NO171065B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRIMIDINE DERIVATIVES - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRIMIDINE DERIVATIVES Download PDF

Info

Publication number
NO171065B
NO171065B NO882233A NO882233A NO171065B NO 171065 B NO171065 B NO 171065B NO 882233 A NO882233 A NO 882233A NO 882233 A NO882233 A NO 882233A NO 171065 B NO171065 B NO 171065B
Authority
NO
Norway
Prior art keywords
solution
compound
evaporated
preparation
formula
Prior art date
Application number
NO882233A
Other languages
Norwegian (no)
Other versions
NO882233L (en
NO882233D0 (en
NO171065C (en
Inventor
Peter James Machin
Joseph Armstrong Martin
Gareth John Thomas
Original Assignee
Hoffmann La Roche
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of NO882233D0 publication Critical patent/NO882233D0/en
Publication of NO882233L publication Critical patent/NO882233L/en
Publication of NO171065B publication Critical patent/NO171065B/en
Publication of NO171065C publication Critical patent/NO171065C/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Description

Foreliggende oppfinnelse vedrører analogifremgangsmåte ved fremstilling av terapeutisk aktive forbindelser med generell The present invention relates to an analogue method for the production of therapeutically active compounds with general

formel I formula I

hvori R<1> representerer hydroksy eller benzoyloksy. wherein R<1> represents hydroxy or benzoyloxy.

Disse forbindelser fremviser verdifulle farmakologiske egenskaper. Spesielt fremviser de antiviral aktivitet og er velegnet i behandling eller forebyggelse av Virusinfek-sjoner, spesielt av retrovirale infeksjoner, slik som visna, HIV og lignede infeksjoner. These compounds exhibit valuable pharmacological properties. In particular, they exhibit antiviral activity and are suitable for treating or preventing viral infections, especially retroviral infections, such as herpes, HIV and similar infections.

1-(2<1>,3'-Dideoksy-2'-fluor-e-D-arabinofuranosyl)-cytosin (i det etterfølgende kalt DFAC) er en spesielt foretrukket forbindelse med formel I. 1-(2<1>,3'-Dideoxy-2'-fluoro-e-D-arabinofuranosyl)-cytosine (hereinafter referred to as DFAC) is a particularly preferred compound of formula I.

Ifølge fremgangsmåten fremskaffet ved foreliggende oppfinnelse blir de tidligere nevnte forbindelser fremstilt ved å fjerne 3<1->hydroksygruppen fra en forbindelse med generell According to the method provided by the present invention, the previously mentioned compounds are prepared by removing the 3<1->hydroxy group from a compound with general

formel II formula II

hvori R<10> representerer en benzoyloksygruppe og wherein R<10> represents a benzoyloxy group and

deretter hvis ønsket å omdanne benzoyloksygruppen R<10> i det oppnådde produkt til en hydroksygruppe. then if desired to convert the benzoyloxy group R<10> in the obtained product into a hydroxy group.

Fjerningen av 3<1->hydroksygruppen fra en forbindelse med formel II i henhold til fremgangsmåtevariant (a) kan utføres ved først å omdanne en slik forbindelse med formel II til det tilsvarende sulfonsyrester, såsom mesylatet, ved behandling med et sylfonsyrehalogenid, såsom metansulfonylklorid, i nærvær av et egnet syrebindende middel, spesielt et tertiært amin, såsom pyridin, og ved en lav temperatur, f.eks. 0 - 5°C. Det på denne måten oppnådde sylfonsyreester kan deretter bli omdannet til 3'-jodid ved kjente metoder, f.eks. ved å behandle med et alkalimetall-jodid, såsom natriumjodid, i et passende medium, såsom et alifatisk keton, f.eks. aceton eller 2-butanon, ved en økende temperatur, fortrinnsvis ved tilbakeløpstemperatur, til blandingen. Det dannede 3<*->jodid kan deretter omdannes til den ønskede forbindelse med formel I, i hvilke R<1> er forestret hydroksy, ved hydrogenering i nærvær av en palladiumkatalysator. Alternativt kan et tidligere nevnt 3'-jodid behandles med tributyltinnhydrid i nærvær av en fri radikalinitiator, f.eks. azobisisobutyronitril i et passende inert organisk løsningsmiddel, såsom et aromatisk hydrokarbon, f.eks. benzen eller toluen, og ved en økende temperatur, f.eks. rundt 60 - 9CC, for å gi den ønskede forbindelse med formel I i hvilken R<1> er forestret hydroksy. The removal of the 3<1->hydroxy group from a compound of formula II according to method variant (a) can be carried out by first converting such a compound of formula II into the corresponding sulfonic acid ester, such as the mesylate, by treatment with a sulfonic acid halide, such as methanesulfonyl chloride, in the presence of a suitable acid-binding agent, especially a tertiary amine, such as pyridine, and at a low temperature, e.g. 0 - 5°C. The sulphonic acid ester obtained in this way can then be converted to 3'-iodide by known methods, e.g. by treating with an alkali metal iodide, such as sodium iodide, in a suitable medium, such as an aliphatic ketone, e.g. acetone or 2-butanone, at an increasing temperature, preferably at reflux temperature, to the mixture. The 3<*->iodide formed can then be converted to the desired compound of formula I, in which R<1> is esterified hydroxy, by hydrogenation in the presence of a palladium catalyst. Alternatively, a previously mentioned 3'-iodide can be treated with tributyltin hydride in the presence of a free radical initiator, e.g. azobisisobutyronitrile in a suitable inert organic solvent, such as an aromatic hydrocarbon, e.g. benzene or toluene, and at an increasing temperature, e.g. about 60 - 9CC, to give the desired compound of formula I in which R<1> is esterified hydroxy.

En ytterligere metode for fjerning av 3<1->hydroksygruppen fra en forbindelse med formel II omfatter først å reagere en slik forbindelse med fenyltionoklorformat, passende i et inert organisk løsningsmiddel, slik som acetonitril, i nærvær av et syrebindende middel, såsom et tertiært amin, f.eks. pyridin, eller 4-dimetyl-aminopyridin, og ved omkring romtemperatur, for å gi en tilsvarende 3<1->O-fenoksytiokar-bonylforbindelse. En slik forbindelse kan deretter omdannes til den ønskede forbindelse med formelen I, i hvilken R<1> er forestret hydroksy, ved å behandle med tributyltinnhydrid i nærvær av en fri radikalinitiator på en måte analog til den som er beskrevet tidligere. I en foretrukket utførelse av denne metode blir forbindelsen med formel II acylert ved 4-aminogruppen forut for reaksjonen med fenyltionoklorformat. I denne utførelsesform er produktet som ble oppnådd etter behandlingen med tributyltinnhydrid et tilsvarende amid til forbindelser med formelen I, i hvilke R<1> er forestret hydroksy. A further method for removing the 3<1->hydroxy group from a compound of formula II comprises first reacting such a compound with phenylthiochloroformate, suitably in an inert organic solvent, such as acetonitrile, in the presence of an acid scavenging agent, such as a tertiary amine , e.g. pyridine, or 4-dimethyl-aminopyridine, and at about room temperature, to give a corresponding 3<1->O-phenoxythiocarbonyl compound. Such a compound can then be converted to the desired compound of formula I, in which R<1> is esterified hydroxy, by treatment with tributyltin hydride in the presence of a free radical initiator in a manner analogous to that described earlier. In a preferred embodiment of this method, the compound of formula II is acylated at the 4-amino group prior to the reaction with phenylthiochloroformate. In this embodiment, the product obtained after treatment with tributyltin hydride is a corresponding amide to compounds of formula I in which R<1> is esterified hydroxy.

Omdannelsen av de forestrede hydroksygrupper i produktet til en hydroksygruppe kan bli utført ved i og for seg kjente metoder, f.eks. ved behandling med en mettet oppløsning av ammoniakk i en alkanol, f.eks. metanol. Når produktet bærer en acylaminogruppe i 4-posisjonen kan denne gruppen bli omdannet samtidig til en aminogruppe. The conversion of the esterified hydroxy groups in the product to a hydroxy group can be carried out by methods known per se, e.g. by treatment with a saturated solution of ammonia in an alkanol, e.g. methanol. When the product carries an acylamino group in the 4-position, this group can be converted simultaneously into an amino group.

En forbindelse med formel I i hvilken R<1> er hydroksy kan bli forestret i henhold til fremgangsmåtevariant (b) for å gi en forbindelse med formel I i hvilken R<1> er forestret hydroksy. Denne forestringen kan utføres ved en i og for seg kjent metode, f.eks. ved å behandle hydrokloridsaltet av en forbindelse med formel I med et passende syrehalogenid i et inert organsk løsningsmiddel, såsom dimetylformamid. A compound of formula I in which R<1> is hydroxy can be esterified according to method variant (b) to give a compound of formula I in which R<1> is esterified hydroxy. This esterification can be carried out by a method known per se, e.g. by treating the hydrochloride salt of a compound of formula I with an appropriate acid halide in an inert organic solvent such as dimethylformamide.

Utgangsforbindelsene med formel II kan fremstilles f.eks. ved å omdanne 3'-acyloksygruppen til en forbindelse med The starting compounds of formula II can be prepared, e.g. by converting the 3'-acyloxy group into a compound with

formel III formula III

hvori R<10> har betydningen som er gitt tidligere og R<2> er wherein R<10> has the meaning previously given and R<2> is

en acylgruppe, an acyl group,

til en 3<1->hydroksygruppe. to a 3<1->hydroxy group.

Denne omdannelsen kan utføres ved kjente metoder, slik som behandling med ammoniakk eller et passende amin, såsom etylamin, metylamin, n-propylamin eller trietylamiin, i en lavere alkanol såsom metanol, passende ved omkring romtemperatur. Det er underforstått at reagenser brukt for å fremkalle omdannelsen og reaksjonsbetingelser velges slik at de ikke frembringer medvirkende omdannelse av den forestrede hydroksygruppen R<10> til hydroksy. This conversion can be carried out by known methods, such as treatment with ammonia or a suitable amine, such as ethylamine, methylamine, n-propylamine or triethylamine, in a lower alkanol such as methanol, suitably at about room temperature. It is understood that reagents used to induce the conversion and reaction conditions are chosen so that they do not produce contributory conversion of the esterified hydroxy group R<10> to hydroxy.

Forbindelsene med formel III ovenfor er kjente forbindelser eller analoge til kjente forbindelser som kan fremstilles på en tilsvarende måte som de kjente forbindelser. The compounds of formula III above are known compounds or analogues of known compounds which can be prepared in a similar manner to the known compounds.

Benzoatet med formel III hvor R<10> er benzoyloksy og R<2> er benzoyl, og det tilsvarende acetat l-(3<1->0-acetyl-5-0-benzoyl-1'deoksy-2'-fluor-P-D-arabinofuranosyl)cytosin (III, rIO <_>benzoyloksy, R<2> = acetyl) anvendt som utgangsmateriale i punkt a) i eksempel 1 nedenfor, er f.eks. beskrevet i J. Med. Chem. 13 (1970) 269-272 og Arch. Pharm. Res. 6 (1983) 79-81 og i Arch. Pharm. Res. 6 (1983) 79-81. The benzoate of formula III where R<10> is benzoyloxy and R<2> is benzoyl, and the corresponding acetate 1-(3<1>0-acetyl-5-0-benzoyl-1'deoxy-2'-fluoro- P-D-arabinofuranosyl)cytosine (III, rIO <_>benzoyloxy, R<2> = acetyl) used as starting material in point a) in example 1 below, is e.g. described in J. Med. Chem. 13 (1970) 269-272 and Arch. Pharm. Res. 6 (1983) 79-81 and in Arch. Pharm. Res. 6 (1983) 79-81.

I aktivitetstesten (B) beskrevet nedenfor, hvor DFAC har en IC50-verdi på lpM, og dets benzoat (I, R<1> = benzoyloksy, produktet fra eksempel 1, punkt d) en IC50-verdi på 1,1>jM, er det ovenfor nevnte tidligere kjente benzoat (III, R<10> = benzoyloksy, R<2> = benzoyl) med en ID50-verdi på 20jjM praktisk talt uvirksomt. Det samme gjelder forbindelsen Acyclovir med en IC50 på 50 yiM. i samme forsøk samt 2'-fluor-2<1->deoksycytidin som, som angitt i CA. 102, 1985, 197587y, har lavere antiviral aktivitet enn Acyclovir. In the activity test (B) described below, where DFAC has an IC50 value of lpM, and its benzoate (I, R<1> = benzoyloxy, the product of Example 1, point d) an IC50 value of 1.1>jM, is the above-mentioned previously known benzoate (III, R<10> = benzoyloxy, R<2> = benzoyl) with an ID50 value of 20jjM practically inactive. The same applies to the compound Acyclovir with an IC50 of 50 yM. in the same experiment as well as 2'-fluoro-2<1->deoxycytidine which, as indicated in CA. 102, 1985, 197587y, has lower antiviral activity than Acyclovir.

Den in vitro antivirale aktivitet av pyrimidin-derivatene fremskaffet ved foreliggende oppfinnelse demonstreres i det etterfølgende forsøk. The in vitro antiviral activity of the pyrimidine derivatives provided by the present invention is demonstrated in the following experiment.

(A) Aktivitet mot lentivirus hos sau (A) Activity against sheep lentivirus

Dette forsøk bruker saue-lentivirus (stamme WLC-1) som er This experiment uses ovine lentivirus (strain WLC-1) which is

dyrket i choroid plexus (SCP)-celler fra sau ved å benytte et medium som inneholder 10% kvegfosterserum. Forbindelsene er testet i 96-brønners mikrokulturplater. Hver brønn inneholder IO<4> SCP-celler som har blitt inkubert i 48 timer. Testforbindelsen som er løst i dimetylsulfoksyd, blir tilsatt for å gi en endelig konsentrasjon på 1% dimetylsulfoksyd sammen med et viruspodestoff som er beregnet til å danne 100% cytopatisk effekt i 12 dager. Etter inkubasjon ved 37°C i 12 dager blir platene festet og farget med krystallfiolett. Beskyttelse i brønner som inneholdt testforbindelser ble bestemt visuelt i forhold til brønner som inneholdt virus alene og uinfiserte brønner. Aktivi-teten (MPC) blir uttrykt som den laveste konsentrasjon av testforbindelse som gir 100% beskyttelse av de infiserte brønner. I dette forsøket har DFAC en MPC på 2,5 uM. cultured in sheep choroid plexus (SCP) cells using a medium containing 10% fetal bovine serum. The compounds have been tested in 96-well microculture plates. Each well contains 10<4> SCP cells that have been incubated for 48 hours. The test compound dissolved in dimethylsulfoxide is added to give a final concentration of 1% dimethylsulfoxide together with a virus inoculum designed to produce 100% cytopathic effect for 12 days. After incubation at 37°C for 12 days, the plates are fixed and stained with crystal violet. Protection in wells containing test compounds was determined visually relative to wells containing virus alone and uninfected wells. The activity (MPC) is expressed as the lowest concentration of test compound which provides 100% protection of the infected wells. In this experiment, DFAC has an MPC of 2.5 µM.

(B) Aktivitet mot HIV (B) Activity against HIV

Dette forsøk bruker HTLV-III (stamme RF) dyrket i C8166-celler (en menneskelig CD4<+> T lymfoblastoidlinje) ved å benytte RPM1 1640-medium med bikarbonatbuffer, antibiotika og 10% kvegfosterserum. En suspensjon med celler blir infisert med 10 ganger TCD50 av viruset, og adsorpsjonen får foregå i 90 minutter ved 37°C. Cellene blir vasket med medium. Testen blir utført i 6 ml vevskulturrør, hvert rør inneholder 2 x IO<5> infiserte celler i 1,5 ml medium. Testforbindelser blir oppløst enten i vandig medium eller i dimetylsulfoksyd, avhengig av løselighet, og en 15 ul løsning av substansen blir tilsatt. Kulturene blir inkubert ved 39"C i 72 timer i en fuktig atmosfære som inneholder 5% karbondioksyd i luft. Kulturene blir deretter sentrifugert, og like deler av supernatanten blir oppløst og utsatt for et antigen-opptagelsesforsøk som benytter et primært antiserum med spesiell aktivitet mot virusprotein 24 og et pepperrot peroksydase-oppdagelsessystem. Fargeutvikling blir påvist spektrofotometrisk og plottet mot den konsentrerte testsub-stans. Konsentrasjonen som danner 50% beskyttelse blir bestemt (IC50)• This experiment uses HTLV-III (strain RF) grown in C8166 cells (a human CD4<+> T lymphoblastoid line) using RPM1 1640 medium with bicarbonate buffer, antibiotics and 10% fetal bovine serum. A suspension of cells is infected with 10 times the TCD50 of the virus, and the adsorption is allowed to take place for 90 minutes at 37°C. The cells are washed with medium. The test is performed in 6 ml tissue culture tubes, each tube containing 2 x 10<5> infected cells in 1.5 ml medium. Test compounds are dissolved either in aqueous medium or in dimethyl sulfoxide, depending on solubility, and a 15 µl solution of the substance is added. The cultures are incubated at 39°C for 72 hours in a humidified atmosphere containing 5% carbon dioxide in air. The cultures are then centrifuged, and equal portions of the supernatant are dissolved and subjected to an antigen uptake assay using a primary antiserum with specific activity against viral protein 24 and a horseradish peroxidase detection system. Color development is detected spectrophotometrically and plotted against the concentrated test substance. The concentration producing 50% protection is determined (IC50)•

I forsøket beskrevet ovenfor utviser DFAC en IC50 på luM. In the experiment described above, DFAC exhibits an IC50 of luM.

Pyrimidinderivatene fremstilt ved foreliggende oppfinnelse kan benyttes som medikament i form av farmasøytiske prepara-ter som inneholder dem i kombinasjon med fkompatible farmasøytiske hjelpestoffer. Disse preparatene kan admini-streres oralt, f.eks. i form av tabletter, dragerte piller, hårdgelatinkapsler, bløtgelatinkapsler, løsninger, emul-sjoner eller suspensjoner; eller parenteralt, f.eks. i form av injeksjonsoppløsinger. The pyrimidine derivatives produced by the present invention can be used as medicine in the form of pharmaceutical preparations containing them in combination with compatible pharmaceutical excipients. These preparations can be administered orally, e.g. in the form of tablets, coated pills, hard gelatin capsules, soft gelatin capsules, solutions, emulsions or suspensions; or parenterally, e.g. in the form of injection solutions.

Følgende eksempler illustrerer fremgangsmåten fremskaffet ved foreliggende oppfinnelse: The following examples illustrate the method provided by the present invention:

Eksempel 1 Example 1

a) En oppløsning som inneholdt 0,94 g 1-(3 *-0-acetyl-5•-O-benzoyl-2<*->deoksy-2<1->fluor-e-D -arabinofuranosyl)cytosin i a) A solution containing 0.94 g of 1-(3*-0-acetyl-5•-O-benzoyl-2<*->deoxy-2<1->fluoro-e-D-arabinofuranosyl)cytosine in

4,9 ml av en 2M-løsning av ammoniakk i metanol ble rørt i 2 timer. Oppløsningen ble fordampet til tørrhet og resten ble omkrystallisert fra etylacetat for å gi 0,64 g l-(5'-0-benzoyl-2•-deoksy-2'-fluor-3-D -arabinofuranosyl)cytosin, smeltepunkt 135-140°C. 4.9 ml of a 2M solution of ammonia in methanol was stirred for 2 hours. The solution was evaporated to dryness and the residue recrystallized from ethyl acetate to give 0.64 g of 1-(5'-0-benzoyl-2•-deoxy-2'-fluoro-3-D-arabinofuranosyl)cytosine, mp 135-140 °C.

b) En oppløsning som inneholdt 0,4 g av produktet i eksempel la) i 5,6 ml tørr pyridin ble rørt ved 0°C mens 0,26 g b) A solution containing 0.4 g of the product in example la) in 5.6 ml of dry pyridine was stirred at 0°C while 0.26 g

metansulfonylklorid ble tilsatt dråpevis. Blandingen ble rørt ved 0-5°C i 20 timer og deretter behandlet med 0,1 ml vann. Etter omrøring i 1 time ble blandingen helt over i 20 ml isvann og ekstrahert med etylacetat. Etylacetatekstrak-tene ble vasket med mettet natriumkloridløsning, tørket over magnesiumsulfat og inndampet for å gi 0,5 g 1-(5 *-0-benzoyl-2'-deoksy-2 »-fluor-3'-O-metylsulfonyl-e-D-arabinofuranosyl)-cytosin. methanesulfonyl chloride was added dropwise. The mixture was stirred at 0-5°C for 20 hours and then treated with 0.1 ml of water. After stirring for 1 hour, the mixture was poured into 20 ml of ice water and extracted with ethyl acetate. The ethyl acetate extracts were washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give 0.5 g of 1-(5*-0-benzoyl-2'-deoxy-2'-fluoro-3'-O-methylsulfonyl-e-D- arabinofuranosyl)-cytosine.

c) En oppløsning av 0,5 g av produktet fra eksempel lb) c) A solution of 0.5 g of the product from example lb)

og 0,9 g natriumjodid i 12 ml tørt 2-butanon ble rørt og and 0.9 g of sodium iodide in 12 ml of dry 2-butanone were stirred and

kokt under tilbakeløp i 16 timer. Den dannede suspensjon ble dampet inn til tørrhet, og resten ble fordelt mellom 20 ml vann og 12 ml etylacetat. Sjiktene ble separert, og vannsjiktet ble ekstrahert med etylacetat. Etylacetatløsnin-gene ble tørket over magnesiumsulfat og dampet inn. Resten ble kromatografert på silikagel med metanol/diklormetan (1:9). Det ble erholdt 0,2 g 1-(5'-O-benzoyl-2<1>,3<1->dideoksy-2'-fluor-3'-jod-P-D-arabinofuranosyl)cytosin. d) En oppløsning av 0,2 g av produktet fra eksempel lc) i 8 ml etanol ble behandlet med en løsning av 0,04 g natrium-bikarbonat i 2 ml vann og deretter hydrogenert i nærvær av 0,06 av 10% palladium-på-karbon-katalysator i 24 timer. Katalysatoren ble fjernet ved filtrering, og-filtratet ble dampet inn til tørrhet. Resten ble fordelt mellom vann og etylacetat. Vannfasen ble separert og ekstrahert med etylacetat. Etylacetatløsningen ble tørket over magnesiumsulfat og dampet inn. Det ble erholdt 0,14 g l-(5'-0-benzoyl-2',3<1->dideoksy-2<1->fluor-3-D-arabinofuranosyl)-cytosin. e) 0,05 g av produktet fra eksempel ld) ble oppløst i 2 ml mettet ammoniakkløsning i metanol. Løsningen fikk stå i tre boiled under reflux for 16 hours. The resulting suspension was evaporated to dryness and the residue was partitioned between 20 ml of water and 12 ml of ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The ethyl acetate solutions were dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with methanol/dichloromethane (1:9). 0.2 g of 1-(5'-O-benzoyl-2<1>,3<1->dideoxy-2'-fluoro-3'-iodo-β-D-arabinofuranosyl)cytosine was obtained. d) A solution of 0.2 g of the product from example lc) in 8 ml of ethanol was treated with a solution of 0.04 g of sodium bicarbonate in 2 ml of water and then hydrogenated in the presence of 0.06 of 10% palladium- on-carbon catalyst for 24 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was partitioned between water and ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate and evaporated. 0.14 g of 1-(5'-O-benzoyl-2',3<1->dideoxy-2<1->fluoro-3-D-arabinofuranosyl)-cytosine was obtained. e) 0.05 g of the product from example ld) was dissolved in 2 ml of saturated ammonia solution in methanol. The solution was left in three

dager og ble så dampet inn til tørrhet. Resten ble oppløst i 2 ml vann og løsningen ble vasket med etylacetat. Den vandige løsning ble frysetørket i 24 timer for å gi 0,02 g DFAC, MS (EI): m/e 229 (M)<+>, 151, 112. days and was then evaporated to dryness. The residue was dissolved in 2 ml of water and the solution was washed with ethyl acetate. The aqueous solution was lyophilized for 24 h to give 0.02 g of DFAC, MS (EI): m/e 229 (M)<+>, 151, 112.

Eksempel 2 Example 2

a) En oppløsning som inneholder 11,8 g av produktet fra eksempel la) i 1180 ml metanol ble rørt og kokt under a) A solution containing 11.8 g of the product from example la) in 1180 ml of methanol was stirred and boiled under

tilbakeløp. Oppløsningen ble behandlet med 12 ml eddiksyreanhydrid og deretter ved timesintervaller i ytterligere 4 timer med 12 ml eddiksyreanhydrid hver gang. Etter 6 timer ble løsningen inndampet til tørrhet og resten ble backflow. The solution was treated with 12 ml of acetic anhydride and then at hourly intervals for a further 4 hours with 12 ml of acetic anhydride each time. After 6 hours, the solution was evaporated to dryness and the residue remained

igjen inndampet to ganger med 300 ml toluen hver gang, deretter oppløst ill metanol og behandlet én gang i timen i løpet av 3 timer med 12 ml eddiksyreanhydrid. Oppløsnin-gen ble inndampet til tørrhet, og resten ble oppløst i diklormetan. Oppløsningen ble vasket med vann, mettet natriumhydrogenkarbonatoppløsning og vann, deretter tørket over natriumsulfat og dampet inn. Resten ble tørket under vakuum for å gi 12,5 g N-acetyl-1-(5<1->O-benzoyl-2'-deoksy-2<1->fluor-3-D-arabinofuranosyl)cytosin. again evaporated twice with 300 ml of toluene each time, then dissolved in methanol and treated once an hour during 3 hours with 12 ml of acetic anhydride. The solution was evaporated to dryness, and the residue was dissolved in dichloromethane. The solution was washed with water, saturated sodium bicarbonate solution and water, then dried over sodium sulfate and evaporated. The residue was dried under vacuum to give 12.5 g of N-acetyl-1-(5<1->O-benzoyl-2'-deoxy-2<1->fluoro-3-D-arabinofuranosyl)cytosine.

b) En oppløsning inneholdende 10,7 g av produktet fra eksempel 2a) og 29,7 g 4-(dimetylamino)pyridin i 295 ml b) A solution containing 10.7 g of the product from example 2a) and 29.7 g of 4-(dimethylamino)pyridine in 295 ml

acetonitril ble rørt under argon og avkjølt ved 5'C mens 5,61 g fenylklortionokarbonat ble tilsatt dråpevis. Blandingen ble rørt ved 5°C i ytterlighere 10 minutter og deretter ved romtemperatur i 3 timer. Den dannede løsningen ble inndampet til tørrhet, og resten ble løst i diklormetan. Oppløsningen ble vasket med isvann, IM saltsyre, vann, mettet natriumhydrogenkarbonatløsning og mettet natrium-kloridløsning, deretter tørket over natriumsulfat og dampet inn. Resten ble tørket under vakuum for å gi 14,2 g N-acetyl-1-(5<1->O-benzoyl-2<1->deoksy-2<1->fluor-3<1->0-fenoksy-tiokarbonyl-3-D-arabinofuranosyl)cytosin. acetonitrile was stirred under argon and cooled at 5°C while 5.61 g of phenylchlorothiocarbonate was added dropwise. The mixture was stirred at 5°C for an additional 10 minutes and then at room temperature for 3 hours. The resulting solution was evaporated to dryness and the residue was dissolved in dichloromethane. The solution was washed with ice water, 1M hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution, then dried over sodium sulfate and evaporated. The residue was dried under vacuum to give 14.2 g of N-acetyl-1-(5<1->O-benzoyl-2<1->deoxy-2<1->fluoro-3<1->0-phenoxy -thiocarbonyl-3-D-arabinofuranosyl)cytosine.

c) En oppløsning inneholdende 14,1 g av produktet fra eksempel 2b) og 0,5 g azobisisobutyronitril i 520 ml tørr c) A solution containing 14.1 g of the product from example 2b) and 0.5 g of azobisisobutyronitrile in 520 ml of dry

toluen ble rørt mens argon ble boblet gjennom løsningen i 10 minutter. 11,28 g tributyltinn-hydrid ble tilsatt, og til-setningen av argon ble fortsatt i ytterligere 30 minutter. Blandingen ble deretter varmet ved 75°C under argon i 3 timer. Oppløsingen ble dampet inn til tørrhet, og resten ble knust med heksan. Produktet ble filtrert fra og renset ved kromatografi på silikagel med hjelp av metanol/diklormetan (1:9). Det ble oppnådd 6,95 g N-acetyl-1-(5<1->0-benzoyl-2<1>,3•-dideoksy-2<1->fluor-3-D-arabinofuranosyl)-cytosin, smp. 191-193,5°C etter omkrystallisering fra toluen. the toluene was stirred while argon was bubbled through the solution for 10 minutes. 11.28 g of tributyltin hydride was added and the addition of argon was continued for another 30 minutes. The mixture was then heated at 75°C under argon for 3 hours. The solution was evaporated to dryness and the residue triturated with hexane. The product was filtered off and purified by chromatography on silica gel using methanol/dichloromethane (1:9). 6.95 g of N-acetyl-1-(5<1->0-benzoyl-2<1>,3•-dideoxy-2<1->fluoro-3-D-arabinofuranosyl)-cytosine were obtained, m.p. . 191-193.5°C after recrystallization from toluene.

d) En oppløsning inneholdende 0,5 g av produktet fra eksempel 2c) i 50 ml metanol som først var blitt mettet med d) A solution containing 0.5 g of the product from example 2c) in 50 ml of methanol which had first been saturated with

ammoniakk ved 0°C, ble rørt i 3 dager. Oppløsningen ble inndampet til tørrhet, og resten ble oppløst i 30 ml vann. Den vandige oppløsning ble vasket med etylacetat og deretter dampet inn til tørrhet. Resten ble omkrystallisert fra etanol for å gi 0,18 g DFAC, smp. 204-207°C. Moderluten fra omkrystalliseringen ble dampet inn, og resten ble oppløst i destillert vann. Den vandige løsningen ble frysetørket, og resten ble omkrystallisert fra etanol for å gi utbytte nr. to på 0,06 g DFAC, smp. 199-203°C. ammonia at 0°C, was stirred for 3 days. The solution was evaporated to dryness and the residue was dissolved in 30 ml of water. The aqueous solution was washed with ethyl acetate and then evaporated to dryness. The residue was recrystallized from ethanol to give 0.18 g of DFAC, m.p. 204-207°C. The mother liquor from the recrystallization was evaporated, and the residue was dissolved in distilled water. The aqueous solution was lyophilized and the residue was recrystallized from ethanol to give a second yield of 0.06 g DFAC, m.p. 199-203°C.

Claims (2)

1. Analogifremgangsmåte ved fremstilling av terapeutisk aktive forbindelser med generell formel hvori R<1> representerer hydroksy eller benzoyloksy, karakterisert ved å fjerne 3'-hydroksygruppen fra en forbindelse med generell formel II hvori R<10> representerer en benzoyloksygruppe og deretter hvis ønsket å omdanne benzoyloksygruppen R<10> i det oppnådde produkt til en hydroksygruppe.1. Analogy method in the preparation of therapeutically active compounds of general formula wherein R<1> represents hydroxy or benzoyloxy, characterized by to remove the 3'-hydroxy group from a compound with general formula II in which R<10> represents a benzoyloxy group and then if desired to convert the benzoyloxy group R<10> in the obtained product into a hydroxy group. 2. Fremgangsmåte ifølge krav 1 ved fremstilling av l-(2<*>,3'-dideoksy-2'-fluor-P-D-arabino-furanosyl)-cytosin, karakterisert ved at det anvendes tilsvarende substituerte utgangsforbindelser.2. Process according to claim 1 for the production of 1-(2<*>,3'-dideoxy-2'-fluoro-β-D-arabino-furanosyl)-cytosine, characterized in that correspondingly substituted starting compounds are used.
NO882233A 1987-05-22 1988-05-20 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRIMIDINE DERIVATIVES NO171065C (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB878712115A GB8712115D0 (en) 1987-05-22 1987-05-22 Pyrimidine derivatives

Publications (4)

Publication Number Publication Date
NO882233D0 NO882233D0 (en) 1988-05-20
NO882233L NO882233L (en) 1988-11-23
NO171065B true NO171065B (en) 1992-10-12
NO171065C NO171065C (en) 1993-01-20

Family

ID=10617762

Family Applications (1)

Application Number Title Priority Date Filing Date
NO882233A NO171065C (en) 1987-05-22 1988-05-20 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRIMIDINE DERIVATIVES

Country Status (19)

Country Link
EP (1) EP0292023A3 (en)
JP (1) JPS63303992A (en)
KR (1) KR880013927A (en)
CN (1) CN88103089A (en)
AU (1) AU602083B2 (en)
DK (1) DK165985C (en)
FI (1) FI882303A (en)
GB (1) GB8712115D0 (en)
HU (1) HU199868B (en)
IL (1) IL86394A0 (en)
IS (1) IS3344A7 (en)
MC (1) MC1934A1 (en)
MX (1) MX11493A (en)
NO (1) NO171065C (en)
NZ (1) NZ224638A (en)
PH (1) PH26909A (en)
PT (1) PT87550B (en)
YU (1) YU46860B (en)
ZA (1) ZA883447B (en)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1340645C (en) * 1987-04-17 1999-07-13 Victor E. Marquez Acid stable dideoxynucleosides active against the cytopathic effects of human immunodeficiency virus
US4908440A (en) * 1987-11-12 1990-03-13 Bristol Myers Company 2',3'-dideoxy-2'-fluoroarabinopyrimidine nucleosides
NZ232912A (en) * 1989-03-17 1992-06-25 Oncogen Ltd Lp Synergistic composition of nucleoside derivatives for inhibiting hiv
CA2073063A1 (en) * 1989-11-06 1991-05-07 Jo Klaveness Nucleoside derivatives
AT400953B (en) * 1994-08-25 1996-05-28 Joern Saischek PENTOFURANOSIDE DERIVATIVES, THEIR PRODUCTION AND USE
EA200700564A1 (en) 1998-02-25 2007-08-31 Эмори Юниверсити 2`-Fluoride
KR101005299B1 (en) 2000-10-18 2011-01-04 파마셋 인코포레이티드 Modified nucleosides for treatment of viral infections and abnormal cellular proliferation
BR0210594A (en) 2001-06-22 2005-11-01 Pharmasset Ltd (beta) -d or (beta) -1,3-halonucleoside
WO2006021341A1 (en) 2004-08-23 2006-03-02 F. Hoffmann-La Roche Ag Antiviral 4’-azido-nucleosides
US8895531B2 (en) 2006-03-23 2014-11-25 Rfs Pharma Llc 2′-fluoronucleoside phosphonates as antiviral agents
AP2009004812A0 (en) 2006-10-10 2009-04-30 Medivir Ab HCV nucleoside inhibitor

Also Published As

Publication number Publication date
NO882233L (en) 1988-11-23
EP0292023A3 (en) 1989-06-14
GB8712115D0 (en) 1987-06-24
NO882233D0 (en) 1988-05-20
CN88103089A (en) 1988-12-07
KR880013927A (en) 1988-12-22
NZ224638A (en) 1990-04-26
JPS63303992A (en) 1988-12-12
ZA883447B (en) 1988-11-22
PT87550B (en) 1992-09-30
DK227388A (en) 1988-11-23
PT87550A (en) 1989-05-31
AU1631788A (en) 1988-11-24
YU93288A (en) 1990-04-30
HU199868B (en) 1990-03-28
FI882303A (en) 1988-11-23
MX11493A (en) 1993-09-01
NO171065C (en) 1993-01-20
PH26909A (en) 1992-12-03
MC1934A1 (en) 1989-05-19
DK165985C (en) 1993-11-08
EP0292023A2 (en) 1988-11-23
DK165985B (en) 1993-02-22
FI882303A0 (en) 1988-05-17
YU46860B (en) 1994-06-24
IL86394A0 (en) 1988-11-15
HUT47127A (en) 1989-01-30
DK227388D0 (en) 1988-04-26
AU602083B2 (en) 1990-09-27
IS3344A7 (en) 1988-11-23

Similar Documents

Publication Publication Date Title
NO171065B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRIMIDINE DERIVATIVES
US8193354B2 (en) Process for preparation of Gemcitabine hydrochloride
Matsuda et al. A simple method for synthesis of amides and peptides through acyl chlorides: A rapid synthesis of thyrotropin releasing hormone
NO164904B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE GRISEOLIC ACID DERIVATIVES.
KR0161982B1 (en) Etoposide analogues
JPH0818986B2 (en) Process for producing 2 &#39;, 3&#39;-dideoxycytidine-2&#39;-ene (2&#39;, 3&#39;-dideoxy-2 &#39;, 3&#39;-didehydrocytidine) for treating patients infected with retrovirus
CS270249B2 (en) Method of purine&#39;s new derivatives production
US4048307A (en) Cyclic adenosine monophosphate 8-substituted derivatives
US4544740A (en) Process for the preparation of 5-(2-bromovinyl)-uridine
EP0625158A1 (en) Therapeutic nucleosides
EP0292101A2 (en) Process for the preparation of 3&#39;-azido-3&#39;-deoxythymidine and intermediates
NO169007B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE URIDIN DERIVATIVES
NO145843B (en) ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC EFFECTIVE N1-GLUCOFURANOSIDE-6-YL-N3-NITROSO URINE
NO822807L (en) PROCEDURE FOR PREPARING 2-BETA-D-RIBOFURANOSYLTHIAZOL-4-CARBOXAMIDE.
JPH0267295A (en) Purine derivative
Baker et al. Synthetic Nucleosides. LVIII. 1, 2 Studies on the Synthesis of cis-2, 3-Diamino Sugars. I. The Nitroguanidine Neighboring Group
Sano et al. A FACILE SYNTHESIS OF 6, 3'-METHANO-URIDINE AND-CYTIDINE FROM A 3-KETOSUGAR: NUCLEOSIDES AND NUCLEOTIDES LXVIII
NO752174L (en)
US4460690A (en) Stimulation of viral growth rate
US4985451A (en) Elaiophylin derivatives, the use thereof as pharmaceuticals, and pharmaceuticals containing them
US5233029A (en) Elaiophylin derivatives and a process for the preparation thereof
Maruyama et al. Synthesis of methylenecyclobutyl-and cyclobutenyl adenine, potent antiviral carbocyclic analogues of oxetanocin A
JPS6152839B2 (en)
RU2034842C1 (en) Quinoline derivative and a method of its synthesis
IL42837A (en) Cardenolide-3-(2&#39;-desoxy-l-glycosides) and process for their manufacture