NO130433B

NO130433B -

Info

Publication number: NO130433B
Application number: NO213671A
Authority: NO
Inventors: T Kamiya; Y Saito; M Hashimoto; H Seki
Original assignee: Fujisawa Pharmaceutical Co
Priority date: 1969-04-18
Filing date: 1971-06-07
Publication date: 1974-09-02
Also published as: AT304570B

Description

Fremgangsmåte for fremstilling av nye Procedure for manufacturing new ones

terapeutisk aktive purinderivater. therapeutically active purine derivatives.

Den foreliggende oppfinnelse angår en analogifremgangsmåte for fremstilling av en ny, terapeutisk aktiv purinforbindelse med formel og salter derav, og det særegne ved analogifremgangsmåten er at en forbindelse med den generelle formel The present invention relates to an analogue method for the production of a new, therapeutically active purine compound of formula and salts thereof, and the distinctive feature of the analogue method is that a compound with the general formula

hvori R og R"*" hver står for hydrogen eller en lavere alkylgruppe med 1-3 karbonatomer, behandles med en sur substans eller en basisk substans i et vandig medium, eventuelt etterfulgt av omdannelse av det dannete produkt, hvis det oppnås i fri form, til et salt derav. wherein R and R"*" each represent hydrogen or a lower alkyl group of 1-3 carbon atoms, treated with an acidic substance or a basic substance in an aqueous medium, optionally followed by conversion of the product formed, if obtained in free form , to a salt thereof.

Som sur substans kan det f.eks. anvendes saltsyre, svovelsyre, maursyre, eddiksyre, benzoesyre eller lignende. Eksempler på basisk substans er natriumhydroksyd, kaliumhydroksyd, natrium-karbonat, kaliumkarbonat, natriummetoksyd, natriumetoksyd, kaliumetoksyd, etc. Det kan også benyttes en sur eller basisk ioneveksler-harpiks. Behandlingen utfores vanligvis ved en temperatur fra romtemperatur og opp til kokepunktstemperaturen for reaksjonsmediet. As an acidic substance, it can e.g. hydrochloric acid, sulfuric acid, formic acid, acetic acid, benzoic acid or the like are used. Examples of basic substances are sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, etc. An acidic or basic ion exchange resin can also be used. The treatment is usually carried out at a temperature from room temperature up to the boiling point temperature of the reaction medium.

Purinforbindelsen med formel I kan omdannes til salter derav, f.eks. metall-» ammonium-, amin- og syre-addisjonssalter på i og for seg kjent måte. The purine compound of formula I can be converted into salts thereof, e.g. metal, ammonium, amine and acid addition salts in a manner known per se.

Purinforbindelsen med formel I og salter derav utover en markert hypokolesterolemisk aktivitet. Forbindelsene kan således anvendes som terapeutiske midler ved behandling av aterosklerose. The purine compound of formula I and salts thereof in addition to a marked hypocholesterolemic activity. The compounds can thus be used as therapeutic agents in the treatment of atherosclerosis.

Eksempel. Example.

6-amino-9-(3-karboksy-2,3-i sopropylidendioksy-propyl)-purin-1-oksyd (300 mg) suspenderes i 10% eddiksyre (10 ml). Suspensjonen oppvarmes under refluks i 30 minutter. En liten mengde aktivt kull tilsettes reaksjonsblandingen og den filtreres. Filtratet konsentreres under redusert trykk. Utfelte krystaller samles ved filtrering og omkrystailiseres fra vann og gir 6-amino-9-(3-karboksy-2,3-dihydroksypropyl)-purin-l-oksyd (165 mg). Smeltepunkt 275°C (spalting). 6-Amino-9-(3-carboxy-2,3-isopropylidenedioxy-propyl)-purine-1-oxide (300 mg) is suspended in 10% acetic acid (10 ml). The suspension is heated under reflux for 30 minutes. A small amount of activated carbon is added to the reaction mixture and it is filtered. The filtrate is concentrated under reduced pressure. Precipitated crystals are collected by filtration and recrystallized from water to give 6-amino-9-(3-carboxy-2,3-dihydroxypropyl)-purine-1-oxide (165 mg). Melting point 275°C (decomposition).

Utgangsforbindelsen, dvs. 6-amin-9-(3-karboksy-2,3-isopropyliden-dioksypropyl)-purin-1-oksyd, kan fremstilles på folgende måte: En suspensjon av adenin-1-oksyd (1,51 g), 2,3-isopropyliden-D-erytronolakton (2,21 g) og kaliumkarbonat (1,38 g) i dimetyl-formamid (50 ml) oppvarmes med omroring i 8 timer under tilbake-lop. Fra reaksjonsblandingen fjernes losningsmidlet ved destillasjon under redusert trykk. Resten loses i en liten mengde vann og filtreres. Filtratet justeres til pH 3 med 5% saltsyre. De utfelte krystaller samles ved filtrering og ga 6-amino-9-(3-karboksy-2,3-isopropylidendioksypropyl)-purin-l-oksyd (0,40 g). Smeltepunkt 270°C (spalting) (omkrystallisert fra metanol). The starting compound, i.e. 6-amine-9-(3-carboxy-2,3-isopropylidene-dioxypropyl)-purine-1-oxide, can be prepared as follows: A suspension of adenine-1-oxide (1.51 g) , 2,3-isopropylidene-D-erythronolactone (2.21 g) and potassium carbonate (1.38 g) in dimethylformamide (50 ml) are heated with stirring for 8 hours under reflux. The solvent is removed from the reaction mixture by distillation under reduced pressure. The residue is dissolved in a small amount of water and filtered. The filtrate is adjusted to pH 3 with 5% hydrochloric acid. The precipitated crystals were collected by filtration to give 6-amino-9-(3-carboxy-2,3-isopropylidenedioxypropyl)-purine-1-oxide (0.40 g). Melting point 270°C (decomposition) (recrystallized from methanol).

Claims

Analogous process for the preparation of a new, therapeutically active purine compound of formula:

and salts thereof, characterized in that a compound with the general formula: in which R and R<1> each stand for hydrogen or lower alkyl with 1-3 carbon atoms, is treated with an acidic substance or a basic substance in an aqueous medium, optionally followed by of conversion of the product formed, if obtained in free form, to the salt thereof.