NO171065B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRIMIDINE DERIVATIVES - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRIMIDINE DERIVATIVES Download PDFInfo
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- 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
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- 238000000034 method Methods 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title claims description 3
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical class C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 229940104302 cytosine Drugs 0.000 claims description 11
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 10
- 239000007858 starting material Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- -1 sulfonic acid halide Chemical class 0.000 description 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 4
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 2
- 229960004150 aciclovir Drugs 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- HBEFYGYBMKPNSZ-UHFFFAOYSA-N s-phenyl chloromethanethioate Chemical compound ClC(=O)SC1=CC=CC=C1 HBEFYGYBMKPNSZ-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- CKTSBUTUHBMZGZ-SHYZEUOFSA-N 2'‐deoxycytidine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 CKTSBUTUHBMZGZ-SHYZEUOFSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical class [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CKTSBUTUHBMZGZ-UHFFFAOYSA-N Deoxycytidine Natural products O=C1N=C(N)C=CN1C1OC(CO)C(O)C1 CKTSBUTUHBMZGZ-UHFFFAOYSA-N 0.000 description 1
- 101100005713 Homo sapiens CD4 gene Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000713747 Ovine lentivirus Species 0.000 description 1
- 101150085390 RPM1 gene Proteins 0.000 description 1
- 206010038997 Retroviral infections Diseases 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000002987 choroid plexus Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- KOSYAAIZOGNATQ-UHFFFAOYSA-N o-phenyl chloromethanethioate Chemical compound ClC(=S)OC1=CC=CC=C1 KOSYAAIZOGNATQ-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
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
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- 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)
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 |
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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
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Application Number | Title | Priority Date | Filing Date |
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NO882233A NO171065C (en) | 1987-05-22 | 1988-05-20 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRIMIDINE DERIVATIVES |
Country Status (19)
Country | Link |
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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)
Publication number | Priority date | Publication date | Assignee | Title |
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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 |
-
1987
- 1987-05-22 GB GB878712115A patent/GB8712115D0/en active Pending
-
1988
- 1988-04-26 DK DK227388A patent/DK165985C/en active
- 1988-05-13 YU YU93288A patent/YU46860B/en unknown
- 1988-05-16 NZ NZ224638A patent/NZ224638A/en unknown
- 1988-05-16 ZA ZA883447A patent/ZA883447B/en unknown
- 1988-05-16 IL IL86394A patent/IL86394A0/en unknown
- 1988-05-16 MX MX1149388A patent/MX11493A/en unknown
- 1988-05-17 AU AU16317/88A patent/AU602083B2/en not_active Ceased
- 1988-05-17 FI FI882303A patent/FI882303A/en not_active Application Discontinuation
- 1988-05-18 PH PH36945A patent/PH26909A/en unknown
- 1988-05-18 HU HU882469A patent/HU199868B/en not_active IP Right Cessation
- 1988-05-19 MC MC881980A patent/MC1934A1/en unknown
- 1988-05-19 JP JP63120806A patent/JPS63303992A/en active Pending
- 1988-05-19 IS IS3344A patent/IS3344A7/en unknown
- 1988-05-20 PT PT87550A patent/PT87550B/en not_active IP Right Cessation
- 1988-05-20 NO NO882233A patent/NO171065C/en unknown
- 1988-05-21 KR KR1019880006017A patent/KR880013927A/en not_active Application Discontinuation
- 1988-05-21 CN CN198888103089A patent/CN88103089A/en active Pending
- 1988-05-24 EP EP88108271A patent/EP0292023A3/en not_active Withdrawn
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 |
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