked effect on cardiac (3-adrenergic receptors, while undesirable effects common to all β-blocking agents (such as suppression of the myocardial contraction and the tonic effect on the bronchial muscle) are markedly lower, and moreover this compound has a therapeutic index which is even better than that of the known 1-isopropylamino-3-(1'14'-ethane-1<1>,2<1>,3<1>,4'-tetrahydronaphth-5'- yloxy)-2-propanol.

De farmakologiske data angitt foran er blitt bekreftet ved kliniske forsok utfort på mennesker. Forbindelsene som fremstilles ifolge oppfinnelsen er ved å utove en sammenlignbar antagonisme mot aktiveringen av sympatetiske |3-adr en erge reseptorer anvendelige for behandlingen av tachycardia (f.eks. hyperkinetisk syndrom, thyrotoxicoses, paroxysmal tachycardia), angina pectoris og myocardiac ischaemia generelt, arteriell hypertensjon og angst-tilstander. The pharmacological data stated above have been confirmed by clinical trials carried out on humans. The compounds produced according to the invention are, by exerting a comparable antagonism against the activation of sympathetic |3-adrenergic receptors, useful for the treatment of tachycardia (e.g. hyperkinetic syndrome, thyrotoxicoses, paroxysmal tachycardia), angina pectoris and myocardiac ischaemia in general, arterial hypertension and anxiety states.

Forbindelsene fremstilt etter nærværende oppfinnelse administreres fortrinnsvis oralt eller parenteralt. The compounds prepared according to the present invention are preferably administered orally or parenterally.

Resultatene av de kliniske forsok har vist at når forbindelsene administreres oralt, kan doser for voksne pasienter variere fra ca. 10 til ca. 40 mg pr. dose, fortrinnsvis ca. 20 mg pr. dose, mens doser på ca. 2,5 mg til ca. 5 mg pr. dose er foretrukket for den parenterale administrasjon. The results of the clinical trials have shown that when the compounds are administered orally, doses for adult patients can vary from approx. 10 to approx. 40 mg per dose, preferably approx. 20 mg per dose, while doses of approx. 2.5 mg to approx. 5 mg per dose is preferred for the parenteral administration.

De farmakologiske preparater som inneholder de aktive forbindelser kan fremstilles ifolge vanlig praksis, og de er f.eks. enten kapsler, tabletter, piller, dråper eller ampuller og suppositorier. The pharmacological preparations containing the active compounds can be prepared according to common practice, and they are e.g. either capsules, tablets, pills, drops or ampoules and suppositories.

Eksempler på stoffer som kan tjene som farmakologiske bærere eller fortynningsmidler for de farmakologiske preparater av de aktive forbindelsene er talkum, gelatin, laktose, stivelse, mag-nesiumstearat, polyvinylpyrrolidon, såvel som andre ikke-giftige forenbare substanser som anvendes i farmakologiske formuleringer. Examples of substances that can serve as pharmacological carriers or diluents for the pharmacological preparations of the active compounds are talc, gelatin, lactose, starch, magnesium stearate, polyvinylpyrrolidone, as well as other non-toxic compatible substances used in pharmacological formulations.

Oppfinnelsen illustreres av de fSigende eksempler. The invention is illustrated by the following examples.

Eksempel 1. Example 1.

l-isopropylamino-3- (8 ' -metoksy-11 , 4 ' -etan-1 '•, 2 1 , 3 ' , 4 ' -tetrahy-dronaft-5'-yloksy)- 2 -propanolhydroklorid (4,5 g) og pyridinhydroklorid (9 g) ble oppvarmet under nitrogen ved 180°C i 2 timer. Den faste masse ble fortynnet i vann (60 ml), og natriumbikarbonat (6 g) ble tilsatt porsjonsvis. Det faste produkt som skilte seg fra ble derpå filtrert og vasket med vann. Krystallisasjon fra etylacetat ga 1-isopropylamino- 3-( 8 ' -hydroksy-1 ',4'-etan-1',2',3',41-tetrahydronaft-5'-yloksy)- 2-propanol (3,8 g; s.p. 134 - 135°C). Hydrokloridet (s.p. 200 - 20l°C) kunne oppnås ved å opplose basen i metanol, mette opp-løsningen med hydrogenkloridgass, fortynne med dietyleter, filtrere den faste felling og krystallisere fra 90 % isopropanol. 1-isopropylamino-3-(8'-methoxy-11,4'-ethan-1'•,21,3',4'-tetrahydronaphth-5'-yloxy)-2-propanol hydrochloride (4.5 g ) and pyridine hydrochloride (9 g) were heated under nitrogen at 180°C for 2 hours. The solid mass was diluted in water (60 ml) and sodium bicarbonate (6 g) was added portionwise. The solid product that separated was then filtered and washed with water. Crystallization from ethyl acetate gave 1-isopropylamino-3-(8'-hydroxy-1',4'-ethane-1',2',3',41-tetrahydronaphth-5'-yloxy)-2-propanol (3,8 g; mp 134 - 135°C). The hydrochloride (b.p. 200 - 201°C) could be obtained by dissolving the base in methanol, saturating the solution with hydrogen chloride gas, diluting with diethyl ether, filtering the solid precipitate and crystallizing from 90% isopropanol.

Ved å folge den samme metode ble l-t-butylamino-3-(8<1->hydroksy-1 1 ,4 '-etan-1 ' , 2' , 3 ' , 4 '-tetrahydronaf t-5 ' -yk>ksy) - 2-propanol (s.p. 151 - 152°C) og dets hydroklorid (s.p. 235 - 237°C) og l-s-butylamino-3-(8'-hydroksy-1',4'-etan-1',2',3',4'-tetrahy-dronaf t-5 ' -yloksy) - 2-propanol og dets hydroklorid (s.p. for hydrokloridet 188 - 190°C), fremstilt. By following the same method, 1-t-butylamino-3-(8<1->hydroxy-1 1 ,4 '-ethane-1 ' , 2' , 3 ' , 4 '-tetrahydronaphth-5 '-yk>ky ) - 2-propanol (m.p. 151 - 152°C) and its hydrochloride (m.p. 235 - 237°C) and 1-s-butylamino-3-(8'-hydroxy-1',4'-ethane-1',2' ,3',4'-tetrahydronaphth-5'-yloxy)-2-propanol and its hydrochloride (m.p. for the hydrochloride 188-190°C), prepd.

Eksempel 2. Example 2.

l-isopropylamino-3-(8'-benzyloksy)-1',4'-etan-1',2',3',4'-tetrahydronaft-5'-yloksy)-2-propanol (10 g) opplost i 300 ml 99% etanol/metylenklorid (1:1; 300 ml) ble hydrogenert ved 4-5 atmosfærer i nærvær av 3 g 5% palladium på karbon. Etter 1 time var adsorpsjonen av hydrogen (2 mol) fullstendig. Blandingen ble filtrert, konsentrert til torrhet, og det faste produkt oppnådd på denne måte krystallisert fra isopropanol for å gi l-isopropylamino-3-(8'-hydroksy-1',4'-etan-1',2',3',4'-tetrahydronaft-5'-yloksy)-2-propanol-hydroklorid (7,2 g; s.p. 198 - 200°C) . 1-isopropylamino-3-(8'-benzyloxy)-1',4'-ethane-1',2',3',4'-tetrahydronaphth-5'-yloxy)-2-propanol (10 g) dissolved in 300 ml of 99% ethanol/methylene chloride (1:1; 300 ml) was hydrogenated at 4-5 atmospheres in the presence of 3 g of 5% palladium on carbon. After 1 hour, the adsorption of hydrogen (2 mol) was complete. The mixture was filtered, concentrated to dryness, and the solid product thus obtained crystallized from isopropanol to give 1-isopropylamino-3-(8'-hydroxy-1',4'-ethane-1',2',3' ,4'-tetrahydronaphth-5'-yloxy)-2-propanol hydrochloride (7.2 g; m.p. 198-200°C).

Eksempel 3. Example 3.

l-isopropylamino-3-(81-metoksybenzonorbornan-5'-yloksy)- 2-propanol-hydroklorid (5 g) opplost i kloroform (300 ml) ble behandlet ved -30°C med bortribromid (10 g). Opplosningen 1-Isopropylamino-3-(81-methoxybenzonorbornan-5'-yloxy)-2-propanol hydrochloride (5 g) dissolved in chloroform (300 ml) was treated at -30°C with boron tribromide (10 g). The resolution

fikk henstå ved 0°C i 2 timer, derpå konsentrert til torrhet, og resten ble opplost i 5%'s saltsyre. Den ble derpå tilbakelopsbehandlet i 24 timer, noytralisert med natriumbikarbonat og ekstrahert med etylacetat (2 x 200 ml). Etter konsentrasjon til torrhet ble resten behandlet med hydrogenklorid i isopropanol. Fortynning med dietyleter felte ut l-isopropylamino-3- (8'-hydroksybenzonorbornan-51-yloksy)-2-propanolhydroklorid (s.p. 178 - 180°C) . was allowed to stand at 0°C for 2 hours, then concentrated to dryness, and the residue was dissolved in 5% hydrochloric acid. It was then refluxed for 24 hours, neutralized with sodium bicarbonate and extracted with ethyl acetate (2 x 200 ml). After concentration to dryness, the residue was treated with hydrogen chloride in isopropanol. Dilution with diethyl ether precipitated 1-isopropylamino-3-(8'-hydroxybenzonorbornan-51-yloxy)-2-propanol hydrochloride (m.p. 178-180°C).

Ved å folge samme metode ble disse forbindelser oppnådd: l-t-butylamino-3-(8'-hydroksybenzonorbornan-5'-yloksy)-2-propanol-hydroklorid, smp. 192-193°C. Following the same method, these compounds were obtained: 1-t-butylamino-3-(8'-hydroxybenzonorbornan-5'-yloxy)-2-propanol hydrochloride, m.p. 192-193°C.

Eksempel 4. Example 4.

5,8-diacetoksy-l,2,3,4-tetrahydroetannaftalen (55 g) i torr metanol (400 ml) ble behandlet med dietylamin (10,5 ml). Opp-løsningen fikk henstå i 48 timer og konsentrert ved romtempe-ratur. Resten ble fortynnet med vann og det slik oppnådde faste produkt ble filtrert og vasket med vann. To krystallisa-sjoner fra cykloheksan ga 5-hydroksy-8-acetoksy-l,4-etan-1,2,3,4-tetrahydronaftalen (23,5 g; s.p. 90 - 91°C). Den sist-nevnte (20 g) ble oppvarmet i 15 timer ved 90°C med epiklorhydrin (80 ml) og en dråpe piperidin. Det overskytende epiklorhydrin ble fordampet og det rå 3-klor-(8<1->acetoksy-1<1>,4'-etan-1',2<1>,3',4<1->tetrahydronaft-5'-yloksy)-2-propanol ble opplost i toluen (200 ml) som inneholder isopropylamin (50 ml). Oppløsningen ble oppvarmet i et forseglet ror i 15 timer ved 100 - 110°C, derpå konsentrert til torrhet og resten ble behandlet med 10%'s saltsyre, idet de uoppløselige materialer ble filtrert fra. Filtratet ble noytralisert med natriumbikarbonat og ekstrahert med etylacetat (3 x 300 ml). Etter fordampning til lite volum og metting med hydrogenkloridgass ble den faste felling filtrert, vasket med eter og krystallisert fra isopropanol for å gi l-isopropylamino-3-(8 1-acetoksy-11 ,4'-etan-.ll,2',3,,4'-tetrahydronaft-5'-yloksy)-2-propanol-hydroklorid (12,2 g; s.p. 186 - 187°C. 5,8-Diacetoxy-1,2,3,4-tetrahydroethanenaphthalene (55 g) in dry methanol (400 mL) was treated with diethylamine (10.5 mL). The solution was allowed to stand for 48 hours and concentrated at room temperature. The residue was diluted with water and the solid product thus obtained was filtered and washed with water. Two crystallizations from cyclohexane gave 5-hydroxy-8-acetoxy-1,4-ethane-1,2,3,4-tetrahydronaphthalene (23.5 g; m.p. 90-91°C). The latter (20 g) was heated for 15 hours at 90°C with epichlorohydrin (80 ml) and a drop of piperidine. The excess epichlorohydrin was evaporated and the crude 3-chloro-(8<1->acetoxy-1<1>,4'-ethane-1',2<1>,3',4<1->tetrahydronaphth-5' -yloxy)-2-propanol was dissolved in toluene (200 mL) containing isopropylamine (50 mL). The solution was heated in a sealed vessel for 15 hours at 100-110°C, then concentrated to dryness and the residue treated with 10% hydrochloric acid, the insoluble materials being filtered off. The filtrate was neutralized with sodium bicarbonate and extracted with ethyl acetate (3 x 300 mL). After evaporation to a small volume and saturation with hydrogen chloride gas, the solid precipitate was filtered, washed with ether and crystallized from isopropanol to give 1-isopropylamino-3-(8 1-acetoxy-11,4'-ethane-.11,2', 3,,4'-tetrahydronaphth-5'-yloxy)-2-propanol hydrochloride (12.2 g; m.p. 186 - 187°C.

Eksempel 5 Example 5

5,8-diacetoksybenzo-norbornan (52 g) ble omdannet til 5-hydroksy-8-acetoksybenzo-norbornan (smp. 69 - 70°C) som ble omsatt med epiklorhydrin og isopropylamin som.i eksempel 4 for å gi l-isopropylamino-3-(8'-acetoksybenzo-norbornan-5<1->yloksy)-2-propanol-hydroklorid (7,5 gj smp. 165 - 167°C). 5,8-diacetoxybenzo-norbornane (52 g) was converted to 5-hydroxy-8-acetoxybenzo-norbornane (m.p. 69-70°C) which was reacted with epichlorohydrin and isopropylamine as in Example 4 to give 1-isopropylamino -3-(8'-acetoxybenzo-norbornan-5<1->yloxy)-2-propanol hydrochloride (7.5 g m.p. 165 - 167°C).

Eksempel 6 Example 6

l-isopropylamino-3-(8<1->acetoksy-1',4'-etan-11,21,3',4"-tetra-hydronaf t-5 1 -yloksy) -2-propanol-hydroklorid (2 g) ble opplost i metanol (50 ml) mettet med hydrogenklorid, og tilbakelopsbehandlet i 1 time. Etter konsentrasjon ble resten krystallisert fra isopropanol for å gi l-isopropylamino-3-(8<1->hydroksy-1' , 4'-etan-1',2',3',4'-tetrahydronaft-5'-yloksy)-2-propanolhydroklorid (1,5 gj smp. 200 - 201°C. 1-isopropylamino-3-(8<1->acetoxy-1',4'-ethane-11,21,3',4"-tetrahydronaphth-5 1 -yloxy)-2-propanol hydrochloride (2 g) was dissolved in methanol (50 mL) saturated with hydrogen chloride, and refluxed for 1 hour. After concentration, the residue was crystallized from isopropanol to give 1-isopropylamino-3-(8<1->hydroxy-1' , 4'- Ethan-1',2',3',4'-tetrahydronaphth-5'-yloxy)-2-propanol hydrochloride (1.5 g m.p. 200 - 201°C.

De folgende forbindelser ble fremstilt på lignende måte: l-t-butylamino-3- (8'' -hydroksy-1', 4'-etan-1 •, 2 ' , 3' , 4'-tetra-hydronaf t-51-yloksy)-2-propanol-hydroklorid, smp. 235 - 237°C» l-s-butylamino-3-(8'-hydroksy-1',4'-etan-1' ,2' , 3' , 4'-tetra-hydronaf t-51-yloksy)-2-propanol-hydroklorid, smp. 188 - 190°C; l-isopropylamino-3-(8'-hydroksybenzo-norbornan-5'-yloksy)-2-propanol-hydroklorid, smp. 178 - 180°C. The following compounds were prepared in a similar manner: 1-t-butylamino-3-(8''-hydroxy-1',4'-ethan-1•,2',3',4'-tetrahydronaphth-51-yloxy )-2-propanol hydrochloride, m.p. 235 - 237°C» 1-s-butylamino-3-(8'-hydroxy-1',4'-ethan-1',2',3',4'-tetrahydronaphth-51-yloxy)-2- propanol hydrochloride, m.p. 188 - 190°C; 1-isopropylamino-3-(8'-hydroxybenzo-norbornan-5'-yloxy)-2-propanol hydrochloride, m.p. 178 - 180°C.

Eksempel 7 Example 7

Acetylklorid (0,98 ml) ble tilsatt til l-isopropylamino-3-(8'-hydroksy-1',4'-etan-1',2',3' ,4«-tetrahydronaft-5■-yloksy)-2-propanol (3,1 g) i torr kloroform (80 ml). Blandingen ble tilbakelopsbehandlet i 4 timer, deretter konsentrert til torrhet, behandlet med vann, filtrert og noytralisert med fast natriumbikarbonat. Den slik fraskilte olje ble ekstrahert med etylacetat (3 x 100 ml), som derpå ble konsentrert til lite volum, mettet med gassholdig hydrogenklorid og til slutt for- Acetyl chloride (0.98 ml) was added to 1-isopropylamino-3-(8'-hydroxy-1',4'-ethan-1',2',3',4'-tetrahydronaphth-5■-yloxy)- 2-propanol (3.1 g) in dry chloroform (80 ml). The mixture was refluxed for 4 hours, then concentrated to dryness, treated with water, filtered and neutralized with solid sodium bicarbonate. The oil thus separated was extracted with ethyl acetate (3 x 100 ml), which was then concentrated to a small volume, saturated with gaseous hydrogen chloride and finally

tynnet med dietyleter. l-isopropylamino-3-(8'-acetoksy-1', 4'-etan-11,2', 3',4'-tetrahydronaft-5'-yloksy)-2-propanol-hydro- diluted with diethyl ether. 1-isopropylamino-3-(8'-acetoxy-1',4'-ethane-11,2',3',4'-tetrahydronaphth-5'-yloxy)-2-propanol-hydro-

klorid ble filtrert og krystallisert fra isopropanol, smp. chloride was filtered and crystallized from isopropanol, m.p.

185-187°C. Forbindelsene som er beskrevet i eksempel 4 og 5 185-187°C. The compounds described in examples 4 and 5

ble fremstilt på lignende måte. was produced in a similar manner.

Claims (1)

Analogifremgangsmåter for fremstilling av terapeutisk aktive 1, 4-metan- og 1,4-etan-tetrahydronaftyloksy-propanoler med den generelle formel (II)Analogous methods for the preparation of therapeutically active 1,4-methane- and 1,4-ethane-tetrahydronaphthyloxy-propanols of the general formula (II) hvor x er 1 eller 2, R"<*>" er en hydroksy-, lavere alkanoyloksy- eller benzoyloksygruppe, og R 2er en alkylgruppe med 1-4 karbonatomer, eller et farmakologisk aksepterbart salt av disse, karakterisert ved at a) gruppen R i en forbindelse med den generelle formel (III) hvor x og R^ er som foran definert, og R 4er en alkyl- eller aralkylgruppe, avspaltes, og når en forbindelse med den generelle formel (II), hvori R"^ er en lavere alkanoyloksy- eller benzoyloksygruppe, er onsket, forestres avetringsproduktet på kjent måte, eller b) en forbindelse med generell formel (IV) eller (V) hvor x er som foran definert, Z er et halogenatom, og R<5> er en lavere alkanoyl- eller benzoylgruppe, omsettes med et amin med den generelle formel hvor R 2 er som foran definert, hvoretter hvis onsket, forsåpes reaksjonsproduktet på kjent måte til en forbindelse med den generelle formel (II), hvor R1 er en hydroksygruppe, og derpå hvis onsket, omsettes forbindelsen med den generelle formel (II) oppnådd ifolge (a) eller (b) med en syre for å gi et farmakologisk aksepterbart salt og/eller, hvis onsket, spaltes en oppnådd blanding av optiske isomere i de isomere.where x is 1 or 2, R"<*>" is a hydroxy, lower alkanoyloxy or benzoyloxy group, and R 2 is an alkyl group of 1-4 carbon atoms, or a pharmacologically acceptable salt thereof, characterized in that a) the group R in a compound of the general formula (III) where x and R^ are as defined above, and R 4 is an alkyl or aralkyl group, is cleaved off, and when a compound of the general formula (II), in which R"^ is a lower alkanoyloxy or benzoyloxy group, is desired, the esterification product is esterified in a known manner, or b) a compound of the general formula (IV) or (V) where x is as defined above, Z is a halogen atom, and R<5> is a lower alkanoyl or benzoyl group, is reacted with an amine of the general formula where R 2 is as defined above, after which, if desired, the reaction product is saponified in a known manner to a compound of the general formula (II), where R 1 is a hydroxy group, and then, if desired, reacting the compound of general formula (II) obtained according to (a) or (b) with an acid to give a pharmacologically acceptable salt and/or, if desired, resolving an obtained mixture of optical isomers into the isomers .
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