NO167572B - Analogifremgangsmaate for fremstilling av et terapeutisk aktivt purinderivat. - Google Patents
Analogifremgangsmaate for fremstilling av et terapeutisk aktivt purinderivat. Download PDFInfo
- Publication number
- NO167572B NO167572B NO87874764A NO874764A NO167572B NO 167572 B NO167572 B NO 167572B NO 87874764 A NO87874764 A NO 87874764A NO 874764 A NO874764 A NO 874764A NO 167572 B NO167572 B NO 167572B
- Authority
- NO
- Norway
- Prior art keywords
- formula
- compound
- preparation
- purine derivative
- therapeutic active
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000003212 purines Chemical class 0.000 title description 2
- 230000001225 therapeutic effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 6
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- WJOWACPJSFGNRM-UHFFFAOYSA-N 2-[2-(2-aminopurin-9-yl)ethyl]propane-1,3-diol Chemical compound NC1=NC=C2N=CN(CCC(CO)CO)C2=N1 WJOWACPJSFGNRM-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108010093894 Xanthine oxidase Proteins 0.000 description 2
- 102100033220 Xanthine oxidase Human genes 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- -1 2- amino- 9-( 4- hydroxy- 3- hydroxyethylbut- 1-yl) purine Chemical compound 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- KXPSHSVVYGZKAV-UHFFFAOYSA-N [2-(acetyloxymethyl)-4-(2-amino-6-chloropurin-9-yl)butyl] acetate Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1Cl KXPSHSVVYGZKAV-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000020247 cow milk Nutrition 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- 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
-
- 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
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Oppfinnelsen vedrører en analogifremgangsmåte for fremstilling et terapeutisk aktivt purinderivat eller et salt derav.
Forbindelsen 9-(4-hydroksy-3-hydroksymetylbut-l-yl)guanin
med formel (A)
er angitt i Synthetic Communications, 2(6), 345 - 351 (1972),
men ingen farmasøytisk aktivitet er blitt angitt for forbindel-
sen i nevnte publikasjon. Vi har senere vist at forbindelsen med formel (A) virkelig har farmasøytisk aktivitet, og dette er beskrevet i vår publiserte europeiske patentsøknad 0141927.
Vi har nå fremstilt en rekke analoger av forbindelsen med formel (A) som har nyttige oral-absorpsjonsegenskaper og omdan-
nes in vivo til forbindelsen med formel (A) som har antiviral aktivitet.
Ved fremgangsmåten i henhold til oppfinnelsen tilveiebringes en forbindelse med formel (I)
eller et salt derav. Denne forbindelse er en spesielt fordelaktig prodroge av forbindelse (A) og viser en 10 ganger så høy konsentrasjon i blodet som ved administrering av forbindelse (A).
Forbindelsen med formel (I) fremkommer i to enantiomere former. Oppfinnelsen inkluderer fremstilling av begge enantiomerer i isolert form og blandinger derav.
Forbindelsene, som fremstilles i henhold til oppfinnelsen kan være i krystallinsk form eller som hydrater, og det er hensikten at begge former omfattes av uttrykket "forbindelse med formel (I)" som her anvendt.
Salter av forbindelsen med formel (I) er fortrinnsvis farmasøytisk akseptable, men ikke-famasøytisk akseptable salter er også innen rammen, av foreliggende oppfinnelse, siden de er nyttige som mellomprodukter ved fremstilling av farmasøytisk akseptable forbindelser.
Eksempler på farmasøytiske akseptable salter av forbindelsen med formel (I) er syreaddisjonssalter dannet med en farmasøytisk akseptabel syre, f.eks. saltsyre, ortofosforsyre og svovelsyre.
Forbindelsene fremstilt i henhold til oppfinnelsen er potensielt anvendelige ved behandling av infeksjoner forårsaket av herpesvirus, f.eks. herpes simplex type 1, herpes simplex type 2 og varicella zoster virus.
Følgelig tilveiebringer oppfinnelsen også en forbindelse med formel (I) eller et farmasøytisk akseptabelt salt derav,
for anvendelse som aktiv terapeutisk substans og spesielt for anvendelse ved behandling av virusinfeksjoner.
Forbindelser med formel (I) kan fremstilles ved reduksjon
av en forbindelse med formel (VIII)
Reduksjonen utføres fortrinnsvis katalytisk, ved anvendelse av palladium-på-trekull, og den påfølgende hydrolyse til forbindelsen med formel (I) kan bekvemt utføres direkte på reaksj onsproduktblandingen.
3
Forbindelser med formel (VIII) kan fremstilles ved å behandle forbindelsen med formel (V),
med en forbindelse med formel (X)
hvor Z er en uttredende gruppe, f.eks. Cl, Br eller I, fortrinnsvis Br.
Forbindelsen med formel (V) er en kjent forbindelse.
Forbindelser med formel (X) hvor Z er brom kan fremstilles ved å bromere en forbindelse med formel (XI)
fortrinnsvis ved behandling med karbontetrabromid og trifenyl-fosfin i et organisk, aprotisk løsningsmiddel, f.eks. dimetyl-formamid.
Forbindelser med formel (X) hvor Z er Cl eller I kan fremstilles på analog måte.
Forbindelser med formel (XI) hvor R4 og R5 er acetylgrupper, kan fremstilles i henhold til følgende skjematiske prosess:
hvor R<6> er en fjernbar beskyttende gruppe.
Passende er R<6> en gruppe som kan fjernes ved hydrolyse eller hydrogenolyse.
Fortrinnsvis er R6 en gruppe som kan fjernes ved hydrogenolyse, f.eks. benzyl. Denne gruppe kan fjernes ved konven-sjonelle metoder, f.eks. ved å anvende hydrogen i nærvær av en palladium/karbon-katalysator.
Det følgende eksempel illustrerer oppfinnelsen.
EKSEMPEL
9-( 4- acetoksy- 3- acetoksymetylbut- l- yl)- 2- aminopurin
En suspensjon av 9-(4-acetoksy-3-acetoksymetylbut-l-yl)-2-amino-6-klorpurin (0,36 g, 1,0 mmol) (fremstilt i henhold til EP-A-141927) og 30 mg av 10% palladium-på-trekull i metanol inneholdende ammoniumformiat (400 mM, 10 ml) ble oppvarmet under tilbakeløp i 30 min. Blandingen ble tillatt å avkjøle, filtrert og løsningsmiddelet fjernet. Resten ble tatt opp i vann og løsningen ekstrahert 2 ganger med kloroform. De organiske skikt ble kombinert, tørket over magnesiumsulfat og løsningsmiddelet fjernet slik at man fikk 9-(4-acetoksy-3-acetoksymetylbut-1-yl)-2-aminopurin (0,29 g, 90%). Rekrystalli-sering utfra etylacetat/heksan ga hvite, skinnende plater (0,25 g, 78%), sm.p. 102 - 104°C; Xmaks (MeOH) 222 (27 500), 244 (4 890) og 309 (7 160) nm; vmaks (KBr) 3340, 3170, 1745, 1730, 1660, 1615 og 1580 cm<-1>; 6R (CDC13) 1,90 - 2,05 (3H, m, 2'-H og 3'-H), 2,07 (6H, s, 2 x CH3), 4,15 (4H, d, J 5,2Hz, 2 x 4'-H), 4,21
(2H, t, J 7,2Hz, 1'-H), 5,16 (2H, br s, 2-NH2), 7,79 (1H, s,
8-H) og 8,70 (1H, s, 6-H); (funnet: C, 52,10; H, 6,00; N, 21,49%. C14H19N5°4 krever C' 52'33'" H' 5,96; N, 21,79%).
BIOLOGISKE DATA
I det følgende er det oppstilt biologiske data i den
hensikt å sammenligne den forbindelse som er fremstilt i henhold til foranstående eksempel, med de kjente forbindelser i sin virkning.
Dataene gjelder forbindelsen i henhold til eksemplet og
dens metabolitt, 9-(4-hydroksy-3-hydroksymetylbut-l-yl)guanin,
som er vist ved formel (A) på side 1 i foreliggende beskrivelse.
Xantin- oksydase- katalysert oksydasjon av 2- amino- 9-( 4- hydroksy-3- hydroksymetylbut- 1- yl) purin
Til en vandig løsning av 2-amino-9 - (4-hydroksy-3-hydroksymetylbut-1-yl)purin (0,5 m£J, 0,7 ml; pH 7) ble det tilsatt kumelk-xantin-oksydase (20ul, 0,4 enhet). Oppløst atmosfære-oksygen ble tillatt å virke som elektronakseptor og endringer i UV-spekte-ret ble målt. Etter 4 minutter var 25% omdannelse inntruffet,
og etter 2,5 timer var omdannelsen i det vesentlige fullstendig. Oksydas jonsproduktet ble identifisert som 9-( 4-hydroksy.-3-hydroksymetylbut-1-yl)guanin ved sitt UV-spektrum og SIN HPLC-reten-sjonstid.
(Inkubasjon av 9-(4-hydroksy-3-hydroksymetylbut-1-yl)-gua-nin med xantin-oksydase under identiske betingelser resulterte ikke i endring over en 2 timers periode.)
Oral absorpsjon av 2- amino- 9-( 4- hydroksy- 3- hydroksyetylbut- 1-yl) purin og 2- amino- 9-( 4- acetoksy- 3- acetoksymetylbut- 1- yl) purin og deres omdannelse til 9-( 4- hydroksy- 3- hydroksymetylbut^ 1- yl)-guanin i mus
Metode
2-amino-9-(4-hydroksy-3-hydroksymetylbut-1-yl)purin, 2-amino-9-(4-acetoksy-3-acetoksymetylbut-1-yl)purin og 9-(4-hydroksy-3-hydroksymetylbut-1-yl)guanin ble administrert ved oral tvangs-fSring (0,2 mmol/kg i 0,1 ml av 1% karboksymetylcellulose) til
20 g hun-Balb/C-mus som hadde fastet i 18 timer. 15, 60 og 180 minutter senere, ble det tappet blod fra 3 mus pr. tidspunkt ved kardialpunktur under anvendelse av hepariniserte sprøyter. Like alikvoter på hvert tidspunkt ble oppsamlet, og samme volum av 16% trikloreddiksyre ble tilsatt. Etter sentrifugering ved 8 500 G for fjerning av utfelte proteiner, ble 0,5 ml supernatant umiddelbart satt til 0,1 ml mettet natriumbikarbonatløsning,
og den resulterende blanding ble analysert ved høyytelse-væske-kromatografi eller lagret ved -20°C før analyse.
Resultater
Ovenstående biologiske data viser at forbindelsen i henhold til eksemplet gir overraskende gode blodspeil sammen-lignet med 9-(4-hydroksy-3-hydroksymetylbut-l-yl)guanin selv.
Claims (1)
- Analogifremgangsmåte for fremstilling av et terapeutisk aktivt purinderivat med formel (I) eller et salt derav, karakterisert ved å redusere en forbindelse med -formel (VIII) og eventuelt å danne et salt derav.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB848423833A GB8423833D0 (en) | 1984-09-20 | 1984-09-20 | Compounds |
| GB858510331A GB8510331D0 (en) | 1985-04-23 | 1985-04-23 | Compounds |
| GB858520618A GB8520618D0 (en) | 1985-08-16 | 1985-08-16 | Compounds |
| PCT/GB1986/000153 WO1987005604A1 (en) | 1984-09-20 | 1986-03-17 | 2-aminopurine derivatives and process for their preparation |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO874764D0 NO874764D0 (no) | 1987-11-16 |
| NO874764L NO874764L (no) | 1987-11-16 |
| NO167572B true NO167572B (no) | 1991-08-12 |
| NO167572C NO167572C (no) | 1991-11-20 |
Family
ID=27262464
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO87874764A NO167572C (no) | 1984-09-20 | 1987-11-16 | Analogifremgangsmaate for fremstilling av et terapeutisk aktivt purinderivat. |
Country Status (24)
| Country | Link |
|---|---|
| EP (1) | EP0182024B1 (no) |
| JP (2) | JPS6185388A (no) |
| KR (1) | KR930006349B1 (no) |
| AT (1) | AT389118B (no) |
| AU (1) | AU589371B2 (no) |
| BG (1) | BG61493B2 (no) |
| CA (1) | CA1262899A (no) |
| CY (1) | CY1747A (no) |
| CZ (1) | CZ283721B6 (no) |
| DE (1) | DE3582399D1 (no) |
| DK (1) | DK167019B1 (no) |
| ES (1) | ES8703876A1 (no) |
| FI (1) | FI87564C (no) |
| GR (1) | GR852272B (no) |
| HK (1) | HK128693A (no) |
| HU (1) | HU198934B (no) |
| IE (1) | IE58141B1 (no) |
| MX (1) | MX165116B (no) |
| MY (1) | MY102473A (no) |
| NL (1) | NL960006I2 (no) |
| NO (1) | NO167572C (no) |
| NZ (1) | NZ213528A (no) |
| PT (1) | PT81160B (no) |
| WO (1) | WO1987005604A1 (no) |
Families Citing this family (44)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE8406538D0 (sv) * | 1984-12-21 | 1984-12-21 | Astra Laekemedel Ab | Novel derivatives of purine |
| GB8628826D0 (en) * | 1986-12-02 | 1987-01-07 | Beecham Group Plc | Pharmaceutical products |
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| DE3855774T2 (de) * | 1987-08-01 | 1997-06-12 | Beecham Group Plc | Purinverbindungen und ihre Herstellung |
| GB8817270D0 (en) * | 1988-07-20 | 1988-08-24 | Beecham Group Plc | Novel process |
| GB8817607D0 (en) * | 1988-07-23 | 1988-09-01 | Beecham Group Plc | Novel process |
| GB8822236D0 (en) * | 1988-09-21 | 1988-10-26 | Beecham Group Plc | Chemical process |
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| CA2009109A1 (en) * | 1989-02-02 | 1990-08-02 | John Hannah | Antiviral acyclonucleosides and acyclonucleotides |
| GB8904855D0 (en) * | 1989-03-03 | 1989-04-12 | Beecham Group Plc | Pharmaceutical treatment |
| GB8922076D0 (en) * | 1989-09-28 | 1989-11-15 | Beecham Group Plc | Novel process |
| GB9004647D0 (en) * | 1990-03-01 | 1990-04-25 | Beecham Group Plc | Pharmaceuticals |
| GB9102127D0 (en) * | 1991-01-31 | 1991-03-13 | Smithkline Beecham Plc | Pharmaceuticals |
| GB9201961D0 (en) | 1992-01-30 | 1992-03-18 | Smithkline Beecham Plc | Pharmaceuticals |
| GB9326177D0 (en) * | 1993-12-22 | 1994-02-23 | Smithkline Beecham Plc | Pharmaceuticals |
| IL111138A (en) * | 1993-10-05 | 1997-04-15 | Smithkline Beecham Plc | Pharmaceutical compositions comprising penciclovir and/or its bioprecursor and/or its derivatives for the treatment and prophylaxis of post-herpetic neuralgia |
| US6124304A (en) * | 1993-10-05 | 2000-09-26 | Smithkline Beecham Plc | Penciclovir for the treatment of zoster associated pain |
| GB9323403D0 (en) * | 1993-11-12 | 1994-01-05 | Smithkline Beecham Plc | Pharmaceuticals |
| GB9323404D0 (en) * | 1993-11-12 | 1994-01-05 | Smithkline Beecham Plc | Pharmaceuticals |
| US6683084B1 (en) | 1993-11-12 | 2004-01-27 | Novartis International Pharmaceutical Ltd. | Use of 2-amino purine derivatives for the treatment and prophylaxis of human herpes virus 6 infections |
| GB9402161D0 (en) * | 1994-02-04 | 1994-03-30 | Wellcome Found | Chloropyrimidine intermediates |
| GB9407698D0 (en) * | 1994-04-19 | 1994-06-15 | Smithkline Beecham Plc | Pharmaceuticals |
| DE4420751A1 (de) * | 1994-06-15 | 1995-12-21 | Basf Ag | Verfahren zur Herstellung von enantiomerenreinen Lactamen |
| WO1996011200A1 (en) * | 1994-10-05 | 1996-04-18 | Chiroscience Limited | Purine and guanine compounds as inhibitors of pnp |
| GB9504497D0 (en) * | 1995-03-07 | 1995-04-26 | Smithkline Beecham Plc | Pharmaceuticals |
| GB9600847D0 (en) | 1996-01-16 | 1996-03-20 | Smithkline Beecham Plc | Pharmaceuticals |
| US7279483B2 (en) | 1996-02-07 | 2007-10-09 | Novartis Ag | Famciclovir monohydrate |
| DE69706833T2 (de) * | 1996-02-07 | 2002-04-11 | Novartis International Pharmaceutical Ltd., Hamilton | Pharmazeutische zusammensetzungen enthaltend famciclovir monohydrat |
| GR1002949B (el) * | 1996-07-20 | 1998-07-29 | Smithkline Beecham P.L.C. | Φαρμακα |
| GB9615253D0 (en) * | 1996-07-20 | 1996-09-04 | Smithkline Beecham Plc | Pharmaceuticals |
| GB9615276D0 (en) * | 1996-07-20 | 1996-09-04 | Smithkline Beecham Plc | Pharmaceuticals |
| CA2251481A1 (en) | 1997-11-12 | 1999-05-12 | Junichi Yasuoka | Purine derivatives having cyclopropane ring |
| GB9807116D0 (en) * | 1998-04-02 | 1998-06-03 | Smithkline Beecham Plc | Novel process |
| SI20022A (sl) * | 1998-07-29 | 2000-02-29 | Kemijski inštitut | Alkilno substituirani purinovi derivati in njihova priprava |
| IL163666A0 (en) | 2002-02-22 | 2005-12-18 | New River Pharmaceuticals Inc | Active agent delivery systems and methods for protecting and administering active agents |
| EP1532151A2 (en) | 2002-08-26 | 2005-05-25 | Teva Pharmaceutical Industries Limited | Crystalline solid famciclovir forms i, ii, iii and preparation thereof |
| SI1583542T1 (sl) | 2003-01-14 | 2008-12-31 | Gilead Sciences Inc | Sestavki in postopki za kombinacijsko antivirusnoterapijo |
| AU2006230269A1 (en) | 2005-03-30 | 2006-10-05 | Novartis Ag | Penciclovir or famciclovir for the treatment of recurrent genital herpes with a one-day application |
| GB2426247A (en) * | 2005-05-20 | 2006-11-22 | Arrow Int Ltd | Methods of preparing purine derivatives such as famciclovir |
| TWI375560B (en) | 2005-06-13 | 2012-11-01 | Gilead Sciences Inc | Composition comprising dry granulated emtricitabine and tenofovir df and method for making the same |
| TWI471145B (zh) | 2005-06-13 | 2015-02-01 | Bristol Myers Squibb & Gilead Sciences Llc | 單一式藥學劑量型 |
| WO2017029298A1 (en) | 2015-08-17 | 2017-02-23 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A topical antiviral composition |
| JP2019504000A (ja) * | 2015-12-08 | 2019-02-14 | レトロフィン， インコーポレイテッド | 神経性障害の処置のための環式ホスフェートおよび環式ホスホロアミデート |
| US20230218644A1 (en) | 2020-04-16 | 2023-07-13 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3376325D1 (en) * | 1982-10-14 | 1988-05-26 | Wellcome Found | Antiviral purine derivatives |
| AU577303B2 (en) * | 1983-08-18 | 1988-09-22 | Novartis International Pharmaceutical Ltd | 9-substituted-2-amino purines |
| EP0141927B1 (en) * | 1983-08-18 | 1991-10-30 | Beecham Group Plc | Antiviral guanine derivatives |
| DE3571810D1 (en) * | 1984-01-26 | 1989-08-31 | Merck & Co Inc | Substituted butyl guanines and their utilization in antiviral compositions |
-
1985
- 1985-09-09 EP EP85111354A patent/EP0182024B1/en not_active Expired - Lifetime
- 1985-09-09 DE DE8585111354T patent/DE3582399D1/de not_active Expired - Lifetime
- 1985-09-18 AU AU47560/85A patent/AU589371B2/en not_active Expired
- 1985-09-18 IE IE230785A patent/IE58141B1/en not_active IP Right Cessation
- 1985-09-18 DK DK424685A patent/DK167019B1/da not_active IP Right Cessation
- 1985-09-18 PT PT81160A patent/PT81160B/pt unknown
- 1985-09-18 GR GR852272A patent/GR852272B/el unknown
- 1985-09-18 CA CA000491028A patent/CA1262899A/en not_active Expired
- 1985-09-18 NZ NZ213528A patent/NZ213528A/xx unknown
- 1985-09-19 ES ES547128A patent/ES8703876A1/es not_active Expired
- 1985-09-19 JP JP60207693A patent/JPS6185388A/ja active Granted
- 1985-10-01 MX MX9010A patent/MX165116B/es unknown
-
1986
- 1986-03-17 AT AT0904286A patent/AT389118B/de not_active IP Right Cessation
- 1986-03-17 KR KR1019870701056A patent/KR930006349B1/ko not_active IP Right Cessation
- 1986-03-17 HU HU863048A patent/HU198934B/hu unknown
- 1986-03-17 WO PCT/GB1986/000153 patent/WO1987005604A1/en active IP Right Grant
-
1987
- 1987-09-29 MY MYPI87002221A patent/MY102473A/en unknown
- 1987-11-16 NO NO87874764A patent/NO167572C/no unknown
- 1987-11-16 FI FI875059A patent/FI87564C/fi not_active IP Right Cessation
-
1991
- 1991-12-19 CZ CS913915A patent/CZ283721B6/cs not_active IP Right Cessation
-
1993
- 1993-05-07 JP JP5130044A patent/JPH0826021B2/ja not_active Expired - Lifetime
- 1993-11-10 BG BG098209A patent/BG61493B2/bg unknown
- 1993-11-18 HK HK1286/93A patent/HK128693A/xx not_active IP Right Cessation
-
1994
- 1994-06-03 CY CY174794A patent/CY1747A/xx unknown
-
1996
- 1996-04-09 NL NL960006C patent/NL960006I2/nl unknown
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