NO179710B - Nye fosfolipidderivater av nukleosider, og legemiddel inneholdende disse - Google Patents
Nye fosfolipidderivater av nukleosider, og legemiddel inneholdende disse Download PDFInfo
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- NO179710B NO179710B NO930587A NO930587A NO179710B NO 179710 B NO179710 B NO 179710B NO 930587 A NO930587 A NO 930587A NO 930587 A NO930587 A NO 930587A NO 179710 B NO179710 B NO 179710B
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- Prior art keywords
- denotes
- dideoxy
- desoxy
- azidothymidine
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- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 125000002525 phosphocholine group Chemical class OP(=O)(OCC[N+](C)(C)C)O* 0.000 description 1
- 229940067631 phospholipid Drugs 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000000039 preparative column chromatography Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 125000005624 silicic acid group Chemical class 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- 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
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- 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
-
- 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
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/26—Preparation of nitrogen-containing carbohydrates
- C12P19/28—N-glycosides
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- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
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- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Wood Science & Technology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- General Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
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- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
Gjenstand for foreliggende oppfinnelse er nye fosfo-lipidderivater av nukleosider som er kjennetegnet ved at de har generell formel I
hvori
Rx betegner en rettkjedet eller forgrenet, mettet alkyl-gruppe med 8-15 karbonatomer,
R2 betegner en rettkjedet eller forgrenet, mettet alkyl-kjede med 8-15 karbonatomer,
n er 0, 1 eller 2, og
gruppen
betegner en rest valgt fra:
- 2',3'-didesoksy-3'-azidouridin
- 2',3'-didesoksyinosin
- 2',3'-didesoksyguanosin
- 2',3'-didesoksycytidin
- 2',3'-didesoksyadenosin
- 3'-desoksythymidin
- 2', 3' -didesoksy-2', 31 -didehydro-N6- (o-metylbenzyl) -
adenosin
- 2 ', 3 ' -didesoksy-2', 3 ' -didehydro-N6- (2-metylpropyl) - adenosin - 2',3'-didesoksy-3'-azidoguanosin-3'-desoksy-3'-azidothymidin
- 2',3'-didesoksy-3'-fluor-5-kloruridin
- 3'-desoksy-3'-fluorthymidin
- 2',3'-didesoksy-3'-fluoradenosin-2',3'-didesoksy-3'-fluor-2,6-diaminopurinribosid
- 2',3'-didesoksy-2',3'-didehydrocytidin
- 3'-desoksy-2',3'-didehydrothymidin
- 3'-desoksy-3'-azidothymidin,
deres tautomerer og deres fysiologisk akseptable salter av uorganiske og organiske syrer henholdsvis baser.
Da forbindelsene av generell formel I inneholder asymmetriske karbonatomer, er også samtlige optisk aktive former og racemiske blandinger av disse forbindelser gjenstand for foreliggende oppfinnelse.
I J. Biol. Chem. 265, 6112 (1990), er det beskrevet fremstilling og anvendelse av liponukleotider som antivirale legemidler. Her ble imidlertid bare de kjente nukleosider, slik som f.eks. AZT og ddC, koblede dimyristoylfosfatidyl- og dipalmitoylfosfatidylrester med deres fettsyreesterstruktur, syntetisert og undersøkt.
I J. Med. Chem. 33, 1380 (1990), er det beskrevet nukleosidkonjugater av tioeterlipider med cytidinfosfat, som utviser en antitumoral virkning og finner anvendelse innen onkologien.
I Chem. Pharm. Bull. 36, 209 (1988), er det beskrevet 5'-( 3-SN-fosfatidyl)nukleosider med antileukemisk aktivitet, så vel som deres enzymatiske syntese fra de tilsvarende nukleosider og fosfocholiner i nærvær av fosfolipase D med transferaseaktivitet.
Den enzymatiske syntese av liponukleotider er bl.a. likeledes beskrevet i Tetrahedron Lett. 28, 199 (1987), og Chem. Pharm. Bull. 36, 5020 (1988).
Forbindelsene ifølge foreliggende oppfinnelse utviser likeledes verdifulle farmakologiske egenskaper. I særdeleshet egner de seg til terapi og profylakse av infeksjoner som er forårsaket av DNA-virus, slik som f.eks. herpes-simplex-virus, cytomegalovirus, papovavirus, varicella-zoster-virus eller Epstein-Barr-virus, eller RNA-virus slik som togavirus, eller i særdeleshet retrovirus slik som onkovirus HTLV-I og II, så vel som lentiviruset visna og humanimmunsvekkelsesviruset HIV-1 og 2.
Særlig egnet har forbindelsene av formel I vist seg å være for behandling av kliniske manifestasjoner av retrovirale Hiv-infeksjoner i mennesker, slik som vedvarende generalisert lymfadenopati (PGL), fremskredet stadium av AIDS-beslektede komplekser (ARC) og det kliniske fullstendige bilde av AIDS.
Det er overraskende nå funnet at forbindelsene av generell formel I hemmer formering av DNA- henholdsvis RNA-virus ved trinnet for virusspesifikk DNA- henholdsvis RNA-transskripsjon. Substansene kan innvirke på formeringen av retrovirus over inhibering av enzymet reverstransskriptase (sammenlign Proe. Nati. Acad. Sei. USA, 83, 1911, 1986, henholdsvis Nature 325, 773, 1987). Av særlig terapeutisk inter-esse er den inhiberende virkning på HIV-viruset, forvolderen av immunsvekkelsessykdommen AIDS. For behandling av AIDS er for tiden bare 3'-azido-3'-desoksythymidin (DE-A-3608606) tilgjengelig for AIDS-pasienter. Imidlertid gjør toksiske bi-virkninger av 3'-azido-3'-desoksythymidin på benmargen hos ca. 50 % av de behandlede pasienter det nødvendig med blodtrans-fusjon. Forbindelsene av generell formel I utviser ikke denne ulempen. De virker antiviralt uten å være cytotoksiske i farmakologisk relevante doser.
Forbindelsene ifølge foreliggende oppfinnelse og deres farmasøytiske tilberedelser kan også anvendes i kombi-nasjon med andre legemidler for behandling og profylakse av de ovenfor angitte infeksjoner. Eksempler på disse midler, som omfatter ytterligere legemidler som kan anvendes for behandling og profylakse av HIV-infeksjoner eller ledsagende syk-dommer av denne sykdom, slik som 3'-azido-3'-desoksythymidin, er 2',3'-didesoksynukleosider slik som f.eks. 2',3'-didesoksycytidin, 2',3'-didesoksyadenosin og 2',3'-didesoksyinosin, asykliske nukleosider (f.eks. acyclovir), interferoner slik som f.eks. A-interferon, renale utskillelsesinhibitorer slik som f.eks. probenicid, nukleosidtransportinhibitorer slik som f.eks. dipyridamol, som også immunmodulatorer slik som f.eks. interleukin II eller stimuleringsfaktorer slik som granulo-cytt-makrofagkolonifaktoren. Forbindelsene ifølge foreliggende oppfinnelse og det andre legemiddel kan administreres enkelt-vis, samtidig eventuelt i en eneste eller to separerte formu-leringer, eller til forskjellige tider, slik at en synergis-tisk effekt oppnås.
Som mulige salter av forbindelsene av generell formel I kommer i første rekke alkali-, jordalkali- og ammoniumsalter av fosfatgruppen i betraktning. Som alkalisalter er litium-, natrium- og kaliumsalter foretrukne. Som jordalkalisalter kommer i særdeleshet magnesium- og kalsiumsalter i betraktning. Blant ammoniumsalter skal det ifølge oppfinnelsen for-stås salter som inneholder ammoniumionet, som kan være substituert opptil fire ganger med alkylrester med 1-4 karbonatomer og/eller aralkylrester, fortrinnsvis benzylrester. Substituen-tene kan herved være like eller forskjellige.
Forbindelsene av generell formel I kan inneholde basiske grupper, i særdeleshet aminogrupper, som kan overføres med egnede syrer til syreaddisjonssalter. Som syrer kommer eksempelvis de følgende i betraktning: saltsyre, bromhydrogen-syre, svovelsyre, fosforsyre, fumarsyre, ravsyre, vinsyre, sitronsyre, melkesyre, maleinsyre eller metansulfonsyre.
I generell formel I betegner Rx fortrinnsvis en rettkjedet C10-C14-alkylgruppe. Rx betegner i særdeleshet en decyl-, undecyl-, dodecyl-, tridecyl- eller tetradecylgruppe.
R2 betegner fortrinnsvis en rettkjedet C10-C14-alkyl-gruppe. R2 betegner i særdeleshet en decyl-, undecyl-, dodecyl-, tridecyl- eller tetradecylgruppe.
Forbindelsene av generell formel I kan fremstilles idet
1) en forbindelse av generell formel II
hvori
Rlf R2 og n har de ovenfor angitte betydninger, omsettes med en
forbindelse av generell formel III
hvori
R3. betegner hydrogen eller en hydroksygruppe som er beskyttet med en for fagmannen velkjent oksygenbeskyttelsesgruppe, og
R4. og R5. betegner hydrogen, halogen, en azido- eller en cyano-gruppe, eller hvor en av restene R4. og R5. betegner en hydroksygruppe som er beskyttet med en for fagmannen velkjent oksygenbeskyttelsesgruppe, eller hvor
R3. og R4. betegner en ytterligere binding, og hvor
B har de ovenfor angitte betydninger,
i nærvær av fosforoksytriklorid og en fosforsyreester og en tertiær nitrogenbase, eksempelvis pyridin eller trietylamin, i et inert løsningsmiddel slik som f.eks. toluen, og etter ut-ført hydrolyse at eventuelt oksygenbeskyttelsesgruppene avspaltes etter vanlige metoder innen nukleosidkjemien, eller
2) en forbindelse av generell formel IV
hvori
Rlr R2 og n har de ovenfor angitte betydninger, omsettes med en forbindelse av generell formel III, hvori R3., R4., R5. og B har de ovenfor angitte betydninger, i nærvær av fosfolipase D i et inert løsningsmiddel slik som f.eks. kloroform, i nærvær av en egnet buffer, og etter endt omsetning at oksygenbeskyttelsesgruppen avspaltes etter vanlige metoder innen nukleosidkjemien.
Fremstillingen av forbindelsene av generell formel II og IV er beskrevet i Lipids 22, 947 (1987), og i DE-A 3039629.
Fremstilling av forbindelsene av generell formel III er beskrevet i f.eks. EP-A 0 286 028 og WO 90/08147.
Lignende forbindelser av generell formel I er beskrevet i EP-A-0350287. Imidlertid er bare 1,2-diesteren av glyserol beskrevet der.
Legemidlet inneholdende forbindelsene av formel I for behandling av virale infeksjoner kan administreres i flytende eller fast form enteralt eller parenteralt. Herved kommer de vanlige administreringsformer i betraktning, slik som f.eks. tabletter, kapsler, drasjeer, siruper, løsninger eller suspen-sjoner. Som injeksjonsmedium anvendes fortrinnsvis vann som inneholder vanlige tilsetninger for reaksjonsløsninger, slik som stabiliseringsmiddel, oppløsningsformidlere og buffere. Slike tilsetninger er eksempelvis tartrat- og sitratbuffer, etanol, kompleksdannere slik som etylendiamintetraeddiksyre og deres ikke-toksiske salter, høymolekylære polymerer slik som flytende polyetylenoksid for viskositetsregulering. Flytende bærerstoffer for injeksjonsløsninger må være sterile og fylles fortrinnsvis i ampuller. Faste bærerstoffer er eksempelvis stivelse, laktose, mannitol, metylcellulose, talkum, høy-disperse kiselsyrer, høymolekylære fettsyrer slik som stearin-syre, gelatin, agar-agar, kalsiumfosfat, magnesiumstearat, animalsk og plantefett, faste høymolekylære polymerer slik som polyetylenglykol etc. Tilberedelser egnet for oral administrering kan om ønsket inneholde smaks- eller søtningsstoffer.
Doseringen kan avhenge av forskjellige faktorer, slik som administreringsmåte, art, alder eller individuell til-stand. Forbindelsene ifølge oppfinnelsen administreres vanlig-vis i mengder på 0,1-100 mg, fortrinnsvis 0,2-80 mg pr. dag og pr. kilo kroppsvekt. Det foretrekkes å fordele dagsdosen på 2-5 administreringer, hvorved det ved hver administrering administreres 1-2 tabletter med et virkestoffinnhold på 0,5-500 mg. Tablettene kan også være retarderte, hvorved antall administreringer pr. dag reduseres til 1-3. Virkestoffinnhol-det i de retarderte tabletter kan utgjøre 2-1000 mg. Virke-stoffet kan også gis som kontinuerlig infusjon, hvorved mengder på 5-1000 mg pr. dag normalt er tilstrekkelig.
Eksempel 1 a
( 3'- desoksv- 3'- azidothymidin)- 5'- fosforsyre-( 3- dodecylmerkapto- 2- decvloksv) propylester
Til en løsning av 1,25 g (3 mmol) 3-dodecylmerkapto-2-decyloksy-l-propanol og 1,2 ml (8,6 mmol) trietylamin i 40 ml absolutt eter ble det under nitrogen og ved 0 °C dråpevis tilsatt 0,42 ml (4,5 mmol) P0C13, og blandingen ble omrørt i 45 minutter. Blandingen ble deretter oppvarmet til romtemperatur og ble dråpevis tilsatt en løsning av 800 mg (3 mmol) 3'-desoksy-3'-azidothymidin (AZT) i en blanding av 15 ml absolutt eter og 20 ml absolutt toluen, og ble omrørt i 6 timer under tilbakeløpskjøling (DC-kontroll).
Etter avkjøling ble 50 ml vann tilsatt, blandingen ble kraftig omrørt i 2 timer, den organiske fase ble deretter fraskilt, tørket over Na2S04 og inndampet i en rotasjons-fordamper. Residuet ble renset ved preparativ søylekromato-grafi på kiselgel 60 med diklormetan/metanol 9:1 som eluer-ingsmiddel. Utbytte 540 mg (24 % av teoretisk). Smp. 187 °C sintring, 220-223 °C spalting under brunfarging, <31>P-NMR: = 0,59 ppm.
Eksempel lb
( 3 ' - desoksy- 3'- azidothymidin)- 5'- fosforsvre-( 3- dodecvl-merkapto- 2- decvloksv) propylester
Analogt med anvisningen i Chem. Pharm. Bull. 36, 5020
(1988), ble 2 mmol AZT og 5000 U fosfolipase D suspendert i
4 ml natriumacetatbuffer/CaCl2, ble tilsatt en løsning av
6 mmol 3-dodecylmerkapto-2-decyloksypropyl-l-fosforsyremono-cholinester i 160 ml kloroform og ble oppvarmet i 8 timer til 45 °C. Blandingen ble deretter tørket over Na2S04, og løsnings-midlet ble fjernet i vakuum. Residuet ble renset ved søyle-kromatografi som angitt i eksempel 1. Utbytte 51 %. Produktet viste seg å være identisk med produktet fra eksempel 1 a (smp., DC, <1>H- og <31>P-NMR).
Eksempel 2
( 3'- desoksy- 3'- azidothymidin)- 5'- fosforsyre-( 3- undecyl-merkapto- 2- undecyloksy) propylester ble fremstilt analogt med eksempel 1 a. Utbytte 27 %, smp. 218-222 °C (spaltning).
Eksempel 3
r2 ' . 3 ' - didesoksy- 2 ' , 3 ' - didehydro- Nf- ( o- metylbenzyl) - adenosinl - 5'- fosforsyre-( 3- dodecylmerkapto- 2- decyloksy) propylester
680 mg (1,37 mmol) fosforsyre-(3-dodecylmerkapto-2-decyloksy)propylester i 20 ml absolutt pyridin ble tilsatt 337 mg (1 mmol) 2',3'-didesoksy-2',3 1-didehydro-N6-(o-metylbenzyl)-adenosin, og etter tilsetning av 1,37 g (6,7 mmol) DCC ble blandingen omrørt i 24 timer ved romtemperatur (DC-kontroll). Deretter ble pyridinet fjernet i vakuum, residuet ble suspendert i eter og ble frafiltrert uoppløst urea. Filtratet ble etter avdamping av løsningsmidlet renset ved søylekromato-grafi på kiselgel 60 med diklormetan/metanol 95/5 som eluer-ingsmiddel. Utbytte 220 mg (26 % av teoretisk). Rf = 0,68 (CH2C12/CH30H/H20 13/5/0,8).
Eksempel 4
( 3'- desoksy- 3'- azidothymidin)- 5'- fosforsyre-( 3dodecylmerkapto-2- decvloksv) propylester
Analogt med eksempel 3 ble fra 13,5 g fosforsyre-(3-dodecylmerkapto-2-decyloksy)propylester, 5,4 g AZT og 27 g DCC i 350 absolutt pyridin ved 30 timers omrøring ved romtemperatur og rensing, som beskrevet ovenfor, det tilsvarende liponukleotid fremstilt i 62 % utbytte (analytiske data er iden-tiske med dem i eksempel 1).
Eksempel 5
( 3'- desoksythymidin)- 5'- fosforsyre-( 3- dodecylmerkapto- 2- decyl-oksy) propylester
Analogt med eksempel 3 ble det fra 1,5 g fosforsyre-(3-dodecylmerkapto-2-decyloksy)propylester, 500 mg 3'-desoksythymidin og 2,6 g DCC i 40 absolutt pyridin ved 24 timers om-røring ved romtemperatur og kromatografisk rensing det tilsvarende liponukleotid fremstilt i 51 % utbytte. Rf = 0,45 (CH2C12/CH30H/H20 12/5/0,8).
Eksempel 6
( 2', 3'- didesoksyinosin)- 5'- fosforsyre-( 3- dodecvl- merkapto- 2-decyloksy) propylester
Analogt med eksempel 3 ble det fra 1,3 g fosforsyre-(3-dodecylmerkapto-2-decyloksy)propylester, 500 mg 2',3'-didesoksyinosin og 2,6 g DCC i 40 absolutt pyridin ved 40 timers omrøring ved romtemperatur og kromatografisk rensing det angitte liponukleotid fremstilt i 61 % utbytte: Rf = 0,38 (CH2C12/CH30H/H20 13/5/0,8).
Claims (5)
1. Forbindelser,
karakterisert ved at de har generell formel I
hvori
Rx betegner en rettkjedet eller forgrenet, mettet alkyl-
gruppe med 8-15 karbonatomer,
R2 betegner en rettkjedet eller forgrenet, mettet alkyl-
kjede med 8-15 karbonatomer,
n er 0, 1 eller 2, og
gruppen
betegner en rest valgt fra: - 2',3'-didesoksy-3'-azidouridin - 2',3'-didesoksyinosin - 2',3'-didesoksyguanosin - 2',3'-didesoksycytidin - 2<1>,3'-didesoksyadenosin - 3'-desoksythymidin - 2 *,3'-didesoksy-2',3'-didehydro-N6- (o-metylbenzyl) - adenosin - 2',3'-didesoksy-2',3'-didehydro-N6- ( 2-metylpropyl)-adenosin - 2',3'-didesoksy-3'-azidoguanosin-3'-desoksy-3'-azidothymidin - 2',3'-didesoksy-3'-fluor-5-kloruridin - 3'-desoksy-3'-fluorthymidin - 2',3'-didesoksy-3'-fluoradenosin-2',3'-didesoksy-3'-fluor-2,6-diaminopurinribosid - 2',3<1->didesoksy-2',3'-didehydrocytidin - 3'-desoksy-2',3'-didehydrothymidin - 3'-desoksy-3'-azidothymidin,
deres tautomerer og deres fysiologisk akseptable salter av uorganiske og organiske syrer henholdsvis baser.
2. Forbindelser ifølge krav 1, karakterisert ved at Rj betegner C10-C14-alkyl.
3. Forbindelser ifølge krav 1 eller 2, karakterisert ved at R2 betegner C8-C12-alkyl.
4. Forbindelser ifølge krav 1, karakterisert ved at Rj betegner dodecyl, R2 betegner decyl, og gruppen
betegner en 2',3'-didesoksy-2',3'-didehydro-N6- ( o-metylbenzyl)-adenosin-, 3<1->desoksy-3'-azidothymidin-, 3 ' -desoksythymidin-eller 2',3'-didesoksyinosinrest.
5. Legemiddel,
karakterisert ved at det inneholder minst én forbindelse ifølge hvilket som helst av kravene 1-4 og vanlige bærer- og hjelpestoffer.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4026265A DE4026265A1 (de) | 1990-08-20 | 1990-08-20 | Neue phospholipid-derivate von nucleosiden, deren herstellung sowie deren verwendung als antivirale arzneimittel |
| PCT/EP1991/001541 WO1992003462A1 (de) | 1990-08-20 | 1991-08-14 | Neue phospholipid-derivate von nucleosiden, deren herstellung sowie deren verwendung als antivirale arzneimittel |
| US08/661,038 US5756711A (en) | 1990-08-20 | 1996-06-10 | Phospholipid derivatives of nucleosides and their use as anti-viral medicaments |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO930587L NO930587L (no) | 1993-02-19 |
| NO930587D0 NO930587D0 (no) | 1993-02-19 |
| NO179710B true NO179710B (no) | 1996-08-26 |
| NO179710C NO179710C (no) | 1996-12-04 |
Family
ID=25896049
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO930587A NO179710C (no) | 1990-08-20 | 1993-02-19 | Nye fosfolipidderivater av nukleosider, og legemiddel inneholdende disse |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US5756711A (no) |
| EP (1) | EP0545966B1 (no) |
| CN (1) | CN1032258C (no) |
| AT (1) | ATE114316T1 (no) |
| CA (1) | CA2090024C (no) |
| DE (2) | DE4026265A1 (no) |
| DK (1) | DK0545966T3 (no) |
| ES (1) | ES2066461T3 (no) |
| FI (1) | FI104176B (no) |
| HK (1) | HK35597A (no) |
| IE (1) | IE64374B1 (no) |
| NO (1) | NO179710C (no) |
| PT (1) | PT98720B (no) |
| SK (1) | SK281826B6 (no) |
| WO (1) | WO1992003462A1 (no) |
Families Citing this family (79)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6599887B2 (en) | 1988-07-07 | 2003-07-29 | Chimerix, Inc. | Methods of treating viral infections using antiviral liponucleotides |
| US5817638A (en) * | 1988-07-07 | 1998-10-06 | Nexstar Pharmaceuticals, Inc. | Antiviral liponucleosides: treatment of hepatitis B |
| US6252060B1 (en) | 1988-07-07 | 2001-06-26 | Nexstar Pharmaceuticals, Inc. | Antiviral liponucleosides: treatment of hepatitis B |
| CA2001401A1 (en) * | 1988-10-25 | 1990-04-25 | Claude Piantadosi | Quaternary amine containing ether or ester lipid derivatives and therapeutic compositions |
| DE4204032A1 (de) * | 1992-02-12 | 1993-08-19 | Boehringer Mannheim Gmbh | Neue liponucleotide, deren herstellunmg sowie deren verwendung als antivirale arzneimittel |
| DE4204031A1 (de) * | 1992-02-12 | 1993-08-19 | Boehringer Mannheim Gmbh | Neue lipidphosphonsaeure-nucleosid-konjugate sowie deren verwendung als antivirale arzneimittel |
| DE4226279A1 (de) * | 1992-08-08 | 1994-02-10 | Boehringer Mannheim Gmbh | Liponucleotide von Seco-Nucleosiden, deren Herstellung sowie deren Verwendung als antivirale Arzneimittel |
| US6080734A (en) * | 1992-08-08 | 2000-06-27 | Roche Diagnostic Gmbh | Liponucleotides of seco-nucleosides, their production as well as their use as antiviral pharmaceutical agents |
| DE69431596T4 (de) * | 1993-06-10 | 2003-10-30 | University Of North Carolina At Chapel Hill, Chapel Hill | (phospho)lipide zum bekämpfen einer hepatitis b-infektion |
| KR0125779B1 (ko) * | 1993-12-04 | 1997-12-19 | 김승호 | 뉴클레오시드 화합물 및 이의 제조방법 |
| DE4418690A1 (de) * | 1994-05-28 | 1996-01-11 | Boehringer Mannheim Gmbh | Neue Lipidester von Nucleosid-Monophosphaten und deren Verwendung als immunsuppressive Arzneimittel |
| DE69535758D1 (de) | 1994-08-29 | 2008-07-03 | Univ Wake Forest | Lipid-analoge zur behandlung von viralen infektionen |
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| US8980899B2 (en) | 2009-10-16 | 2015-03-17 | The Regents Of The University Of California | Methods of inhibiting Ire1 |
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| US9278135B2 (en) | 2010-04-26 | 2016-03-08 | Chimerix Inc. | Methods of treating retroviral infections and related dosage regimes |
| AU2011255218B2 (en) | 2010-05-21 | 2015-03-12 | Infinity Pharmaceuticals, Inc. | Chemical compounds, compositions and methods for kinase modulation |
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| CA2824197C (en) | 2011-01-10 | 2020-02-25 | Michael Martin | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
| JP6130305B2 (ja) | 2011-02-23 | 2017-05-17 | インテリカイン， エルエルシー | キナーゼ阻害剤の組み合わせおよびそれらの使用 |
| CN103930422A (zh) | 2011-07-19 | 2014-07-16 | 无限药品股份有限公司 | 杂环化合物及其用途 |
| CA2842190A1 (en) | 2011-07-19 | 2013-01-24 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
| AR091790A1 (es) | 2011-08-29 | 2015-03-04 | Infinity Pharmaceuticals Inc | Derivados de isoquinolin-1-ona y sus usos |
| JP6342805B2 (ja) | 2011-09-02 | 2018-06-13 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 置換ピラゾロ［３，４−ｄ］ピリミジンおよびその用途 |
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| MX2016004340A (es) | 2013-10-04 | 2016-08-08 | Infinity Pharmaceuticals Inc | Compuestos heterociclicos y usos de los mismos. |
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| WO2015160975A2 (en) | 2014-04-16 | 2015-10-22 | Infinity Pharmaceuticals, Inc. | Combination therapies |
| RS63250B1 (sr) | 2014-09-15 | 2022-06-30 | Univ California | Nukleotidni analozi |
| US9708348B2 (en) | 2014-10-03 | 2017-07-18 | Infinity Pharmaceuticals, Inc. | Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof |
| US10160761B2 (en) | 2015-09-14 | 2018-12-25 | Infinity Pharmaceuticals, Inc. | Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same |
| US10377782B2 (en) | 2015-09-15 | 2019-08-13 | The Regents Of The University Of California | Nucleotide analogs |
| CN105288648B (zh) * | 2015-10-14 | 2018-11-06 | 东南大学 | 一种亲水性药物的磷脂化合物、其药物组合物及应用 |
| WO2017161116A1 (en) | 2016-03-17 | 2017-09-21 | Infinity Pharmaceuticals, Inc. | Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors |
| US10919914B2 (en) | 2016-06-08 | 2021-02-16 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| MX2018016227A (es) | 2016-06-24 | 2019-07-08 | Infinity Pharmaceuticals Inc | Terapias de combinacion. |
| DE112020006626A5 (de) | 2020-03-30 | 2022-12-08 | Chiracon Gmbh | Fosalvudin und Fozivudintidoxil zur Anwendung bei der Behandlung der Krankheit Covid-19 und die Verwendung von deren strukturvereinfachten Derivaten |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4291024A (en) * | 1978-04-10 | 1981-09-22 | Turcotte Joseph G | Cytotoxic liponucleotide analogs |
| US4283394A (en) * | 1979-08-06 | 1981-08-11 | Research Corporation | Cytotoxic nucleoside-corticosteroid phosphodiesters |
| US4622392A (en) * | 1984-06-21 | 1986-11-11 | Health Research Inc. (Roswell Park Division) | Thiophospholipid conjugates of antitumor agents |
| US5223263A (en) * | 1988-07-07 | 1993-06-29 | Vical, Inc. | Liponucleotide-containing liposomes |
| DE3778626D1 (de) * | 1986-09-27 | 1992-06-04 | Toyo Jozo Kk | Nukleosid-phospholipid-konjugat. |
| US5194654A (en) * | 1989-11-22 | 1993-03-16 | Vical, Inc. | Lipid derivatives of phosphonoacids for liposomal incorporation and method of use |
-
1990
- 1990-08-20 DE DE4026265A patent/DE4026265A1/de not_active Withdrawn
-
1991
- 1991-08-14 WO PCT/EP1991/001541 patent/WO1992003462A1/de active IP Right Grant
- 1991-08-14 CA CA002090024A patent/CA2090024C/en not_active Expired - Fee Related
- 1991-08-14 ES ES91914553T patent/ES2066461T3/es not_active Expired - Lifetime
- 1991-08-14 SK SK92-93A patent/SK281826B6/sk not_active IP Right Cessation
- 1991-08-14 AT AT91914553T patent/ATE114316T1/de not_active IP Right Cessation
- 1991-08-14 DK DK91914553.2T patent/DK0545966T3/da active
- 1991-08-14 DE DE59103595T patent/DE59103595D1/de not_active Expired - Fee Related
- 1991-08-14 EP EP91914553A patent/EP0545966B1/de not_active Expired - Lifetime
- 1991-08-20 CN CN91105815A patent/CN1032258C/zh not_active Expired - Fee Related
- 1991-08-20 PT PT98720A patent/PT98720B/pt not_active IP Right Cessation
-
1993
- 1993-02-19 IE IE293091A patent/IE64374B1/en not_active IP Right Cessation
- 1993-02-19 NO NO930587A patent/NO179710C/no not_active IP Right Cessation
- 1993-02-19 FI FI930753A patent/FI104176B/fi active
-
1996
- 1996-06-10 US US08/661,038 patent/US5756711A/en not_active Expired - Lifetime
-
1997
- 1997-03-20 HK HK35597A patent/HK35597A/xx not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK0545966T3 (da) | 1995-05-08 |
| SK9293A3 (en) | 1993-07-07 |
| FI930753A (fi) | 1993-02-19 |
| CA2090024A1 (en) | 1992-02-21 |
| PT98720B (pt) | 1999-02-26 |
| FI930753A0 (fi) | 1993-02-19 |
| ES2066461T3 (es) | 1995-03-01 |
| HK35597A (en) | 1997-03-27 |
| US5756711A (en) | 1998-05-26 |
| PT98720A (pt) | 1992-07-31 |
| EP0545966B1 (de) | 1994-11-23 |
| AU654670B2 (en) | 1994-11-17 |
| WO1992003462A1 (de) | 1992-03-05 |
| DE4026265A1 (de) | 1992-02-27 |
| DE59103595D1 (de) | 1995-01-05 |
| IE912930A1 (en) | 1992-02-26 |
| FI104176B1 (fi) | 1999-11-30 |
| EP0545966A1 (de) | 1993-06-16 |
| CA2090024C (en) | 2000-05-02 |
| IE64374B1 (en) | 1995-07-26 |
| NO179710C (no) | 1996-12-04 |
| NO930587L (no) | 1993-02-19 |
| SK281826B6 (sk) | 2001-08-06 |
| CN1032258C (zh) | 1996-07-10 |
| NO930587D0 (no) | 1993-02-19 |
| ATE114316T1 (de) | 1994-12-15 |
| AU8325191A (en) | 1992-03-17 |
| FI104176B (fi) | 1999-11-30 |
| CN1059149A (zh) | 1992-03-04 |
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| MM1K | Lapsed by not paying the annual fees |