NO144632B - ANALOGUE PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE DIANHYDROHEXITID ACYL DERIVATIVES - Google Patents

ANALOGUE PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE DIANHYDROHEXITID ACYL DERIVATIVES Download PDF

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NO144632B
NO144632B NO754374A NO754374A NO144632B NO 144632 B NO144632 B NO 144632B NO 754374 A NO754374 A NO 754374A NO 754374 A NO754374 A NO 754374A NO 144632 B NO144632 B NO 144632B
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dianhydro
abs
preparation
dulcitol
benzene
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NO144632C (en
NO754374L (en
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Laszlo Oetvoes
Sandor Eckhardt
Anna Szabolcs
Ilona Elekes
Zsuzsa Somfai
Janos Sugar
Laszlo Institoris
Sandor Virag
Agoston David
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Chinoin Gyogyszer Es Vegyeszet
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D303/00Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02Compounds containing oxirane rings
    • C07D303/12Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/16Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D303/00Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02Compounds containing oxirane rings
    • C07D303/12Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/14Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by free hydroxyl radicals

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  • Organic Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Epoxy Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

Foreliggende oppfinnelse vedrører en analogifremgangsmåte ved fremstillling av nye terapeutisk aktive forbindelser med formel - The present invention relates to an analogue method for the preparation of new therapeutically active compounds with the formula -

I IN

hvori Q betyr en acetyl-, kloracetyl-, p-karbometoksy-propionyl-, 3-fenyl-propionyl- eller y- fenyl-butyryl-gruppe. wherein Q represents an acetyl, chloroacetyl, p-carbomethoxy-propionyl, 3-phenyl-propionyl or γ-phenyl-butyryl group.

Bianhydro-sukkeralkohol-derivatene av diepoksydtypen, som L-l,2-3,4-diepoksy-butan, 1,2-5,6-dianhydro-D-mannitol og 1,2-5,6-dianhydro-dulcitol er kjente midler med anticarcino- The bianhydro-sugar alcohol derivatives of the diepoxide type, such as L-1,2-3,4-diepoxy-butane, 1,2-5,6-dianhydro-D-mannitol and 1,2-5,6-dianhydro-dulcitol are known agents with anticarcino-

gen virkning (Jarman, M. Ross. W.X.j.: The formation of epox- gen action (Jarman, M. Ross. W.X.j.: The formation of epox-

ides from substituted hexitols. Carbonhydrate Research 9,139. ides from substituted hexitols. Carbohydrate Research 9,139.

1969, Jarman, M. Ross, W.CJ.: Formation of 1,2-5,6-dianhydro-D-mannitol from 1,6-dibroma- and 1,6-dimethanesulphonoxy-l,6-dideoxy-D-mannitol. Dhem.Ind. 42, 1789. 1967, Elson, A.L. , 1969, Jarman, M. Ross, W.CJ.: Formation of 1,2-5,6-dianhydro-D-mannitol from 1,6-dibromo- and 1,6-dimethanesulphonoxy-1,6-dideoxy-D- mannitol. Dhem.Ind. 42, 1789. 1967, Elson, A.L. ,

Jarman, M. Ross, W.C.J.: Toxicity, haematological effeets and antitumour activity of epoxides derived from disubstituted hexitols. Europ.J.Cancer 4, 617. 1968.) Jarman, M. Ross, W.C.J.: Toxicity, haematological effects and antitumour activity of epoxides derived from disubstituted hexitols. Europ.J.Cancer 4, 617. 1968.)

Blant disse forbindelsene besitter 1,2-5,6-dianhydro- Among these compounds, 1,2-5,6-dianhydro-

dulcitol de gunstigste farmakologiske egenskapene. dulcitol the most favorable pharmacological properties.

(Nemeth, L., Institåris, L., Somfai, S., Gal, F., Pålyi , I., (Nemeth, L., Institåris, L., Somfai, S., Gal, F., Pålyi, I.,

Sugér, J., Csuka, 0., Szentirmay, Z. , Kellner, B.:. Pharmaco- Sugér, J., Csuka, 0., Szentirmay, Z. , Kellner, B.:. Pharmaco-

logy and antitumoral effect of dulcitoldiepoxide. (1,2-5,6-dianhydro-galactitol, NSC-132313). Cancer Chemotherapy Rep. logy and antitumoral effect of dulcitol diepoxide. (1,2-5,6-dianhydro-galactitol, NSC-132313). Cancer Chemotherapy Rep.

1.56, 593. 1972, Institåris, L., Nemet, L., Somfai, S., Gål, 1.56, 593. 1972, Institåris, L., Nemet, L., Somfai, S., Gål,

F., Hercsel, I., Zaka, S., Kellner, B.: Investigation into F., Hercsel, I., Zaka, S., Kellner, B.: Investigation into

the Correlation of Cytostatic Activity with the in vitro Di- the Correlation of Cytostatic Activity with the in vitro Di-

epoxide Formation on.some. Terminally Substituted Hexitols. epoxide Formation on.some. Terminally Substituted Hexitols.

Neiplasma 17, 1, 15-24. 1970). Neiplasma 17, 1, 15-24. 1970).

De intramolekylære reaksjonene mellom de frie hydroksylgruppene The intramolecular reactions between the free hydroxyl groups

og epoksydringene forårsaker dog i pufret vandig losning også and the epoxy rings cause, however, in buffered aqueous solution as well

i fravær av biologiske medier omvandlinger av forbindelsene. in the absence of biological media transformations of the compounds.

Disse omvandlingene gir med henblikk på den cytostatiske virkningen ugunstige eller toksiske metabolitter. These transformations give unfavorable or toxic metabolites with regard to the cytostatic effect.

For å unngå nevnte folger tas tilsvarende beskyttelsesgrupper To avoid the aforementioned consequences, corresponding protective groups are taken

til hjelp som avspaltes under biologiske betingelser, hvorved diepoksyforbindelsene oppstår som aktive metabolitter. Des- for help that is broken down under biological conditions, whereby the diepoxy compounds arise as active metabolites. Dec-

suten modifiserer beskyttelsesgruppene av hydroksylgruppen los-elighetskarakteren av det ekstremt vannloselig heksitol-diepoksydet med henblikk på den cytostatiske virkningen for det meste gunstig. suten, the protecting groups of the hydroxyl group modify the solubility character of the extremely water-insoluble hexitol diepoxide with a view to the cytostatic effect mostly favorably.

Anvendelsen av slike forbindelser viser seg også fordelaktig The use of such compounds also proves advantageous

utfra andre farmakologiske overlegninger. De tidligere tumor-forsokene tyder på dette: som ble gjennomfort under anvendelse av enkelte medlemmer i denne forbindelsesrekken. Resultater viser f.eks. den betydelige senkningen av toksisiteten og virkningensendringene som utoves på tumorspekteret (forskjel- based on other pharmacological considerations. The previous tumor experiments indicate this: which were carried out using individual members of this compound series. Results show e.g. the significant lowering of the toxicity and the effect changes that are exerted on the tumor spectrum (difference

lige tumortyper). equal tumor types).

Undersokelse av den toksikologiske og anticar. cinoqene virkningen til 1, 2- 5„ 6- dianhvdro- 3, 4- diacyl- dulcitol Investigation of the toxicological and anticar. cinoqene the action of 1, 2- 5„ 6- dianhvdro- 3, 4- diacyl- dulcitol

Antitumorvirkningen til de fremstilte diepoksy-diacyl-dulcitol-derivatene uridersokes på transplanterte tumorer av ani-malsk opprinnelse. Hver av de fremstilte forbindélsene hindret avhengig av dosen veksten av de transplanterte tumorene. The anti-tumor effect of the produced diepoxy-diacyl-dulcitol derivatives was investigated on transplanted tumors of animal origin. Each of the prepared compounds inhibited the growth of the transplanted tumors in a dose-dependent manner.

Den toksikologiske og anticarcinogene virkningen av 4,6-diepoksy-diacyl-dulcitol ble sammenlignet den oppnådde virkningen til 1,2-5,6-dianhydro-dulcitol (utgangsdulcitol) i forskjellige forsokssystemer. The toxicological and anticarcinogenic effect of 4,6-diepoxy-diacyl-dulcitol was compared to the obtained effect of 1,2-5,6-dianhydro-dulcitol (starting dulcitol) in different test systems.

Betegnelse av forbindelsene Designation of the compounds

DAD = 1,2-5, 6-dianhydro-dulcitol DAD = 1,2-5, 6-dianhydrodulcitol

Diac-DAD = 1,2-5,6-dianhydro-3,4-di-(acetyl)-dulcitol DS - DAD = 1,2-5,6-dianhydro-3,4-di-(p-karbometoksy-propionyl)-dulcitol Diac-DAD = 1,2-5,6-dianhydro-3,4-di-(acetyl)-dulcitol DS - DAD = 1,2-5,6-dianhydro-3,4-di-(p-carbomethoxy- propionyl)-dulcitol

FB - DAD = 1,2-5,6-dianhydro-3 ,4-di (jf-f enyl-butyryl) -dulcitol FP - DAD = 1,2-5,6-dianhydro-3 ,4-di-((3-f enyl-propionyl )-dulcitol FB - DAD = 1,2-5,6-dianhydro-3,4-di(jf-phenyl-butyryl)-dulcitol FP - DAD = 1,2-5,6-dianhydro-3,4-di-( (3-phenyl-propionyl)-dulcitol

CA-DAD = 1,2-5,6-dianhydro-3,4-di-(kloracetyl)-dulcitol CA-DAD = 1,2-5,6-dianhydro-3,4-di-(chloroacetyl)-dulcitol

Akutt toksisitet Acute toxicity

Den akutte toksisiteten ble bestemt på normale Swiss-mus. Dødeligheten ble fastslått etter engangs dosering etter 21 dager. The acute toxicity was determined on normal Swiss mice. Mortality was determined after single dosing after 21 days.

Toksisiteten synker parallelt tilnærmet molekylvektens okning. Dodelighet oppnås så vel etter intraperitoneal som etter oral forgiftning på 5.-9. dag. Derav vises samtidig at alle midler (virkestoffer) også resorberes godt i mage-tarm-trakten. The toxicity decreases in parallel with the increase in molecular weight. Mortality is achieved both after intraperitoneal and after oral poisoning on the 5th-9th. day. This also shows that all agents (active substances) are also well absorbed in the gastrointestinal tract.

Kumulerende egenskaper ( toksisk kumulering) Cumulative properties (toxic cumulation)

Kumuleringsresten ble bestemt ifolge Druckreys metode. The cumulative residual was determined according to Druckrey's method.

t t

Virkning på transplantasjonstumorer Effect on transplant tumors

a) Ehrlich Ascites Carcinoma a) Ehrlich Ascites Carcinoma

Tumoren med 5 mill. tumorceller ble injisert i.p. i en mus. The tumor with 5 million tumor cells was injected i.p. in a mouse.

Behandlingen ble påbegynt 24 timer etter tumorinjiseringen og gjentatt daglig over 6 henholdsvis 8 dager. The treatment was started 24 hours after the tumor injection and repeated daily over 6 and 8 days respectively.

b) Walker 256 Carcinosarcoma Intramuscularis b) Walker 256 Carcinosarcoma Intramuscularis

Etter 24 timer fra injiseringen av 20 mill. tumorceller ble After 24 hours from the injection of 20 million tumor cells,

det gjennomfart en engangsbehandling. For bestemmelse av de terapeutiske indeksene ble det tatt den minste dosen som på den 10. dag forte til en bedommelse av en 90% overskridende tumorinhibering. it underwent a one-time treatment. For the determination of the therapeutic indices, the smallest dose was taken which, on the 10th day, resulted in a judgment of tumor inhibition exceeding 90%.

Alle undersokte midler er meget virksomme. Den terapeutiske indeksen for de nye midlene er gunstigere enn den for de usub-stituerte DAD, grensedosisen utgjor ved forbindelsene DAD, Diac-DAD og CA-DAD 8-10 mM, ved DS-, FB- og FP-DAD det dobbelte. All investigated means are very effective. The therapeutic index for the new agents is more favorable than that for the unsubstituted DAD, the limiting dose for the compounds DAD, Diac-DAD and CA-DAD is 8-10 mM, for DS-, FB- and FP-DAD it is twice that.

Den gjennom diacyl-diepoksydene fremkalte betydelig minskning av toksisiteten ledsages bare av en måtelig minskning av den anticarcinogene virkningen. The significant reduction in toxicity brought about by the diacyl diepoxides is accompanied by only a moderate reduction in the anticarcinogenic effect.

c) Virkning på Harding- Passey s. c. Melanoma c) Effect on Harding-Passey s. c. Melanoma

Den 1angsomtvoksende, mindre påvirkbare kjente tumoren ble The slow-growing, less susceptible tumor was known

fremkalt gjennom s.c. transplantasjon av et stykke tumorvev. Behandlingen ble begynt 24 timer etter transplantasjonen. induced through s.c. transplantation of a piece of tumor tissue. Treatment was started 24 hours after transplantation.

Målingene skjedde på den 21. dag av forsoket. The measurements took place on the 21st day of the experiment.

Virkningen av de foreslåtte forbindelsene på disse langsomt-voksende, mindre' ømfintlige tumorer overfor anticarcinogene midler, overgår vesentlig virkningen av de epoksyder som tjener som kontroll. The effect of the proposed compounds on these slow-growing, less sensitive tumors to anticarcinogenic agents significantly exceeds the effect of the epoxides that serve as controls.

d) Virkning på Guérin Carcinoma d) Effect on Guérin Carcinoma

Virkningen av Diac-DAD er avhengig av dosen. Virkningen av The effect of Diac-DAD is dose dependent. The effect of

de andre midlene ved samme dose er likeledes gunstig. the other remedies at the same dose are likewise beneficial.

Sammenfattende kan man fastslå at toksisiteten av de undersokte diepoksy-diacyl-dulcitol-forbindelsene i sammenligning med det opprinnelige epoksydet er sunket. Den anticarcinogene virkning av midlet kunne påvises på flere transplanterbare Tumor (Ehrlich ascites, Walker Carcinosarcoma, Harding-Passey Melanoma, Guérin Carcinoma), i enkelte tilfeller har disse sogar en bedre tumorinhibering enn det opprinnelige diepoksydet In summary, it can be stated that the toxicity of the examined diepoxy-diacyl-dulcitol compounds in comparison with the original epoxide has decreased. The anticarcinogenic effect of the agent could be demonstrated on several transplantable tumors (Ehrlich ascites, Walker Carcinosarcoma, Harding-Passey Melanoma, Guérin Carcinoma), in some cases these even have a better tumor inhibition than the original diepoxide

(Harding-Passey Melanoma). (Harding-Passey Melanoma).

Den beregnede terapeutiske indeks for Walker Carcinosarcoma er bedre hos alle nye midler enn den for DAD. Midlene resorberes godt i mage-tarm-trakten. The calculated therapeutic index for Walker Carcinosarcoma is better with all new agents than that for DAD. The agents are well absorbed in the gastrointestinal tract.

Med hensyn til rekkefølgen for innføring av acyloksygruppen og epoksydringen er to prinsipielle veier mulige: a) Påfølgende oppbygning av epoksydringen ut fra 3,4-diacyl-derivater With regard to the order of introduction of the acyloxy group and the epoxidation, two principal paths are possible: a) Subsequent construction of the epoxidation from 3,4-diacyl derivatives

b) Acylering av 1,2-5,6-dianhydro-heksitol. b) Acylation of 1,2-5,6-dianhydro-hexitol.

For fremstilling av de nye forbindelsene valgte man veien b), For the production of the new compounds, route b) was chosen.

fordi oksiranringdannelse etter acyleringen er forbundet med vanskeligheter. Ringslutningen skjer nemlig i alkalisk medium, hvori substituentene kan avspaltes. because oxirane ring formation after the acylation is associated with difficulties. The ring closure takes place in an alkaline medium, in which the substituents can be split off.

1,2-5,6-dianhydro-heksitol Forbindelse av formel I 1,2-5,6-Dianhydrohexitol Compound of formula I

Foreliggende oppfinnelse er altså karakterisert ved at man omsetter det tilsvarende 1,2-5,6-dianhydro-heksitol med et acyleringsmiddel som angir de innledningsvis definerte Q-grupper. The present invention is thus characterized by reacting the corresponding 1,2-5,6-dianhydrohexitol with an acylating agent which indicates the Q groups defined at the outset.

I nærmere detalj fremstilles de nye forbindelsene som føl-ger: 1 mol 1,2-5,6-dianhydroheksitol opploses i vannfritt, organisk løsningsmiddel, fordelaktig i benzen eller i en benzen-homolog ved et volum/vektdelsforhold på 40. Deretter tilsetter man losningen 2,0-3,01 mol av en organisk syrebindende base eller et uorganisk syrebindende middel. I enkelte tilfeller kan den syrebindende basen (f. eks. triétylamin eller pyridin) tilsettes i stort overskudd. Derved tjener dette overskuddet som løsningsmiddel. Losningen som inneholder det syrebindende midlet tilsetter man 2 mol acyleringsmiddel i form av en for-tynnet, ca. 0,5 m løsning, sådann at reaksjonstemperaturen i hvert.fall forblir under reaksjonsblandingens kokepunkt. En tilsetningstemperatur på 20-50°C er hensiktsmessig. Etter avslutningen av tilsetningen rores reaksjonsblandingen 10-180 min. ved denne temperaturen. I mange tilfeller er det nbd-vendig å rore 10-24 timer etterpå ved romtemperatur. In more detail, the new compounds are prepared as follows: 1 mol of 1,2-5,6-dianhydrohexitol is dissolved in an anhydrous, organic solvent, advantageously in benzene or in a benzene homolog at a volume/weight ratio of 40. Then one adds the solution 2.0-3.01 mol of an organic acid-binding base or an inorganic acid-binding agent. In some cases, the acid-binding base (e.g. triethylamine or pyridine) can be added in large excess. Thereby, this surplus serves as a solvent. To the solution containing the acid-binding agent, 2 mol of acylating agent are added in the form of a diluted, approx. 0.5 m solution, such that the reaction temperature in any case remains below the boiling point of the reaction mixture. An addition temperature of 20-50°C is appropriate. After the end of the addition, the reaction mixture is stirred for 10-180 min. at this temperature. In many cases, it is not necessary to stir 10-24 hours afterwards at room temperature.

Opparbeidingen av reaksjonsblandingen kan skje på to forskjellige måter, avhengig av om det som acyleringsmiddel anvendes syrehalogenid, henholdsvis syreanhydrid eller ester. The preparation of the reaction mixture can take place in two different ways, depending on whether an acid halide, acid anhydride or ester is used as the acylating agent.

a) Ved acyleringen med syrehalogenider filtreres de utfelte saltene etter reaksjonen henholdsvis etterroringen fra reaksjonsblandingen og vaskes med et vannfritt organisk løsnings-middel, fordelaktig med benzen. Den rene losningen inndampes ved en temperatur på 50°C til tbrrhet, resten blandes med metylalkohol eller andre løsningsmidler (fortrinnsvis med eter, etylacetat eller andre blandinger o.s.v.), og avkjøles så. Etter krystallisasjonen frafiltreres det erholdte produktet. Fra moderluten kan det utvinnes ved konsentrasjon eller utfel-ning med løsningsmiddel ytterligere krystallinsk produkt a) During the acylation with acid halides, the precipitated salts are filtered after the reaction or the afterstirring from the reaction mixture and washed with an anhydrous organic solvent, advantageously with benzene. The pure solution is evaporated at a temperature of 50°C to dryness, the residue is mixed with methyl alcohol or other solvents (preferably with ether, ethyl acetate or other mixtures, etc.), and then cooled. After crystallization, the product obtained is filtered off. Additional crystalline product can be recovered from the mother liquor by concentration or precipitation with a solvent

(II generasjon). Produktet utgjor nær 10-20% av det opprinne- (II generation). The product accounts for close to 10-20% of the originating

lige produktet (I generasjon). same product (I generation).

De erholdte produktene så vel I som II generasjon renses eventuelt ved omkrystallisasjon, eventuelt flere gangers omkrystallisasjon (hovedsakelig ved II generasjon). The obtained products, both I and II generation, are optionally purified by recrystallization, possibly several times of recrystallization (mainly in II generation).

b) Ved acyleringen med syreanhydrider eller estere inndampes reaksjonsblandingen etter reaksjonens avslutning til halvparten b) During the acylation with acid anhydrides or esters, the reaction mixture is evaporated to half after the end of the reaction

av dets opprinnelige volum og den inndampede reaksjonsblandingen helles under omrbring i 2-3 ganger volumet isvann. Den vandige fasen adskilles fra den organiske fasen. Såfremt, den vandige fase har en sur pHj vaskes den organiske fasen nbytral of its original volume and the evaporated reaction mixture is poured with stirring into 2-3 times the volume of ice water. The aqueous phase is separated from the organic phase. If the aqueous phase has an acidic pH, the organic phase is washed neutrally

helst ved utrystning med 5-10%'ig natriumhydrogenkarbonat-lbsning. Etter adskillelsen som folger den siste vaskingen inndampes den organiske fasen under redusert trykk og resten opp-arbeides videre ifblge forskriften i punkt a). (Blanding med løsningsmiddel, utkrystallisasjon og eventuelle omkrystallisa-sjoner). preferably by shaking with a 5-10% sodium bicarbonate solution. After the separation that follows the final washing, the organic phase is evaporated under reduced pressure and the residue is further worked up according to the regulations in point a). (Mixing with solvent, crystallization and possible recrystallizations).

Som utgangsstoffer anvendes 1,2-5,6-dianhydro-D-mannitol (smeltepunkt: 64-66°C, [oc]^ = +40° i vann, c = 1,25) hhv. 1,2-5,6-dianhydro-dulcitol (smeltepunkt: 98,5°C , [oc]D = +2° As starting materials, 1,2-5,6-dianhydro-D-mannitol is used (melting point: 64-66°C, [oc]^ = +40° in water, c = 1.25) or 1,2-5,6-dianhydro-dulcitol (melting point: 98.5°C , [oc]D = +2°

i vann, c = 1,25). Fremstillingen av disse forbindelsene er beskrevet i litteraturen. (Jarman, M. Ross, W.C.J.: The formation of epoxides from substituted hexitols. Carbohydrate Research 9, 139.1969, jarman, M. Ross, W.C.J.: Formation of 1,2-5,6-dianhydro-D-mannitol from 1,6-dibromo- and 1,6-dime-thanesulphonoxy-1,6-dideoxy-D-mannitol. Chem. Ind. 4_2, 1789. 1967). in water, c = 1.25). The preparation of these compounds is described in the literature. (Jarman, M. Ross, W.C.J.: The formation of epoxides from substituted hexitols. Carbohydrate Research 9, 139.1969, jarman, M. Ross, W.C.J.: Formation of 1,2-5,6-dianhydro-D-mannitol from 1,6 -dibromo- and 1,6-dime-thanesulphonoxy-1,6-dideoxy-D-mannitol. Chem. Ind. 4_2, 1789. 1967).

Som medium henholdsvis lbsningsmiddel finner de vannfrie organiske løsningsmidler anvendelse som ikke står i noen kjemisk vekselvirkning med reaksjonskomponentene, d.v.s. ikke reagerer med dem. Egnede løsningsmidler er de homologe av alifatisker-, cykloalkyl- og aromatiske hydrokarboner eller halogenerte hydrokarboner. Som medium er sogar de organiske syrebindende basene (f. eks. trietylamin, pyridin, o.s.v.) egnet, når de anvendes i tilsvarende overskudd. For vasking av det frafiltrerte saltet tar man hensiktsmessig den mengden vannfritt løsningsmiddel som svarer til den opprinnelige mengden anvendt løsningsmiddel for å unngå at det oppstår en losningsmiddel-blanding. Slike losningsmiddelblandinger vanskeliggjør nemlig opparbeidingen av reaksjonsblandingen. As a medium or solvent, the anhydrous organic solvents are used which are not in any chemical interaction with the reaction components, i.e. do not react with them. Suitable solvents are the homologues of aliphatic, cycloalkyl and aromatic hydrocarbons or halogenated hydrocarbons. As a medium, even the organic acid-binding bases (e.g. triethylamine, pyridine, etc.) are suitable, when they are used in a corresponding excess. For washing the filtered salt, the amount of anhydrous solvent is suitably taken which corresponds to the original amount of solvent used to avoid the formation of a solvent mixture. Such solvent mixtures make it difficult to work up the reaction mixture.

Som acyleringsmidler kommer syrehalogenider, syreanhydrider, blandede syreanhydrider eller ester, fortrinnsvis forbindelser med den generelle formel R-CO-X på tale, hvori R betyr en eventuelt substituert alkyl-, aryl-, aralkyl-, cykloalkyl-, alkyliden-cykloalkyl-, heterocyklisk eller alkyliden-heterocyklisk gruppe; X et halogenatbm eller en OR'-gruppe - hvori R' står for alkyl-, aryl-, acyl- eller aralkyl-gruppen. Acid halides, acid anhydrides, mixed acid anhydrides or esters, preferably compounds with the general formula R-CO-X, are mentioned as acylating agents, where R means an optionally substituted alkyl-, aryl-, aralkyl-, cycloalkyl-, alkylidene-cycloalkyl-, heterocyclic or alkylidene heterocyclic group; X a halogen atom or an OR' group - in which R' stands for the alkyl, aryl, acyl or aralkyl group.

Som syrebindende midler kan anvendes tertiære aminer, trialkyl-aminer, deres homologe, videre alkalikarbonater. Anvendelsen av trietylamin som loser 1,2-5,6-dianhydro-heksitider godt og hvorav de dannede salter lett kunne isoleres viste seg som fordelaktige. Tertiary amines, trialkyl amines, their homologues, further alkali carbonates can be used as acid binding agents. The use of triethylamine, which dissolves 1,2-5,6-dianhydrohexitides well and from which the formed salts could be easily isolated, proved advantageous.

Reaksjonsbetingelser: Acyleringen skjer i sin alminnelighet ved- en temperatur på 20-50°C. En unntagelse danner syrehalo-genidene som i oc-stilling er utstyrt med store romutfyllende grupper. Ved anvendelse av dem ved 50°C er en reaksjonstid på 1-3 timer nødvendig for å gjennomføre reaksjonen med godt utbytte. Den maksimale temperaturen kan nå kokepunktet for det anvendte losningsmidlet, henholdsvis reaksjonsblandingen. Temperaturen reguleres normalt ved tilsetningshastigheten Reaction conditions: The acylation generally takes place at a temperature of 20-50°C. An exception is the acid halides, which in the oc position are equipped with large space-filling groups. When using them at 50°C, a reaction time of 1-3 hours is necessary to carry out the reaction with good yield. The maximum temperature can reach the boiling point of the solvent used, or the reaction mixture. The temperature is normally regulated by the rate of addition

av acyleringsmidlet. En ytre kjøling er knapt nødvendig. of the acylating agent. An external cooling is hardly necessary.

Den benyttes bare når tilsetningen av acyleringsmidlet skjer It is only used when the addition of the acylating agent takes place

for raskt i begynnelsen. too fast in the beginning.

Det er særlig viktig at utgangsf.orbindelsene, løsningsmidler, syrebindende midler og reagensene (acyleringsmiddel) er full-stendig vannfrie. Denne tilstanden må ubetinget kontrolleres for anvendelsen og»om nodvendig, må forbindelsene underkastes videre vannfjerning og rensning. It is particularly important that the starting compounds, solvents, acid-binding agents and the reagents (acylating agent) are completely anhydrous. This condition must be checked before use and, if necessary, the compounds must be subjected to further water removal and cleaning.

Den farmakologiske anvendelsen av de anticarcinogene nye acy-lerte dianhydro-heks±ol-forbindelsene kan skje på forskjellige måter: Per os: den rene aktivsubstansen selv eller den rene aktivsubstansen med de for tablettering vanlige hjelpemidler (stivelse, laktose, talkum) blandet i form av tabletter. The pharmacological application of the anticarcinogenic new acylated dianhydro-hex±ol compounds can take place in different ways: Per os: the pure active substance itself or the pure active substance with the usual excipients for tableting (starch, lactose, talc) mixed in the form of tablets.

Intravenost: i vandig losning eller i losning i et fysiologisk inert organisk løsningsmiddel (forskjellige glykoler, o.s.v.) Intravenous: in aqueous solution or in solution in a physiologically inert organic solvent (various glycols, etc.)

Intramuskulært: i form av losning som ovenfor angitt eller Intramuscular: in the form of a solution as indicated above or

i form av suspensjon. in the form of suspension.

Intraperitonealt eller intracavitalis: også i form av losninger eller suspensjoner som ovenfor. Intraperitoneal or intracavitalis: also in the form of solutions or suspensions as above.

Lokalt: (in loco): i huden eller på operasjonsstedet anvendes aktivsubstansen selv eller blandet med vanlige antibakterielle-og sårmidler (su1fonamider, cortikoider, vitaminer, o.s.v.). Locally: (in loco): in the skin or at the site of the operation, the active substance is used by itself or mixed with common antibacterial and wound agents (sulphonamides, corticoids, vitamins, etc.).

Aktivsubstanskonsentrasjon i de forskjellige preparatene: Active substance concentration in the various preparations:

Fremstillingen av de anticarcinogene forbindelsene ifolge oppfinnelsen belyses gjennom de følgende eksempler. The production of the anticarcinogenic compounds according to the invention is illustrated through the following examples.

Eksempel 1 Example 1

Fremstilling av 1, 2- 5, 6- dianhydro- 3, 4- diacetyl- dulcitol Preparation of 1, 2- 5, 6- dianhydro- 3, 4- diacetyl- dulcitol

I en 100 ml trehalvskolbe med rorer, tilbakelopskjoler og dråpetrakt forelegges 1,46 g (10 minol) dianhydro-dulcitol og 60 ml abs. benzen og rores 10 min. ved romtemperatur. 1.46 g (10 minol) of dianhydrodulcitol and 60 ml of abs. benzene and stir for 10 min. at room temperature.

Til losningen settes 2,8 ml (20 mmol) abs. trietylamin (eller 2,45 gd.v.s. 20 m ol vannfritt kaliumkarbonat) og 2,45 g d.v.s. 1,4 7 ml (20 nmol) friskt destillert acetylbromid lost i 5 ml abs. benzen, rores 20 min. ved romtemperatur, så avsuges det utfelte trietylamin-hydrobromid på et glassfilter G3 og vaskes grundig med abs. benzen. De samlede filtratene inndampes i vakuum, den resterende sirup tilsettes 15 ml abs. eter og 5 ml abs. metylalkohol og avkjoles, hvorved straks en krystallinsk felling inntreffer. Blandingen blir latt stå natten over i kjoleskap, de utfelte krystallene avsuget og deretter omkrystallisert fra metylalkohol. Man får hvite nålaktige krystaller. Utbytte: 1,65 g ( 71 ,!/ <>) . Smeltepunkt: 91°C$Add 2.8 ml (20 mmol) of abs. triethylamine (or 2.45 gd.v.s. 20 m ol anhydrous potassium carbonate) and 2.45 g i.e. 1.4 7 ml (20 nmol) freshly distilled acetyl bromide dissolved in 5 ml abs. benzene, stir for 20 min. at room temperature, then the precipitated triethylamine hydrobromide is suctioned off on a glass filter G3 and washed thoroughly with abs. benzene. The combined filtrates are evaporated in vacuo, the remaining syrup is added to 15 ml abs. ether and 5 ml abs. methyl alcohol and cooled, whereby a crystalline precipitation immediately occurs. The mixture is left overnight in a refrigerator, the precipitated crystals are suctioned off and then recrystallized from methyl alcohol. White needle-like crystals are obtained. Yield: 1.65 g ( 71 ,!/ <>) . Melting point: 91°C$

Rf = 0,63 (benzen : metylalkohol = 90:15) - Rf = 0.63 (benzene : methyl alcohol = 90:15) -

Eksempel 2 Example 2

Fremstilling av 1, 2- 5, 6- dianhydro- 3, 4- diacetyl- dulcitol med eddiksvreanh<y>drid Preparation of 1,2-5,6-dianhydro-3,4-diacetyl-dulcitol with acetic acid

I en 100 ml trehalvskolbe med rorer, tilbakelopskjoler og dråpetrakt forelegges 1,46 g (10 mmol) dianhydro-dulcitol og 60 ml abs. benzen (eller vannfritt toluen) og rores 10 1.46 g (10 mmol) of dianhydrodulcitol and 60 ml of abs. benzene (or anhydrous toluene) and stirred 10

min. ved romtemperatur. Til losningen settes 2,8 ml (20 mmol) abs. trietylamin, 2,04 g d.v.s. 2,0 ml (20 mmol) friskt destillert eddiksyreanhydrid lost i 5 ml benzen over en time ved romtemperatur, så rores videre to timer ved 50°C. Losningen inndampes til torrhet, opptas så med 20 ml vann, rystes med 30 ml benzen, benzenet vaskes med en 10%'ig natriumhydrogen-karbonatolosning, torkes over magnesiumsulfat, filtreres og inndampes. Til den resterende sirup settes 15 ml abs. eter my. at room temperature. Add 2.8 ml (20 mmol) of abs. triethylamine, 2.04 g i.e. 2.0 ml (20 mmol) of freshly distilled acetic anhydride dissolved in 5 ml of benzene over one hour at room temperature, then stirred for a further two hours at 50°C. The solution is evaporated to dryness, then taken up with 20 ml of water, shaken with 30 ml of benzene, the benzene is washed with a 10% sodium hydrogen carbonate solution, dried over magnesium sulphate, filtered and evaporated. Add 15 ml abs to the remaining syrup. ether

og 5 ml abs. metanol, avkjoles, hvorved en momentan krystallinsk utfeining opptrer. Blandingen blir latt stå over natten i kjoleskap, så frafiltreres de utfelte krystallene og omkrystalliseres fra metylalkohol. Man erholder hvite nålaktige krystaller. Utbytte: 1,65 g (71,7%); Smeltepunkt: 91°C-, Rf = 0,63 (benzen : metylalkohol = 90:15). and 5 ml abs. methanol, is cooled, whereby a momentary crystalline phase occurs. The mixture is left overnight in a refrigerator, then the precipitated crystals are filtered off and recrystallized from methyl alcohol. White needle-like crystals are obtained. Yield: 1.65 g (71.7%); Melting point: 91°C-, Rf = 0.63 (benzene : methyl alcohol = 90:15).

Eksempel 3 Example 3

Fremstilling av 1. 2- 5, 6- dianhvdro- 3, 4- diacetyl- dulcitol med p- nitrofenylacetat Preparation of 1. 2- 5, 6- dianhydro- 3, 4- diacetyl- dulcitol with p- nitrophenyl acetate

I en 100 ml trehalvskolbe med rorer, tilbakelopskjoler og dråpetrakt forelegges 1,46 g (10 mmol) dianhydro-dulcitol og 60 ml abs. benzen (eller vannfritt dikloretan) og rores 10 min. ved romtemperatur. Losningen tilsettes 2,8 ml (20 mmol) abs. trietylamin og 3,62 g (20 mmol) p-nitro-fenylacetat, rores 6 timer ved 50°C og blir latt stå natten over ved romtemperatur. Losningen som inneholder det organiske losningsmidlet blir rystet med 20 ml vann og torket over magnesiumsulfat. 1.46 g (10 mmol) of dianhydrodulcitol and 60 ml of abs. benzene (or anhydrous dichloroethane) and stirred for 10 min. at room temperature. The solution is added to 2.8 ml (20 mmol) abs. triethylamine and 3.62 g (20 mmol) p-nitro-phenylacetate, is stirred for 6 hours at 50°C and is left to stand overnight at room temperature. The solution containing the organic solvent is shaken with 20 ml of water and dried over magnesium sulfate.

Den resterende sirup blir tilsatt 15 ml abs. eter og avkjolt. Blandingen får stå natten over i kjoleskap, så blir de utfelte krystaller suget av på et glassfilter G2. Utbytte: 2,5 g. Smeltepunkt: 72-78°c. Det således erholdte gule krystallinske produktet renses som folger: Krystallene loses i 20 ml benzen og behandles med dietylamino-propylamin. Etter en time tilsettes 10 ml vann og det hele fylles i en skylletrakt, den vandige fasen adskilles og opera-sjonen gjentas med 10 ml vann. Benzenlosningen torkes over magnesiumsulfat og inndampes. Den resterende sirup tilsettes 15 ml abs. eter og 5 ml abs. metanol og blir latt stå natten over i kjoleskap, så suges krystallene av. The remaining syrup is added to 15 ml abs. ether and cooled. The mixture is allowed to stand overnight in a refrigerator, then the precipitated crystals are sucked off on a glass filter G2. Yield: 2.5 g. Melting point: 72-78°c. The yellow crystalline product thus obtained is purified as follows: The crystals are dissolved in 20 ml of benzene and treated with diethylamino-propylamine. After one hour, 10 ml of water is added and the whole is filled into a rinsing funnel, the aqueous phase is separated and the operation is repeated with 10 ml of water. The benzene solution is dried over magnesium sulphate and evaporated. The remaining syrup is added to 15 ml abs. ether and 5 ml abs. methanol and is left overnight in a refrigerator, then the crystals are sucked off.

Utbytte: 1,58 g (69%); Smeltepunkt: 90°C. Yield: 1.58 g (69%); Melting point: 90°C.

Rf = 0,63 (benzen : metylalkohol = 90:18). Rf = 0.63 (benzene : methyl alcohol = 90:18).

Analyse Analysis

Når 1,2-5,6-dianhydro-D-mannitol tas som utgangsmaterial When 1,2-5,6-dianhydro-D-mannitol is taken as the starting material

oppnås etter ovenstående metode 1,65 g (70%) 1,2-5,6-dianhydro-3,4-diacetyl-D-mannitol. obtained by the above method 1.65 g (70%) 1,2-5,6-dianhydro-3,4-diacetyl-D-mannitol.

Eksempel 4 Example 4

Fremstilling av 1, 2- 5, 6- dianhvdro- 3. 4- di- kloracetyl- dulcitol Preparation of 1, 2- 5, 6- dianhdro- 3. 4- di- chloroacetyl- dulcitol

I en 200 ml trehalvskolbe med rorer, tilbakelopskjoler og dråpetrakt forelegges 5 g (34 mmol) dianhydro-dulcitol og 150 ml abs. benzen. Etter fire timers rbring tilsettes blandingen 10 ml (70 mmol) abs. trietylamin (eller 5,7 ml abs. pyridin) 5 g (34 mmol) of dianhydrodulcitol and 150 ml of abs. benzene. After stirring for four hours, 10 ml (70 mmol) of abs are added to the mixture. triethylamine (or 5.7 ml abs. pyridine)

og så innen ca. 5 min. ved romtemperatur tildryppes 8,94 g and then within approx. 5 min. at room temperature, 8.94 g are added dropwise

(6 ml; 68 mmol) friskt destillert kloracetyl-kloridlosning (6 mL; 68 mmol) freshly distilled chloroacetyl chloride solution

i 5 ml abs. benzen. Blandingen rores 30 min. ved romtemperatur, så avsuges trietylamin-hydrokloridet på et glassfilter G3 og filterkaken vaskes grundig med benzen. De samlede filtratene inndampes i vakuum. Den resterende sirupen tilsettes 15 ml abs. eter og 10 ml abs. metylalkohol, avkjoles, hvorved en momentant krystallutfelling inntreffer. Blandingen blir latt stå natten over i kjoleskap, så avsuges de utfelte krystallene og omkrystalliseres fra metylalkohol. Man erholder hvite nålaktige krystaller. in 5 ml abs. benzene. The mixture is stirred for 30 min. at room temperature, then the triethylamine hydrochloride is suctioned off on a glass filter G3 and the filter cake is thoroughly washed with benzene. The combined filtrates are evaporated in vacuo. The remaining syrup is added to 15 ml abs. ether and 10 ml abs. methyl alcohol, is cooled, whereby a momentary crystal precipitation occurs. The mixture is left overnight in a refrigerator, then the precipitated crystals are suctioned off and recrystallized from methyl alcohol. White needle-like crystals are obtained.

Utbytte: 4,4 g (43%); Smeltepunkt: 102°C. Yield: 4.4 g (43%); Melting point: 102°C.

Analyse: Analysis:

De videre eksemplene 5-8 er sammenfattet tabellarisk for å gi bedre oversikt. Sluttproduktene i de følgende eksemplene ble fremstilt som på den i de foregående eksemplene beskrevne måte. The further examples 5-8 are summarized in tabular form to provide a better overview. The end products in the following examples were prepared as in the manner described in the preceding examples.

Claims (1)

Analogifremgangsmåte ved fremstilling av nye terapeuAnalogy method in the production of new therapies tisk aktive forbindelser med formel Itically active compounds of formula I hvori Q betyr en acetyl-, kloracetyl-, 6-karbometoksy-propionyl-, 3-fenyl-propionyl- eller y-fenyl-butyryl-gruppe, karakterisert ved at man omsetter det tilsvarende 1,2-5,6-dianhydroheksitol med et acyleringsmiddel som er istand til å avgi en som ovenfor angitt Q-gruppe.in which Q means an acetyl, chloroacetyl, 6-carbomethoxy-propionyl, 3-phenyl-propionyl or y-phenyl-butyryl group, characterized by reacting the corresponding 1,2-5,6-dianhydrohexitol with a acylating agent which is capable of emitting a Q group as indicated above.
NO754374A 1974-12-24 1975-12-23 ANALOGUE PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE DIANHYDROHEXITID ACYL DERIVATIVES NO144632C (en)

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