NO128869B - - Google Patents

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NO128869B
NO128869B NO693770A NO377069A NO128869B NO 128869 B NO128869 B NO 128869B NO 693770 A NO693770 A NO 693770A NO 377069 A NO377069 A NO 377069A NO 128869 B NO128869 B NO 128869B
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formula
compound
reacted
compounds
tert
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NO693770A
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Norwegian (no)
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J Shavel
S Farber
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Warner Lambert Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
    • C07D303/26—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds having one or more free hydroxyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Neurology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Epoxy Compounds (AREA)

Description

Denne oppfinnelse angår en fremgangsmåte for fremstilling av terapeutisk aktive forbindelser med formelen: This invention relates to a method for the preparation of therapeutically active compounds with the formula:

hvor R er alkyl med 1-6 karbonatomer, og aminopropanol-sidekjeden er substituert på 5-, 6- eller 7-stillingen i den aromatiske ring, og farmakologisk akseptable syreaddisjonssalter derav. where R is alkyl with 1-6 carbon atoms, and the aminopropanol side chain is substituted at the 5-, 6- or 7-position in the aromatic ring, and pharmacologically acceptable acid addition salts thereof.

Innføring av en keto-gruppe forsterker virkningen av den frem- Introduction of a keto group enhances the effect of the

stilte forbindelse minst 7 ganger sammenlignet med den tilsvarende forbindelse uten keto-gruppe. Dette er beskrevet i en artikkel i J.Med.Chem. vol. 13 (1970), side 684-8, hvor det henvises til av-snittet på side 685 med tittelen "Structure activity relationships", stil compound at least 7 times compared to the corresponding compound without a keto group. This is described in an article in J.Med.Chem. Vol. 13 (1970), pages 684-8, where reference is made to the section on page 685 entitled "Structure activity relationships",

se særlig linje 8 og 9 efter formelågemaet i høyre spalte. see especially lines 8 and 9 after the formula entry in the right-hand column.

De nye forbindelser med formel I er funnet å ha fl-adrenerg The new compounds of formula I have been found to have β-adrenergic

blokkerende aktivitet både ved injisering og oral administrering i pattedyr så som hunder, katter, aper og lignende. Den13- blocking activity both by injection and oral administration in mammals such as dogs, cats, monkeys and the like. The 13-

adrenerge blokkerende aktivitet for disse forbindelser bestemmes ved å administrere varierende doser av isoproterenol efter å ha gitt prøvedyret forbindelser med formel I. Det ble funnet at den hjertekontraktile aktivitet og hjertehastighetsreaksjonen overfor isoproterenol blokkeres ved hjelp av disse forbindelser i varierende grad avhergLg av den administrerte dose. Som et eksempel på den IS-adrenerge blokkerende aktivitet for disse forbindelser, ble forbindelsen 5[3-(tert-butylamino) -2-hydroksypropoksy ]tetralon-hydroklorid administrert intravenøst til bedøvede hunder i en dose på 6,7 ^ug/kg. Hundene ble derefter gitt 0,3 /*g/kg isoproterenol. Denne forbindelse var istand til å undertrykke 50%av isoproterenol-virkningene på hundenes hjertehastighet, og synes å være den mest aktive av de nye forbindelser. adrenergic blocking activity of these compounds is determined by administering varying doses of isoproterenol after giving the test animal compounds of formula I. It was found that the heart contractile activity and the heart rate response to isoproterenol are blocked by means of these compounds to varying degrees depending on the administered dose. As an example of the IS-adrenergic blocking activity of these compounds, the compound 5[3-(tert-butylamino)-2-hydroxypropoxy]tetralone hydrochloride was administered intravenously to anesthetized dogs at a dose of 6.7 µg/kg. The dogs were then given 0.3 µg/kg isoproterenol. This compound was able to suppress 50% of the isoproterenol effects on the heart rate of dogs, and appears to be the most active of the new compounds.

Disse forbindelser er nyttige når I3-adrenerge blokkerende midler These compounds are useful as I3-adrenergic blocking agents

som f.eks. propranolol ønskes, f.eks. i slike tilfeller som angina pectoris, hjertearrytmi og andre iskemiske tilstander. like for example. propranolol is desired, e.g. in such cases as angina pectoris, cardiac arrhythmia and other ischemic conditions.

Dosemengden kan varieres alt efter alder, kjønn, kroppsvekt og art av det pattedyr som behandles, og er i området fra ca. 0,1 The dose amount can be varied depending on the age, sex, body weight and species of the mammal being treated, and is in the range from approx. 0.1

til ca. 1 mg/kg kroppsvekt, enten oralt eller ved injisering. to approx. 1 mg/kg body weight, either orally or by injection.

I henhold til oppfinnelsen kan forbindelsene med formel I også fremstilles i form av farmasøytisk akseptable syreaddisjonssalter, f.eks. hydroklorider, hydrobromider, fosfater, sulfater eller salter avledet fra organiske syrer så som laktater, salicylater og lignende. According to the invention, the compounds of formula I can also be prepared in the form of pharmaceutically acceptable acid addition salts, e.g. hydrochlorides, hydrobromides, phosphates, sulphates or salts derived from organic acids such as lactates, salicylates and the like.

I henhold til oppfinnelsen kan man også fremstille d- eller 1- According to the invention, d- or 1-

optiske isomerer eller den racemiske blanding, såvel som deres salter eller derivater beskrevet ovenfor. optical isomers or the racemic mixture, as well as their salts or derivatives described above.

Forbindelsene fremstilt i henhold til oppfinnelsen anvendes hensiktsmessig i preparater som er egnet for oral eller parenteral administrering. De farmasøytiske preparater som er egnet for oral administrering, kan være i form av tabletter, kapsler, vandige eller oljeaktige oppløsninger og lignende, og suspensjoner som lett fremstilles ved kjente metoder. F.eks. kan tabletter lages ved å blande den valgte aktive bestanddel med kjente farmasøytiske eksipienser, så som kalsiumfosfat, laktose eller mannitol, og granulére med slike midler som akasiegummi eller en gelatinopp-løsning, og derefter presse sammen til tabletter. Disse forbindelser kan også gies i en slik form at de gir en forlenget virkning i dyrekroppen. Doseringsformer som er egnet for parenteral administrering, kan lages ved å oppløse eller suspendere den valgte aktive bestanddel i et parenteralt akseptabelt bæremiddel så som sterilt vann, sterilt saltvann, olje og lignende. The compounds produced according to the invention are suitably used in preparations which are suitable for oral or parenteral administration. The pharmaceutical preparations which are suitable for oral administration can be in the form of tablets, capsules, aqueous or oily solutions and the like, and suspensions which are easily prepared by known methods. E.g. tablets can be made by mixing the selected active ingredient with known pharmaceutical excipients, such as calcium phosphate, lactose or mannitol, and granulating with such agents as acacia gum or a gelatin solution, and then compressing into tablets. These compounds can also be given in such a form that they provide a prolonged effect in the animal's body. Dosage forms suitable for parenteral administration can be made by dissolving or suspending the selected active ingredient in a parenterally acceptable carrier such as sterile water, sterile saline, oil and the like.

For å øke det terapeutiske spektrum kan forbindelsene også blandes med sedativer så som fenobarbital, smertestillende midler så som aspirin, eller kardiovaskulære midler, så som pentaerytritol-tetranitrat, pentaerytritol-trinitrat osv. To increase the therapeutic spectrum, the compounds can also be mixed with sedatives such as phenobarbital, analgesics such as aspirin, or cardiovascular agents such as pentaerythritol tetranitrate, pentaerythritol trinitrate, etc.

I henhold til oppfinnelsen fremstilles forbindelsene med formel I ved at en forbindelse med formelen According to the invention, the compounds of formula I are prepared by a compound of the formula

hvor OH er i 5-, 6- eller 7-stilling, omsettes med hvor X = halogen så somCl, for å gi henholdsvis where OH is in the 5-, 6- or 7-position, is reacted with where X = halogen such as Cl, to give respectively

Generelt omsettes utgangsmaterialene II og ill eller II og VI enten under tilbakeløpskjøling uten oppløsningsmiddel, eller de omsettes ved romtemperatur i en alkoholisk oppløsning inneholdende et lite overskudd (1,1 mol) av en base så som natr.iumhydroksyd, kaliumhydroksyd eller natriummetoksyd for å gi mellomprodukter med strukturene V og VI. De således erholdte mellomprodukter V og VI behandles derefter, f.eks. under tilbakeløpskjøling, med det passende amin med formelen NI^R/hvor R har den ovenfor an-gitte betydning. Som egnede oppløsningsmidler for disse omset-ninger kan f.eks. nevnes lavere alifatiske alkoholer så som metanol, etanol og lignende. De ønskede sluttprodukter utvinnes på kjente måter, og eventuelt omdannes de til syreaddisjonssalter. In general, the starting materials II and II or II and VI are reacted either under reflux without solvent, or they are reacted at room temperature in an alcoholic solution containing a small excess (1.1 mol) of a base such as sodium hydroxide, potassium hydroxide or sodium methoxide to give intermediates with structures V and VI. The thus obtained intermediates V and VI are then processed, e.g. under reflux, with the appropriate amine of the formula N1^R/where R has the meaning given above. As suitable solvents for these reactions, e.g. mention is made of lower aliphatic alcohols such as methanol, ethanol and the like. The desired end products are recovered in known ways, and optionally converted into acid addition salts.

Utgangsfenolen II erholdes ved behandling av den tilsvarende The starting phenol II is obtained by treating the corresponding one

eter som er kommersielt tilgjengelige, med hydrogenbromid i eddiksyre. commercially available ethers, with hydrogen bromide in acetic acid.

Det er funnet at under de betingelser som anvendes for fremstilling av de nye forbindelser med formel I, er det ikke mulig å binde sidekjeden til 8-stillingen. It has been found that under the conditions used for the preparation of the new compounds of formula I, it is not possible to bind the side chain to the 8-position.

De følgende eksempler, hvor alle temperaturer er gitt i °C, skal tjene til å illustrere oppfinnelsen ytterligere. The following examples, where all temperatures are given in °C, shall serve to further illustrate the invention.

EKSEMPEL 1 EXAMPLE 1

a) 5-( 2, 3- epok sypropylok sy)- 1- te tralon a) 5-( 2, 3- epoccypropyllocy)- 1- te tralone

En oppløsning av 8,3 g NaOH i 36,5 ml vann fortynnes med 292 ml etanol og derefter tilsettes 28,5 g 5-hydroksy-tetralon og 98 g epiklorhydrin. Blandingen omrøres ved romtemperatur i 16 timer, og får derefter stå to dager. Oppløsningen inndampes derefter, og residuet fordeles mellom 180 ml vann og 250 ml kloroform. Det fraskilte vandige lag ekstraheres med ytterligere 100 ml kloroform. De samlede organiske faser vaskes to ganger med 100 ml vann, tørres og konsentreres for å gi 41 g residuum. Dette opp-løses i 280 ml eter og avkjøles, og 4,5 g krystaller frafiltreres. Filtratet ble strippet for å gi 34 g råprodukt, og dette ble des-tillert ved 136-144°/0,08 mm Hg for å gi 26,1 g. b) 3, 4- dihvdro- 5- r 2- hydroksy- 3-( isopropylamino) propyloksy1- 1( 2H)-naftalenon- hvdroklorid A solution of 8.3 g of NaOH in 36.5 ml of water is diluted with 292 ml of ethanol and then 28.5 g of 5-hydroxy-tetralone and 98 g of epichlorohydrin are added. The mixture is stirred at room temperature for 16 hours, and is then allowed to stand for two days. The solution is then evaporated, and the residue is distributed between 180 ml of water and 250 ml of chloroform. The separated aqueous layer is extracted with a further 100 ml of chloroform. The combined organic phases are washed twice with 100 ml of water, dried and concentrated to give 41 g of residue. This is dissolved in 280 ml of ether and cooled, and 4.5 g of crystals are filtered off. The filtrate was stripped to give 34 g of crude product, and this was distilled at 136-144°/0.08 mm Hg to give 26.1 g. b) 3,4-dihydro-5- r 2-hydroxy- 3-(isopropylamino)propyloxy1-1(2H)-naphthalenone hydrochloride

26,1 g (0,12 mol) epoksydet fra trinn a) og 34,8 g (0,59 mol) isopropylamin i 121 ml 95% etanol tilbakeløpsbehandles i 40 minutter. Reaksjonsblandingen ble inndampet, og residuet ble krystallisert 26.1 g (0.12 mol) of the epoxide from step a) and 34.8 g (0.59 mol) of isopropylamine in 121 ml of 95% ethanol are refluxed for 40 minutes. The reaction mixture was evaporated, and the residue was crystallized

fra 240 ml cykloheksan for å gi 29,5 g, sm.p. 77-80°. Dette opp-løses i 135 ml kloroform, og HCl-gass bobles inn inntil blandingen er sur. Til denne sure blanding settes 25 ml eter, og omrøring fortsettes inntil fast stoff utfelles. Ytterligere 240 ml eter from 240 ml of cyclohexane to give 29.5 g, m.p. 77-80°. This is dissolved in 135 ml of chloroform, and HCl gas is bubbled in until the mixture is acidic. 25 ml of ether is added to this acidic mixture, and stirring is continued until solid material is precipitated. Additional 240 ml of ether

tilsettes og omrøring fortsettes en stund, blandingen filtreres, vaskes med eter og tørres for å gi 33 g, sm.p. 195-197,5°. Omkrystallisering fra 320 ml absolutt etanol gir produktet, sm.p. 196,5-198°. is added and stirring is continued for a while, the mixture is filtered, washed with ether and dried to give 33 g, m.p. 195-197.5°. Recrystallization from 320 ml of absolute ethanol gives the product, m.p. 196.5-198°.

EKSEMPEL 2 EXAMPLE 2

a) 3-( tetralon- 5- oksv)- 1, 2- epoksy- propan a) 3-( tetralone- 5- oxv)- 1, 2- epoxy- propane

3-( tetralon- 5- oksy)- 1- klor- 2- hydroksy- propan 3-( tetralone- 5-oxy)- 1- chloro- 2- hydroxy- propane

13,8 g 5-hydroksytetralon oppløses i 75 ml epiklorhydrin, og opp-løsningen tilbakeløpsbehandles i 44 timer. Overskudd av epiklorhydrin fjernes i vakuum ved oppvarmning på vannbad, residuet des-tilleres i et kortveis destillasjonsapparat, og det taes 5 frak-sjoner, k.p. 160-2l0°/0,2 mm Hg. Alle har sterk ketonabsorbsjon og de siste to har også sterk hydroksylabsorbsjon. Av tidligere forsøk finner man at lav hydroksylabsorbsjon faller sammen med lave kloranalyser, og høy hydroksylabsorbsjon faller sammen med høye kloranalyser, og man kan derfor slutte seg til at man får en blanding av epoksyforbindelsen og klorhydrinet. Disse frak-sjoner blandes og anvendes til omsetning med aminer. b) 5— r 3 — ( tert- butylamino)- 2- hydroksypropyloksy1tetralon 13.8 g of 5-hydroxytetralone are dissolved in 75 ml of epichlorohydrin, and the solution is refluxed for 44 hours. Excess epichlorohydrin is removed in vacuum by heating on a water bath, the residue is distilled in a short-path distillation apparatus, and 5 fractions are taken, b.p. 160-2l0°/0.2 mm Hg. All have strong ketone absorption and the last two also have strong hydroxyl absorption. From previous experiments, it was found that low hydroxyl absorption coincides with low chlorine analyses, and high hydroxyl absorption coincides with high chlorine analyses, and one can therefore conclude that a mixture of the epoxy compound and the chlorohydrin is obtained. These fractions are mixed and used for reaction with amines. b) 5— r 3 — ( tert-butylamino)- 2- hydroxypropyloxy1tetralone

6 ml av blandingen av epoksy- og klorhydrinforbindelser oppløses 6 ml of the mixture of epoxy and chlorohydrin compounds are dissolved

i 100 ml 95% alkohol, og 24 ml t-butylamin tilsettes, og blandingen tilbakeløpsbehandles på dampbad i to timer. Oppløsningsmiddelet avdrives derefter, residuet utgnies med mettet natriumbikarbonat-oppløsning og eter, og 9,2 g av basen frafiltreres. Dette materiale behandles med alkoholisk HCl, og det utfelte NaCl frafiltreres. Oppløsningen strippes, og residuet omkrystalliseres fra acetonitril, sm.p. 170-171°C. in 100 ml of 95% alcohol, and 24 ml of t-butylamine are added, and the mixture is refluxed on a steam bath for two hours. The solvent is then evaporated, the residue is triturated with saturated sodium bicarbonate solution and ether, and 9.2 g of the base is filtered off. This material is treated with alcoholic HCl, and the precipitated NaCl is filtered off. The solution is stripped, and the residue is recrystallized from acetonitrile, m.p. 170-171°C.

To omkrystalliseringer fra acetonitril gir sm.p. 226-228°C. Two recrystallizations from acetonitrile give m.p. 226-228°C.

EKSEMPEL 3 EXAMPLE 3

5- f 2- hydroksy- 3-( isopropylamino) propyloksy1tetralon 5-f 2-hydroxy-3-(isopropylamino)propyloxy1tetralone

7 ml av blandingen av epoksy- og klorhydrinforbindelser fra eksempel 2a) oppløses i 100 ml 95% alkohol, og 28 ml isopropylamin tilsettes, og oppløsningen tilbakeløpsbehandles i to timer.Oppløsningsmiddelet avdrives, og residuet utgnies med mettet natriumbikarbonatoppløsning og ekstraheres med eter som er vasket med vann og tørret. Den beregnede mengde alkoholiskHCl tilsettes for å danne hydrokloridet som frafiltreres (4 g). To omkrystalliseringer fra alkohol gir den analytiske prøve, sm.p. 198,5-199,5°. EKSEMPEL. 4 5— f( 3- tert- butylamino)- 2- hydroksypropyloksy1- 3, 4- dihvdro- 1( 2H)-naftalenon 7 ml of the mixture of epoxy and chlorohydrin compounds from example 2a) are dissolved in 100 ml of 95% alcohol, and 28 ml of isopropylamine is added, and the solution is refluxed for two hours. The solvent is distilled off, and the residue is triturated with saturated sodium bicarbonate solution and extracted with washed ether with water and dried. The calculated amount of alcoholic HCl is added to form the hydrochloride which is filtered off (4 g). Two recrystallizations from alcohol give the analytical sample, m.p. 198.5-199.5°. EXAMPLE. 4 5— f(3-tert-butylamino)-2-hydroxypropyloxy1-3,4-dihydro-1(2H)-naphthalenone

20,1 g (0,918 mol) epoksyd fremstilt som i eksempel la) og 33 g tert-butylamin i 90 ml 95% etanol tilbakeløpsbehandles i 40 minutter.Reaksjonsblandingen inndampes, og residuet krystalliseres fra 90 ml cykloheksan for å gi 25,8 g, sm.p. 84-86°. Dette opp-løses i 115 ml kloroform, og HCl-gass bobles inn inntil blandingen er sur, blandingen avkjøles og fortynnes med 15 ml eter. Når krystaller utskilles, tilsettes ytterligere 2,5 ml eter, og om-røring fortsettes en stund. Krystallene filtreres, vaskes med eter og tørres for å gi 28 g, sm.p. 223-225°. Omkrystallisering fra absolutt etanol gir sm.p. 223,5-225,5°. 20.1 g (0.918 mol) of epoxide prepared as in example la) and 33 g of tert-butylamine in 90 ml of 95% ethanol are refluxed for 40 minutes. The reaction mixture is evaporated, and the residue is crystallized from 90 ml of cyclohexane to give 25.8 g, sm.p. 84-86°. This is dissolved in 115 ml of chloroform, and HCl gas is bubbled in until the mixture is acidic, the mixture is cooled and diluted with 15 ml of ether. When crystals separate, another 2.5 ml of ether is added and stirring is continued for a while. The crystals are filtered, washed with ether and dried to give 28 g, m.p. 223-225°. Recrystallization from absolute ethanol gives m.p. 223.5-225.5°.

Claims (2)

1. Analogifremgangsmåte for fremstilling av terapeutisk aktive forbindelser med formelen 1. Analogy method for the preparation of therapeutically active compounds of the formula hvor R er alkyl med 1-6 karbonatomer, og aminopropanol-sidekjeden er substituert på 5-, 6- eller 7-stillingen i den aromatiske ring, og farmakologisk akseptable syreaddisjonssalter derav,karakterisert vedat en forbindelse med formelen: where R is alkyl with 1-6 carbon atoms, and the aminopropanol side chain is substituted at the 5-, 6- or 7-position in the aromatic ring, and pharmacologically acceptable acid addition salts thereof, characterized in that a compound with the formula: omsettes med en forbindelse med formelen is reacted with a compound with the formula hvor X er halogen, hvorefter det erholdte reaksjonsprodukt omsettes med en forbindelse med formelen NI^R»hvor R har oven-nevnte betydning, og forbindelsen med formel (I) omdannes eventuelt til et syreaddisjonssalt.where X is halogen, after which the reaction product obtained is reacted with a compound of the formula NI^R», where R has the above-mentioned meaning, and the compound of formula (I) is optionally converted into an acid addition salt. 2. Fremgangsmåte ifølge krav 1 for fremstilling av 5-[3-(tert.butylamino)-2-hydroksypropylQksy]tetralon,karakterisert vedat 5-hydroksytetralon omsettes med epiklorhydrin, hvorefter reaksjonsproduktet omsettes med tert.-butylamin.2. Method according to claim 1 for the production of 5-[3-(tert.butylamino)-2-hydroxypropyl Qxy]tetralone, characterized in that 5-hydroxytetralone is reacted with epichlorohydrin, after which the reaction product is reacted with tert.-butylamine.
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US3959486A (en) * 1970-05-27 1976-05-25 Imperial Chemical Industries Limited Method for producing β-adrenergic blockage with alkanolamine derivatives
DE2130393C3 (en) * 1970-06-22 1981-02-26 E.R. Squibb & Sons Inc., New York, N.Y. (V.St.A.) 6,7-dihydroxy -5,6,7,8-tetrahydronaphthyloxyaminopropanols and their salts with acids and their use in combating heart disease
FR2119843B1 (en) * 1970-12-28 1974-03-22 Laroche Navarro Labo
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US3966749A (en) * 1975-02-10 1976-06-29 Interx Research Corporation Novel synthesis of optically active m-acyloxy-α-[(methylamino)methyl]benzyl alcohols, the pharmaceutically acceptable acid addition salts thereof and intermediate useful in the preparation thereof
GB1493848A (en) * 1975-07-24 1977-11-30 Beecham Group Ltd Aryltetralins
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US4176183A (en) * 1977-05-02 1979-11-27 Merck & Co., Inc. Novel naphthyridines
US4270005A (en) * 1977-11-14 1981-05-26 Pfizer Inc. 1,9-Dihydroxyoctahydrophenanthrenes and intermediates therefor
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DE2943406A1 (en) * 1979-10-26 1981-05-07 Basf Ag, 6700 Ludwigshafen AMINO DERIVATIVES OF 2-METHYL-5- (2-HYDROXYSTYRYL) -1,3,4-THIADIAZOL
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US5225565A (en) * 1988-09-15 1993-07-06 The Upjohn Company Antibacterial 3-(fused-ring substituted)phenyl-5β-amidomethyloxazolidin-2-ones
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