CZ304734B6 - Způsob přípravy 9-[2-(fosfonomethoxy)propyl]adeninu a 9-[2-(fosfonomethoxy)ethyl]adeninu - Google Patents

Způsob přípravy 9-[2-(fosfonomethoxy)propyl]adeninu a 9-[2-(fosfonomethoxy)ethyl]adeninu Download PDF

Info

Publication number
CZ304734B6
CZ304734B6 CZ2013-310A CZ2013310A CZ304734B6 CZ 304734 B6 CZ304734 B6 CZ 304734B6 CZ 2013310 A CZ2013310 A CZ 2013310A CZ 304734 B6 CZ304734 B6 CZ 304734B6
Authority
CZ
Czechia
Prior art keywords
adenine
phosphonomethoxy
propyl
ethyl
mol
Prior art date
Application number
CZ2013-310A
Other languages
English (en)
Inventor
Mark W. Becker
Harlan H. Chapman
Tomas Cihlar
Eugene J. Eisenberg
Gong-Xin He
Michael R. Kernan
William A. Lee
Ernest J. Prisbe
John C. Rohloff
Mark L. Sparacino
Original Assignee
Gilead Sciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=22821718&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CZ304734(B6) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Gilead Sciences, Inc. filed Critical Gilead Sciences, Inc.
Publication of CZ304734B6 publication Critical patent/CZ304734B6/cs

Links

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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/18—Testing for antimicrobial activity of a material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Virology (AREA)
  • Wood Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • Toxicology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Biophysics (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • General Engineering & Computer Science (AREA)
  • Cell Biology (AREA)
  • Food Science & Technology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)

Abstract

Řešení popisuje zlepšený způsob přípravy 9-[2-(fosfonomethoxy)propyl]adeninu a 9-[2-(fosfonomethoxy)ethyl]adeninu s použitím alkoxidu hořečnatého.

Description

Oblast techniky
Vynález se týká způsobu přípravy 9-[2-(fosfonomethoxy)propyl]adeninu a 9-[2-(fosfonomethoxy)ethyl]adeninu.
Dosavadní stav techniky
Je známo mnoho methoxyfosfonátových analogů nukleotidů. Tyto sloučeniny mají obecně strukturu A-OCH2P(O)(OR)2, kde A je zbytek analogu nukleosidu a R je nezávisle buď vodík nebo různé chránicí nebo prekursorové funkční skupiny. Viz US patenty 5 663 159, 5 977 061 a 5 798 340, Oliyai et al., Pharmaceutical Research 16(11): 1687-1693 (1999), Stella et al., J. Med. Chem. 23(12):1275-1282 (1980), Aarons, L., Boddy, A. a Petrák, K. (1989) Novel Drug Delivery and Its Therapeutic Application (Prescott, J. F. a Nimmo, W. S. ed.), str. 121-126; Bundgaard, H. (1985) Design of Prodrugs (Bundgaard, H., ed.) str. 70-74 a 79-92; Banerjee, Ρ. K. a Amidon,
G. L. (1985) Design of Prodrugs (Bundgaard, H., ed.) str. 118-121; Notáři, R. E. (1985) Design of Prodrugs (Bundgaard, H., ed.) str. 135-156; Stella, V. J. a Himmelstein, K. J. (1985) Design of Prodrugs (Bundgaard, H., ed.) str. 177-198; Jones, G. (1985) Design of Prodrugs (Bundgaard,
H. ed.) str. 199-241; Connors, T. A. (1985) Design of Prodrugs (Bundgaard, H. ed.) str. 291— 316. Veškerá literatura a citace patentů jsou výslovně uvedeny literárním odkazem.
Podstata vynálezu
Podstata předloženého vynálezu je způsob přípravy 9-[2-(fosfonomethoxy)propyl]adeninu (nadále označovaného „PMPA“) nebo 9-[2-(fosfonomethoxy)ethyl]adeninu (nadále označovaného jako „PMEA“) za použití alkoxidu hořečnatého, který spočívá v reakci 9-(2-hydroxypropyl)adeninu nebo 9-(2-hydroxyethyl)adeninu, chráněného p-toluensulfonyloxymethylfosfonátem a alkoxidu hořečnatého, a získání PMPA, resp. PMEA.
Předložený vynález zahrnuje zlepšený způsob přípravy PMEA a (£)-PMPA. Tento způsob zahrnuje reakci 9-(2-hydroxypropyl)adeninu (HPA) nebo 9-(2-hydroxyethyl)adeninu (HEA) s alkoxidem hořečnatým, následné přidání chráněného aglykonu synthonu p-toluensulfonyloxymethylfosfonátu (tosylátu) k reakční směsi a izolace PMPA, resp. PMEA.
S výhodou se HPA používá jako obohacený nebo izolovaný R enantiomer. Jestliže se použije chirální směs HPA, může se po dokončení syntézy z chirální směsi PMPA izolovat R-PMPA.
Tosylát se typicky chrání nižšími alkylovými skupinami, ale jiné vhodné skupiny budou odborníkovi znalému oboru zřejmé. Může být výhodné použít tosylát předem substituovaný fosfonátovými substituenty prekursoru léčiva, které mohou působit jako chránicí skupiny při tosylační reakci, čímž umožňují obejít odstranění chránicí skupiny (deprotekční krok) a přímo získat prekursor léčiva nebo jeho meziprodukt.
Alkylová skupina alkoxidu hořečnatého není kritická a může to být kterýkoliv větvený nebo lineární alkyl Ci-Cé, ale s výhodou t-butyl (pro PMPA) nebo isopropyl (pro PMEA). Reakční podmínky také nejsou kritické, ale s výhodou zahrnují zahřívání reakční směsi asi na 70 až 75 °C při současném míchání nebo mírném protřepávání.
Jestliže není zájem zachovat fosfonátové substituenty, produkt se zbaví chránících skupin (obvykle pomocí bromtrimethylsilanu, když chránicí skupinou tosylátu je alkyl), a produkt se pak získá krystalizací nebo jiným konvenčním způsobem, který je odborníkovi znalému oboru zřejmý.
Vynález bude lépe pochopen na základě následujících příkladů.
Příklady provedení
Příklad 1
NH2
.OH
Příprava PMEA z adeninu za použití isopropoxidu hořečnatého.
K suspenzi adeninu (16,8 g, 0,124 mol) v dimethylformamidu (DMF) (41,9 ml) byl přidán ethylen karbonát (12,1 g, 0,137 mol) a hydroxid sodný (0,100 g, 0,0025 mmol). Směs byla přes noc zahřívána na 130 °C. Reakce byla zchlazena pod 50 °C a byl přidán toluen (62,1 ml). Suspenze byla dále chlazena na 5 °C po dobu 2 hodin, zfiltrována a promyta toluenem (2x). Vlhký pevný produkt byl vysušen ve vakuu při 65 °C s výtěžkem 20,0 g (90%) 9-(2-hydroxyethyl)adeninu ve formě špinavě bílé pevné látky. T.t. 238 až 240 °C.
9-(2-hydroxyethyl)adenin (HEA) (20,0 g, 0,112 mol) byl suspendován v DMF (125 ml) a zahřát na 80 °C. Ke směsi byl přidán isopropoxid hořečnatý (11,2 g, 0,0784 mol) nebo alternativně tbutoxid hořečnatý a následně diethyl /7-toluensulfonyloxymethylfosfonát (66,0 g, 0,162 mol) po dobu jedné hodiny. Směs byla míchána při 80 °C po dobu 7 hodin. 30 ml těkavých látek bylo odstraněno vakuovou destilací a k reakční směsi bylo znovu přidáno 30 ml čerstvého DMF. Po zchlazení na teplotu místnosti byl přidán bromtrimethylsilan (69,6 g, 0,450 mol) a směs byla zahřívána na 80 °C po dobu 6 hodin. Reakční směs byla zkoncentrována na hustou gumovitou látku. Tato gumovitá látka byla rozpuštěna v 360 ml vody, extrahována 120 ml dichlormethanu, upravena na pH 3,2 hydroxidem sodným a výsledná suspenze přes noc míchána při teplotě místnosti. Suspenze byla zchlazena na 4 °C po dobu jedné hodiny. Pevné produkty byly odděleny filtrací, promyty vodou (2x), a vysušeny ve vakuu při 56 °C s výtěžkem 20 g (65,4 %) 9-[2(fosfonomethoxy)ethyl]adeninu (PMEA) jako bílé pevné látky. T.t.: >200 °C rozklad. 'HNMR (D2O) · 3,49 (t, 2H); 3,94 (t, 2H); 4,39 (t, 2H); 8,13 (s, 1H); 8,22 (s, IH).
CZ 304734 Β6
Příklad 2
H Me
Příprava PMEA z adeninu za použití Z-butoxidu hořečnatého
K suspenzi adeninu (40 g, 0,296 mol) v DMF (41,9 ml) byl přidán (Á)-propylen karbonát (34,5 g, 0,338 mol) a hydroxid sodný (0,480 g, 0,012 mmol). Směs byla přes noc zahřívána na 130 °C. Reakční směs byla zchlazena na 100°C a byl přidán toluen (138 ml) a následně kyselina methansulfonová (4,7 g, 0,049 mol), při čemž byla reakční teplota udržována mezi 100 až 110 °C. Byl přidán další toluen (114 ml), aby se vytvořil homogenní roztok. Roztok byl chlazen na 3 °C po dobu 7 hodin a pak udržován na 3 °C po dobu jedné hodiny. Výsledná pevná látka byla vysušena ve vakuu při 80 °C s výtěžkem 42,6 g (75%) (7?)-9-[2-(hydroxy)propyl]adeninu (HPA) ve formě špinavě bílé pevné látky. T.t. 188 až 190 °C.
H Ma
(7?/-9-[2-(hydroxy)propyl]adenin (HPA) (20,0 g, 0,104 mol) byl suspendován v DMF (44,5 ml) a zahřát na 65 °C. Ke směsi byl po dobu jedné hodiny přidáván t-butoxid hořečnatý (14,2 g, 0,083 mol), nebo alternativně isopropoxid hořečnatý, a následně p-toluensulfonyloxymethylfosfonát (66,0 g, 0,205 mol) po dobu dvou hodin, při čemž byla teplota udržována na 78 °C.
Směs byla při 75 °C míchána po dobu 4 hodin. Po zchlazení pod 5 °C byl přidán bromtrimethylsilan (73,9 g, 0,478 mol) a směs vyhřívána na 77 °C po 3 hodiny. Po skončení byla reakční směs zahřátá na 80 °C a těkavé látky byly odděleny destilací za atmosférického tlaku. Zbytek byl rozpuštěn ve vodě (120 ml) při 50 °C a pak extrahována ethylacetátem (101 ml). pH vodné fáze bylo nastaveno na pH 1,1 hydroxidem sodným, naočkováno autentickým (7?}-PMPA a pH vodné vrstvy bylo znovu nastaveno na pH 2,1 hydroxidem sodným. Výsledná suspenze byla přes noc míchání při teplotě místnosti. Suspenze byla chlazena na 4 °C po 3 hodiny. Pevný produkt byl oddělen filtrací, promyt vodou (60 ml) a vysušen ve vakuu při 50 °C s výtěžkem 18,6 g (63,5 %) surového (Á)-9-[2-(fosfonomethoxy)propyl]adeninu (PMPA) ve formě špinavě bílé pevné látky.
Surový (7?)-9-[2-(fosfonomethoxy)propyl]adenin byl zahříván pod zpětným chladičem ve vodě (255 ml) až se veškeré pevné látky rozpustily. Roztok byl chlazen na teplotu místnosti po více než 4 hodiny. Výsledná suspenze byla chlazena na 4 °C po dobu tří hodin. Pevný produkt byl oddělen filtrací, promyt vodou (56 ml) a acetonem (56 ml), a vysušen ve vakuu při 50 °C s výtěžkem 15,0 g (50,4 %) (7?)-9-[2-(fosfonomethoxy)propyl]adeninu (PMPA) ve formě bílé pevné látky. T.t.: 278 až 280 °C.

Claims (4)

  1. PATENTOVÉ NÁROKY
    5 1. Způsob přípravy 9-[2-(fosfonomethoxy)propyl]adeninu nebo 9-[2-(fosfonomethoxy)ethyl] adeninu, vyznačený tím, že zahrnuje reakci 9-<2-hydroxypropyl)adeninu nebo 9—(2hydroxyethyl)adeninu, alkoxidu hořečnatého a chráněného p-toluensulfonyloxymethylfosfonátu.
  2. 2. Způsob podle nároku 1, vyznačený tím, že fosfonát ^-toluensulfonyloxymethyl ío fosfonátu je chráněný ethyl esterem.
  3. 3. Způsob podle nároku 1, vyznačený tím, že alkoxidem je alkoxid Ct-Cý.
  4. 4. Způsob podle nároku 1, vyznačený tím, že alkoxid je vybrán z t—butyl— nebo iso
    15 propyloxidu.
CZ2013-310A 2000-07-21 2001-07-20 Způsob přípravy 9-[2-(fosfonomethoxy)propyl]adeninu a 9-[2-(fosfonomethoxy)ethyl]adeninu CZ304734B6 (cs)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US22002100P 2000-07-21 2000-07-21

Publications (1)

Publication Number Publication Date
CZ304734B6 true CZ304734B6 (cs) 2014-09-10

Family

ID=22821718

Family Applications (2)

Application Number Title Priority Date Filing Date
CZ2003-413A CZ304886B6 (cs) 2000-07-21 2001-07-20 Prekurzory léčiv na bázi fosfonátových analogů nukleotidů a způsoby jejich výběru a přípravy
CZ2013-310A CZ304734B6 (cs) 2000-07-21 2001-07-20 Způsob přípravy 9-[2-(fosfonomethoxy)propyl]adeninu a 9-[2-(fosfonomethoxy)ethyl]adeninu

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CZ2003-413A CZ304886B6 (cs) 2000-07-21 2001-07-20 Prekurzory léčiv na bázi fosfonátových analogů nukleotidů a způsoby jejich výběru a přípravy

Country Status (37)

Country Link
US (10) US20020119443A1 (cs)
EP (3) EP1301519B2 (cs)
JP (4) JP4651264B2 (cs)
KR (2) KR100767432B1 (cs)
CN (2) CN100402539C (cs)
AP (1) AP1466A (cs)
AU (3) AU8294101A (cs)
BE (1) BE2016C018I2 (cs)
BG (1) BG66037B1 (cs)
BR (1) BRPI0112646B8 (cs)
CA (3) CA2893174A1 (cs)
CY (2) CY2016008I1 (cs)
CZ (2) CZ304886B6 (cs)
DK (2) DK2682397T3 (cs)
EA (1) EA004926B1 (cs)
EE (1) EE05366B1 (cs)
ES (2) ES2536972T5 (cs)
FR (1) FR16C0013I2 (cs)
HK (1) HK1243711A1 (cs)
HR (2) HRP20030047B1 (cs)
HU (2) HU230960B1 (cs)
IL (1) IL153658A0 (cs)
IS (1) IS2985B (cs)
LT (2) LT2682397T (cs)
LU (1) LU93029I2 (cs)
MX (1) MXPA03000587A (cs)
NL (1) NL300803I2 (cs)
NO (6) NO336718B1 (cs)
NZ (3) NZ536942A (cs)
OA (1) OA12393A (cs)
PL (1) PL213214B1 (cs)
PT (2) PT2682397T (cs)
SI (2) SI2682397T1 (cs)
TR (1) TR200300055T2 (cs)
UA (1) UA75889C2 (cs)
WO (1) WO2002008241A2 (cs)
ZA (1) ZA200210271B (cs)

Families Citing this family (237)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ304886B6 (cs) * 2000-07-21 2015-01-07 Gilead Sciences, Inc. Prekurzory léčiv na bázi fosfonátových analogů nukleotidů a způsoby jejich výběru a přípravy
US7388002B2 (en) * 2001-11-14 2008-06-17 Biocryst Pharmaceuticals, Inc. Nucleosides, preparation thereof and use as inhibitors of RNA viral polymerases
EP1450809A4 (en) * 2001-11-14 2006-07-19 Biocryst Pharm Inc NUCLEOSIDES, THEIR PREPARATION AND USE AS AN INHIBITORS OF RNA VIRUS POLYMERASES
BR0309557A (pt) * 2002-04-26 2005-03-01 Gilead Sciences Inc Inibidores da transcriptase reversa não nucleosìdeos
US20050239054A1 (en) * 2002-04-26 2005-10-27 Arimilli Murty N Method and compositions for identifying anti-HIV therapeutic compounds
EP1532157A4 (en) 2002-05-13 2009-02-25 Metabasis Therapeutics Inc NEW PRODRUGS FROM PMEA TO PHOSPHONIC ACID BASE AND ITS ANALOG
HRP20140379A2 (hr) * 2003-01-14 2014-07-18 Gilead Sciences, Inc. Pripravci i metode za kombiniranu antivirusnu terapiju
WO2005002626A2 (en) * 2003-04-25 2005-01-13 Gilead Sciences, Inc. Therapeutic phosphonate compounds
US7432261B2 (en) * 2003-04-25 2008-10-07 Gilead Sciences, Inc. Anti-inflammatory phosphonate compounds
WO2004096287A2 (en) 2003-04-25 2004-11-11 Gilead Sciences, Inc. Inosine monophosphate dehydrogenase inhibitory phosphonate compounds
CN101410120A (zh) * 2003-04-25 2009-04-15 吉里德科学公司 抗炎的膦酸酯化合物
US20050261237A1 (en) * 2003-04-25 2005-11-24 Boojamra Constantine G Nucleoside phosphonate analogs
US20090247488A1 (en) * 2003-04-25 2009-10-01 Carina Cannizzaro Anti-inflammatory phosphonate compounds
US7452901B2 (en) 2003-04-25 2008-11-18 Gilead Sciences, Inc. Anti-cancer phosphonate analogs
WO2004096285A2 (en) * 2003-04-25 2004-11-11 Gilead Sciences, Inc. Anti-infective phosphonate conjugates
US7407965B2 (en) * 2003-04-25 2008-08-05 Gilead Sciences, Inc. Phosphonate analogs for treating metabolic diseases
EA200501676A1 (ru) * 2003-04-25 2006-04-28 Джилид Сайэнс, Инк. Фосфонатсодержащие ингибиторы киназы (варианты), способ их получения, фармацевтическая композиция, лекарственная форма на их основе и способ ингибирования киназы у млекопитающего (варианты)
US7470724B2 (en) * 2003-04-25 2008-12-30 Gilead Sciences, Inc. Phosphonate compounds having immuno-modulatory activity
ATE490788T1 (de) 2003-04-25 2010-12-15 Gilead Sciences Inc Antivirale phosphonate analoge
WO2005044308A1 (en) * 2003-10-24 2005-05-19 Gilead Sciences, Inc. Phosphonate analogs of antimetabolites
WO2005044279A1 (en) 2003-10-24 2005-05-19 Gilead Sciences, Inc. Purine nucleoside phosphonate conjugates
WO2005042773A1 (en) * 2003-10-24 2005-05-12 Gilead Sciences, Inc. Methods and compositions for identifying therapeutic compounds
US20070281907A1 (en) * 2003-12-22 2007-12-06 Watkins William J Kinase Inhibitor Phosphonate Conjugates
MXPA06006899A (es) * 2003-12-22 2006-09-04 Gilead Sciences Inc Derivados de carbovir y abacavir 4'-sustituidos asi como compuestos relacionados con actividad antiviral de virus de inmunodeficiencia humana y virus de la hepatitis c.
US20050153990A1 (en) * 2003-12-22 2005-07-14 Watkins William J. Phosphonate substituted kinase inhibitors
DE602004028763D1 (de) * 2003-12-30 2010-09-30 Gilead Sciences Inc Te zur behandlung von virenerkrankungen
EP1732569B1 (en) * 2004-01-21 2009-10-14 Gilead Sciences, Inc. Use of adefovir or tenofovir for inhibiting mmtv-like viruses involved in breast cancer and primary biliary cirrhosis
US7079156B1 (en) 2004-05-14 2006-07-18 Nvidia Corporation Method and system for implementing multiple high precision and low precision interpolators for a graphics pipeline
US8416242B1 (en) 2004-05-14 2013-04-09 Nvidia Corporation Method and system for interpolating level-of-detail in graphics processors
US8411105B1 (en) 2004-05-14 2013-04-02 Nvidia Corporation Method and system for computing pixel parameters
US8432394B1 (en) 2004-05-14 2013-04-30 Nvidia Corporation Method and system for implementing clamped z value interpolation in a raster stage of a graphics pipeline
JP5142716B2 (ja) 2004-06-08 2013-02-13 リガンド・ファーマシューティカルズ・インコーポレイテッド サイクリックエステルのルイス酸介在合成法
PT1778251E (pt) * 2004-07-27 2011-06-29 Gilead Sciences Inc Análogos de fosfonato de compostos inibidores de vih
US20070003608A1 (en) * 2005-04-08 2007-01-04 Almond Merrick R Compounds, compositions and methods for the treatment of viral infections and other medical disorders
US8642577B2 (en) 2005-04-08 2014-02-04 Chimerix, Inc. Compounds, compositions and methods for the treatment of poxvirus infections
CN100359315C (zh) * 2005-05-26 2008-01-02 林维宣 兽药残留能力验证样品及制备方法
TWI471145B (zh) 2005-06-13 2015-02-01 Bristol Myers Squibb & Gilead Sciences Llc 單一式藥學劑量型
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
US8076303B2 (en) 2005-12-13 2011-12-13 Spring Bank Pharmaceuticals, Inc. Nucleotide and oligonucleotide prodrugs
CN100396689C (zh) * 2006-03-07 2008-06-25 中国医学科学院医药生物技术研究所 一组具有抑制hiv-1/hbv病毒复制活性的替诺福韦单酯化合物
NZ572368A (en) 2006-05-16 2011-04-29 Gilead Sciences Inc Method and compositions for treating hematological malignancies
EP2046792B1 (en) * 2006-07-12 2015-02-25 Mylan Laboratories Limited Process for the preparation of tenofovir
US7951789B2 (en) 2006-12-28 2011-05-31 Idenix Pharmaceuticals, Inc. Compounds and pharmaceutical compositions for the treatment of viral infections
US7964580B2 (en) 2007-03-30 2011-06-21 Pharmasset, Inc. Nucleoside phosphoramidate prodrugs
AU2008302676B2 (en) * 2007-06-26 2013-02-28 University Of Wyoming Research Corporation D/B/A Western Research Institute Treatment and prevention systems for acid mine drainage and halogenated contaminants
US8441497B1 (en) * 2007-08-07 2013-05-14 Nvidia Corporation Interpolation of vertex attributes in a graphics processor
US8993542B2 (en) * 2008-01-25 2015-03-31 Chimerix Inc. Methods of treating viral infections
TWI444384B (zh) 2008-02-20 2014-07-11 Gilead Sciences Inc 核苷酸類似物及其在治療惡性腫瘤上的用途
EP2291386B1 (en) 2008-04-25 2016-01-13 Cipla Limited Crystalline form of tenofovir disoproxil and a process for its preparation
US8173621B2 (en) 2008-06-11 2012-05-08 Gilead Pharmasset Llc Nucleoside cyclicphosphates
EP2307434B1 (en) * 2008-07-02 2014-02-12 IDENIX Pharmaceuticals, Inc. Compounds and pharmaceutical compositions for the treatment of viral infections
UA103329C2 (ru) 2008-07-08 2013-10-10 Гилиад Сайенсиз, Инк. Соли соединений-ингибиторов вич
PA8855601A1 (es) 2008-12-23 2010-07-27 Forformidatos de nucleósidos
NZ617066A (en) 2008-12-23 2015-02-27 Gilead Pharmasset Llc Nucleoside analogs
WO2010075554A1 (en) * 2008-12-23 2010-07-01 Pharmasset, Inc. Synthesis of purine nucleosides
TWI583692B (zh) 2009-05-20 2017-05-21 基利法瑪席特有限責任公司 核苷磷醯胺
US8618076B2 (en) 2009-05-20 2013-12-31 Gilead Pharmasset Llc Nucleoside phosphoramidates
WO2011011519A1 (en) 2009-07-21 2011-01-27 Chimerix, Inc. Compounds, compositions and methods for treating ocular conditions
US10023600B2 (en) 2009-09-21 2018-07-17 Gilead Sciences, Inc. Processes and intermediates for the preparation of 1′-substituted carba-nucleoside analogs
AU2011216243B2 (en) 2010-02-12 2015-07-09 Chimerix, Inc. Nucleoside phosphonate salts
CL2011000718A1 (es) 2010-03-31 2012-04-09 Gilead Pharmasset Llc Proceso para la preparacion de compuestos fosforados enantiomericos.
US8563530B2 (en) 2010-03-31 2013-10-22 Gilead Pharmassel LLC Purine nucleoside phosphoramidate
WO2011123586A1 (en) 2010-04-01 2011-10-06 Idenix Pharmaceuticals, Inc. Compounds and pharmaceutical compositions for the treatment of viral infections
EP2563367A4 (en) 2010-04-26 2013-12-04 Chimerix Inc Methods of treating retroviral infections and related dosage regimes
PE20130807A1 (es) * 2010-07-19 2013-07-27 Gilead Sciences Inc Metodos para la preparacion de profarmacos de fosforamidato diastereomericamente puros
US20120027752A1 (en) 2010-07-22 2012-02-02 Gilead Sciences, Inc. Methods and compounds for treating paramyxoviridae virus infections
WO2012075140A1 (en) 2010-11-30 2012-06-07 Pharmasset, Inc. Compounds
WO2012079035A1 (en) 2010-12-10 2012-06-14 Sigmapharm Laboratories, Llc Highly stable compositions of orally active nucleotide analogues or orally active nucleotide analogue prodrugs
ZA201103820B (en) 2010-12-13 2012-01-25 Laurus Labs Private Ltd Process for the preparation of tenofovir
EP2691409B1 (en) 2011-03-31 2018-02-21 Idenix Pharmaceuticals LLC. Compounds and pharmaceutical compositions for the treatment of viral infections
WO2012154698A2 (en) * 2011-05-06 2012-11-15 Mckenna Charles E Method to improve antiviral activity of nucleotide analogue drugs
CA2835932C (en) * 2011-05-19 2020-03-24 Gilead Sciences, Inc. Processes and intermediates for preparing anti-hiv agents
AU2014271320B2 (en) * 2011-08-16 2017-02-23 Gilead Sciences, Inc. Tenofovir alafenamide hemifumarate
EP3831832A1 (en) * 2011-08-16 2021-06-09 Gilead Sciences, Inc. Tenofovir alafenamide hemifumarate
RS56975B1 (sr) 2011-09-16 2018-05-31 Gilead Pharmasset Llc Metode za lečenje hcv-a
CN103842366B (zh) 2011-10-07 2017-06-16 吉利德科学公司 制备抗病毒核苷酸类似物的方法
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
ES2734495T3 (es) 2011-12-22 2019-12-10 Geron Corp Análogos de guanina como sustratos de telomerasa y afectores de la longitud de los telómeros
AU2013204731C1 (en) 2012-02-03 2017-08-31 Gilead Sciences, Inc. Therapeutic compounds
WO2013115916A1 (en) 2012-02-03 2013-08-08 Gilead Sciences, Inc. Combination therapy comprising gs-7340 and cobicistat for use in the treatment of viral infections
CN107312039B (zh) 2012-08-30 2019-06-25 江苏豪森药业集团有限公司 一种替诺福韦前药的制备方法
GB201215696D0 (en) * 2012-09-03 2012-10-17 Ithemba Pharmaceuticals Pty Ltd A process for the preparation of (R)-9-[2-(Phosphonometh-Oxy)propyl]adenine (PMPA)
JP2015536940A (ja) * 2012-10-29 2015-12-24 シプラ・リミテッド 抗ウイルス性ホスホネート類似体及びその製造方法
CN102899327B (zh) * 2012-11-06 2014-06-11 清华大学深圳研究生院 一种抗病毒的小核酸及其温度敏感型凝胶制剂与应用
KR20150082613A (ko) * 2012-11-16 2015-07-15 머크 샤프 앤드 돔 코포레이션 인간 포스파티딜이노시톨 3-키나제 델타의 퓨린 억제제
CN103848868B (zh) * 2012-12-04 2017-04-12 蚌埠丰原涂山制药有限公司 制备替诺福韦的方法
CN103848869B (zh) * 2012-12-04 2016-12-21 上海医药工业研究院 制备替诺福韦的方法
EP2950786B1 (en) 2013-01-31 2019-11-27 Gilead Pharmasset LLC Combination formulation of two antiviral compounds
CN104072539B (zh) * 2013-03-25 2017-03-29 安徽贝克联合制药有限公司 替诺福韦双(4‑乙酰氨基苯酚氧基)酯及其制备方法和其应用
WO2014187314A1 (zh) * 2013-05-21 2014-11-27 成都先导药物开发有限公司 一种药物靶标捕获方法
US9676803B2 (en) 2013-06-07 2017-06-13 Cipla Limited Efficient process for separation of diastereomers of 9-[(R)-2-[[(R,S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]propyl]adenine
SG11201600919UA (en) 2013-08-27 2016-03-30 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
WO2015040640A2 (en) * 2013-09-20 2015-03-26 Laurus Labs Private Limited An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof
EP2860185A1 (en) 2013-10-09 2015-04-15 Zentiva, k.s. An improved process for the preparation of Tenofovir disoproxil and pharmaceutically acceptable salts thereof
IN2013CH05455A (cs) * 2013-11-27 2015-08-07 Laurus Labs Private Ltd
IN2014MU00118A (cs) 2014-01-14 2015-08-28 Mylan Lab Ltd
TWI660965B (zh) 2014-01-15 2019-06-01 美商基利科學股份有限公司 泰諾福韋之固體形式
CN104804042B (zh) * 2014-01-24 2018-01-19 齐鲁制药有限公司 核苷酸膦酸酯类化合物、其药物组合物、制备方法及用途
WO2015120057A1 (en) 2014-02-05 2015-08-13 Gilead Sciences, Inc. Pharmaceutical combinations against co-infection with hiv and tuberculosis
EP3105238A4 (en) 2014-02-13 2017-11-08 Ligand Pharmaceuticals, Inc. Prodrug compounds and their uses
WO2015127848A1 (zh) * 2014-02-27 2015-09-03 四川海思科制药有限公司 一种取代的氨基磷酸酯类衍生物、其制备方法及其应用
CN105001262B (zh) * 2014-04-18 2017-09-01 四川海思科制药有限公司 芳基取代的磷酰胺类衍生物及其在医学上的应用
CN105531281B (zh) * 2014-04-21 2017-12-15 四川海思科制药有限公司 一种核苷类似物及其中间体的制备方法
CN105085571A (zh) * 2014-05-20 2015-11-25 四川海思科制药有限公司 替诺福韦艾拉酚胺复合物及其制备方法和用途
CN105518012B (zh) * 2014-06-25 2018-03-02 四川海思科制药有限公司 一种取代的氨基酸硫酯类化合物、其组合物及应用
EP3164136A4 (en) 2014-07-02 2018-04-04 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
HRP20220651T1 (hr) 2014-09-15 2022-08-19 The Regents Of The University Of California Nukleotidni analozi
KR101703258B1 (ko) 2014-12-30 2017-02-06 한미정밀화학주식회사 고순도의 (r)-9-[2-(포스포노메톡시)프로필]아데닌의 제조방법
KR101703257B1 (ko) 2014-09-30 2017-02-06 한미정밀화학주식회사 고순도의 (r)-9-[2-(포스포노메톡시)프로필]아데닌의 제조방법
CN106687467A (zh) * 2014-09-30 2017-05-17 韩美精密化学株式会社 高纯度（r）‑9‑[2‑（磷酰甲氧基）丙基]腺嘌呤的制备方法
EP3203995A4 (en) 2014-10-09 2019-05-15 Board of Regents of the University of Nebraska COMPOSITIONS AND METHODS OF DELIVERING THERAPY AGENTS
TWI767201B (zh) 2014-10-29 2022-06-11 美商基利科學股份有限公司 絲狀病毒科病毒感染之治療
CN108148094A (zh) * 2014-11-12 2018-06-12 四川海思科制药有限公司 一种替诺福韦艾拉酚胺富马酸盐晶型c及其制备方法和用途
CN104558036A (zh) * 2014-12-11 2015-04-29 杭州和泽医药科技有限公司 一种替诺福韦艾拉酚胺半反丁烯二酸盐晶型及其制备方法
EP3240793A1 (en) 2015-01-03 2017-11-08 Mylan Laboratories Ltd. Processes for the preparation of amorphous tenofovir alafenamide hemifumarate and a premix thereof
WO2016187160A1 (en) * 2015-05-16 2016-11-24 Godx, Inc. Point of need testing device and methods of use thereof
CN106188139B (zh) 2015-05-29 2020-02-18 江苏天士力帝益药业有限公司 替诺福韦单苄酯磷酸酰胺前药、其制备方法及应用
CZ2015384A3 (cs) 2015-06-05 2016-12-14 Zentiva, K.S. Pevné formy Tenofovir alafenamidu
EP4092037A1 (en) * 2015-06-17 2022-11-23 Gilead Sciences, Inc. Co-crystals, salts and solid forms of tenofovir alafenamide
SI3316868T1 (sl) 2015-06-30 2020-04-30 Gilead Sciences, Inc. Farmacevtske formulacije, ki vsebujejo tenofovir in emtricitabin
MY192607A (en) 2015-08-10 2022-08-29 Merck Sharp & Dohme Antiviral beta-amino acid ester phosphodiamide compounds
TWI616452B (zh) * 2015-08-26 2018-03-01 Preparation method of nucleoside analog and intermediate thereof
TWI620754B (zh) * 2015-08-26 2018-04-11 Method for preparing amino phosphate derivative and preparation method thereof
TWI616453B (zh) * 2015-08-27 2018-03-01 Substituted amino acid thioester compounds, compositions and uses thereof
WO2017037608A1 (en) * 2015-08-28 2017-03-09 Laurus Labs Private Limited Solid forms of tenofovir alafenamide and salts thereof, processes for its preparation and pharmaceutical compositions thereof
HUE057928T2 (hu) 2015-09-16 2022-06-28 Gilead Sciences Inc Coronaviridae családba tartozó vírus okozta fertõzések kezelésére szolgáló eljárások
EA201890654A1 (ru) 2015-11-09 2018-10-31 Джилид Сайэнс, Инк. Терапевтические композиции для лечения вируса иммунодефицита человека
CN106800573B (zh) * 2015-11-25 2020-03-10 四川海思科制药有限公司 一种核苷酸膦酸酯一水合物及其制备方法和在医药上的应用
US10745428B2 (en) 2015-12-10 2020-08-18 Idenix Pharmaceuticals Llc Antiviral phosphodiamide prodrugs of tenofovir
CN106866737B (zh) * 2015-12-11 2020-11-20 南京圣和药物研发有限公司 膦酸衍生物及其应用
WO2017106069A1 (en) 2015-12-15 2017-06-22 Merck Sharp & Dohme Corp. Antiviral oxime phosphoramide compounds
WO2017118928A1 (en) 2016-01-06 2017-07-13 Lupin Limited Process for the separation of diastereomers of tenofovir alafenamide
PT3411378T (pt) 2016-02-02 2020-07-28 Sandoz Ag Formas cristalinas de monofumarato de tenofovir alafenamida
WO2017133517A1 (zh) * 2016-02-03 2017-08-10 四川海思科制药有限公司 一种磷酰胺衍生物及制备方法和用途
CN108350007B (zh) * 2016-03-01 2020-04-10 深圳市塔吉瑞生物医药有限公司 一种取代的腺嘌呤化合物及其药物组合物
CN107179355B (zh) * 2016-03-11 2021-08-10 广东东阳光药业有限公司 一种分离检测替诺福韦艾拉酚胺及其有关物质的方法
CZ2016156A3 (cs) 2016-03-17 2017-09-27 Zentiva, K.S. Způsob přípravy diastereomerně čistého Tenofoviru Alafenamidu nebo jeho solí
CN107226826A (zh) * 2016-03-25 2017-10-03 江苏奥赛康药业股份有限公司 替诺福韦艾拉酚胺富马酸盐化合物及其药物组合物
WO2017211325A1 (zh) 2016-06-05 2017-12-14 上海诚妙医药科技有限公司 富马酸替诺福韦艾拉酚胺盐的新晶型、制备方法及其用途
CN107698621A (zh) * 2016-06-20 2018-02-16 杭州和泽医药科技有限公司 一种腺嘌呤衍生物的膦酸酯前药及其在医药上的应用
WO2017221189A1 (en) * 2016-06-22 2017-12-28 Laurus Labs Limited An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof
CN106317116A (zh) * 2016-08-19 2017-01-11 张红利 磷酰胺核苷类化合物及其药学上可接受的盐与应用、药物组合物
UY37367A (es) 2016-08-19 2018-03-23 Gilead Sciences Inc Nuevos compuestos para uso en el tratamiento de una infección viral y composiciones de los mismos
US10449208B2 (en) 2016-08-25 2019-10-22 Merck Sharp & Dohme Corp. Antiviral prodrugs of tenofovir
CN106380484A (zh) * 2016-08-29 2017-02-08 杭州百诚医药科技股份有限公司 一种替诺福韦艾拉酚胺的新晶型及其制备方法
WO2018042331A1 (en) 2016-08-31 2018-03-08 Glaxosmithkline Intellectual Property (No.2) Limited Combinations and uses and treatments thereof
WO2018051250A1 (en) 2016-09-14 2018-03-22 Viiv Healthcare Company Combination comprising tenofovir alafenamide, bictegravir and 3tc
WO2018080903A1 (en) 2016-10-26 2018-05-03 Merck Sharp & Dohme Corp. Antiviral aryl-amide phosphodiamide compounds
CN106565785B (zh) * 2016-11-09 2019-11-12 周雨恬 一种具有抗hbv/hiv活性的核苷氨基磷酸酯类化合物及其盐和用途
CN108129514A (zh) * 2016-12-01 2018-06-08 北京美倍他药物研究有限公司 磷酸/膦酸衍生物的单一异构体及其医药用途
MX2019007262A (es) * 2016-12-22 2019-09-05 Merck Sharp & Dohme Compuestos antivirales de bencilamina fosfodiamida.
WO2018119013A1 (en) 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. Antiviral aliphatic ester prodrugs of tenofovir
WO2018115046A1 (en) 2016-12-23 2018-06-28 Sandoz Ag Crystalline solid forms of tenofovir alafenamide
AR110768A1 (es) 2017-01-31 2019-05-02 Gilead Sciences Inc Formas cristalinas de tenofovir alafenamida
WO2018153977A1 (en) 2017-02-24 2018-08-30 Hexal Ag Stable composition of tenofovir alafenamide
RU2659388C1 (ru) 2017-02-28 2018-07-02 Васильевич Иващенко Александр Нуклеотиды, включающие N-[(S)-1-циклобутоксикарбонил]фосфорамидатный фрагмент, их аналоги и их применение
RU2647576C1 (ru) * 2017-02-28 2018-03-16 Васильевич Иващенко Александр Циклобутил (S)-2-[[[(R)-2-(6-аминопурин-9-ил)-1-метил-этокси]метил-фенокси-фосфорил]амино]-пропаноаты, способ их получения и применения
CN106866739B (zh) * 2017-03-10 2018-11-02 华东师范大学 一种(r)-1-(6-氨基-9h-嘌呤-9-基)2-苯酯的制备方法
AU2018235754B2 (en) 2017-03-14 2021-04-08 Gilead Sciences, Inc. Methods of treating feline coronavirus infections
WO2018175325A1 (en) 2017-03-20 2018-09-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Hiv post-exposure prophylaxis
CN108794530A (zh) * 2017-04-26 2018-11-13 上海医药工业研究院 一种替诺福韦丙酚酰胺盐晶型及其制备方法和用途
CA3178212A1 (en) 2017-05-01 2018-11-08 Gilead Sciences, Inc. Crystalline forms of (s)-2-ethylbutyl 2-(((s)-(((2r,3s,4r,5r)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate
KR102379965B1 (ko) * 2017-05-19 2022-03-29 주식회사 종근당 테노포비르의 효율적인 제조방법
CN107266499B (zh) * 2017-06-05 2019-07-02 珠海优润医药科技有限公司 一种抗病毒化合物及其制备方法
US12090163B2 (en) 2017-06-30 2024-09-17 Cipla Limited Pharmaceutical compositions
ES3000461T3 (en) 2017-07-11 2025-02-28 Gilead Sciences Inc Compositions comprising an rna polymerase inhibitor and cyclodextrin for treating viral infections
WO2019021319A1 (en) 2017-07-27 2019-01-31 Cipla Limited PHARMACEUTICAL COMPOSITIONS
EP3661937B1 (en) 2017-08-01 2021-07-28 Gilead Sciences, Inc. Crystalline forms of ethyl ((s)-((((2r,5r)-5-(6-amino-9h-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-l-alaninate (gs-9131) for treating viral infections
AR112412A1 (es) 2017-08-17 2019-10-23 Gilead Sciences Inc Formas de sal de colina de un inhibidor de la cápside del vih
CN107655987B (zh) * 2017-09-08 2020-11-03 厦门蔚扬药业有限公司 一种替诺福韦艾拉酚胺及其异构体的hplc检测方法
CN107522743A (zh) * 2017-09-30 2017-12-29 深圳科兴生物工程有限公司 一种半富马酸替诺福韦艾拉酚胺工业化连续生产方法
WO2019084020A1 (en) 2017-10-24 2019-05-02 Gilead Sciences, Inc. METHODS OF TREATING PATIENTS CO-INFECTED BY A VIRUS AND TUBERCULOSIS
CN109942632B (zh) * 2017-12-20 2021-08-31 上海博志研新药物研究有限公司 替诺福韦艾拉酚胺中间体的制备方法
CN109942633B (zh) * 2017-12-20 2021-08-31 上海新礼泰药业有限公司 替诺福韦艾拉酚胺中间体的制备方法
US20200407382A1 (en) 2017-12-30 2020-12-31 Cipla Limited Polymorphic forms of (9-[(r)-2-[[(s)-[[(s)-1-(isopropoxycarbonyl)ethyl]amino]phenoxy phosphinyl]methoxy]propyl] adenine and pharmaceutically acceptable salts thereof
CA3087932A1 (en) 2018-01-09 2019-07-18 Ligand Pharmaceuticals, Inc. Acetal compounds and therapeutic uses thereof
US12110308B2 (en) 2018-01-10 2024-10-08 Nucorion Pharmaceuticals, Inc. Phosphor(n)amidatacetal and phosph(on)atalcetal compounds
EP3737359A4 (en) * 2018-01-12 2021-11-03 Board of Regents of the University of Nebraska ANTIVIRAL MEDICINES AND FORMULATIONS OF THEM
EP3752495B1 (en) 2018-02-15 2023-07-19 Gilead Sciences, Inc. Pyridine derivatives and their use for treating hiv infection
CN116854630A (zh) 2018-02-16 2023-10-10 吉利德科学公司 用于制备可用于治疗逆转录病毒科病毒感染的治疗性化合物的方法和中间体
CN108101943B (zh) * 2018-02-28 2020-11-24 顾世海 一种替诺福韦前药或可药用盐及其在医药上的应用
WO2019199756A1 (en) 2018-04-09 2019-10-17 Board Of Regents Of The University Of Nebraska Antiviral prodrugs and formulations thereof
TWI842721B (zh) 2018-07-16 2024-05-21 美商基利科學股份有限公司 用於治療hiv之蛋白殼抑制劑
US11826375B2 (en) 2018-07-19 2023-11-28 Merck Sharp & Dohme Llc Phosphinic amide prodrugs of tenofovir
AU2019344929B2 (en) 2018-09-19 2023-03-30 Gilead Sciences, Inc. Integrase inhibitors for the prevention of HIV
CA3128961A1 (en) 2019-03-22 2020-10-01 Hang CHU Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use
JP7625542B2 (ja) 2019-07-17 2025-02-03 ヌクオリオン ファーマシューティカルズ インコーポレイテッド 環状デオキシリボヌクレオチド化合物
WO2021011891A1 (en) 2019-07-18 2021-01-21 Gilead Sciences, Inc. Long-acting formulations of tenofovir alafenamide
WO2021015818A1 (en) 2019-07-19 2021-01-28 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Hiv pre-exposure prophylaxis
US20220296619A1 (en) 2019-08-19 2022-09-22 Gilead Sciences, Inc. Pharmaceutical formulations of tenofovir alafenamide
CA3152013A1 (en) 2019-08-22 2021-02-25 Emory University Nucleoside prodrugs and uses related thereto
EP4031141A4 (en) * 2019-09-20 2023-10-18 Abbott Rapid Diagnostics International Unlimited Company ANTIBODIES TO TENOFOVIR AND DERIVATIVES THEREOF
CN114727999A (zh) 2019-11-26 2022-07-08 吉利德科学公司 用于预防hiv的衣壳抑制剂
CN118662520A (zh) 2020-01-27 2024-09-20 吉利德科学公司 用于治疗SARS CoV-2感染的方法
EP4085062A1 (en) 2020-02-20 2022-11-09 Cipla Limited Novel salts and/or co-crystals of tenofovir alafenamide
EP4118085A2 (en) 2020-03-12 2023-01-18 Gilead Sciences, Inc. Methods of preparing 1'-cyano nucleosides
WO2021188959A1 (en) 2020-03-20 2021-09-23 Gilead Sciences, Inc. Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same
WO2021202669A2 (en) 2020-04-01 2021-10-07 Reyoung Corporation Nucleoside and nucleotide conjugate compounds and uses thereof
WO2021207049A1 (en) 2020-04-06 2021-10-14 Gilead Sciences, Inc. Inhalation formulations of 1'-cyano substituted carbanucleoside analogs
KR20210125298A (ko) 2020-04-08 2021-10-18 주식회사 파마코스텍 테노포비어 알라펜아미드 헤미타르트레이트의 신규한 제조방법
EP4143199A4 (en) 2020-04-21 2024-07-03 Ligand Pharmaceuticals, Inc. NUCLEOTIDE PRODRUG COMPOUNDS
CA3179226A1 (en) 2020-05-29 2021-12-02 Tomas Cihlar Remdesivir treatment methods
CR20220675A (es) 2020-06-24 2023-02-15 Gilead Sciences Inc Análogos de nucleósido de 1´- ciano y usos de los mismos
CA3181690A1 (en) 2020-06-25 2021-12-30 Chienhung CHOU Capsid inhibitors for the treatment of hiv
CN113970612B (zh) * 2020-07-22 2023-08-01 北京四环制药有限公司 一种高效液相色谱法测定丙酚替诺福韦有关物质的方法
HUE067491T2 (hu) 2020-08-27 2024-10-28 Gilead Sciences Inc Vegyületek és eljárások vírusfertõzések kezelésére
CN112336695B (zh) * 2020-09-28 2023-01-03 华北制药华坤河北生物技术有限公司 一种富马酸丙酚替诺福韦片剂及其制备方法和有关物质的检测方法
CA3195799A1 (en) 2020-11-11 2022-05-19 Stephen R. Martin Methods of identifying hiv patients sensitive to therapy with gp120 cd4 binding site-directed antibodies
US11667656B2 (en) 2021-01-27 2023-06-06 Apotex Inc. Crystalline forms of Tenofovir alafenamide
CN113075307B (zh) * 2021-03-08 2025-03-11 瑞阳制药股份有限公司 富马酸丙酚替诺福韦异构体的检测方法
CN113214322B (zh) * 2021-04-30 2022-10-25 山东立新制药有限公司 替诺福韦绿色环保的制备方法
WO2022251594A1 (en) * 2021-05-27 2022-12-01 Antios Therapeutics, Inc. Pharmacokinetics and dose-related improvments in subjects treated with phosphoramidate clevudine prodrugs
TW202342447A (zh) 2021-12-03 2023-11-01 美商基利科學股份有限公司 用於ｈｉｖ病毒感染之治療性化合物
EP4440700A1 (en) 2021-12-03 2024-10-09 Gilead Sciences, Inc. Therapeutic compounds for hiv virus infection
EP4440702B1 (en) 2021-12-03 2025-05-21 Gilead Sciences, Inc. Therapeutic compounds for hiv virus infection
CN114369120A (zh) * 2022-01-28 2022-04-19 石家庄龙泽制药股份有限公司 一种丙酚替诺福韦关键中间体的制备方法
PE20250683A1 (es) 2022-03-02 2025-03-04 Gilead Sciences Inc Compuestos y metodos para el tratamiento de infecciones virales
TWI856796B (zh) 2022-04-06 2024-09-21 美商基利科學股份有限公司 橋聯三環胺甲醯基吡啶酮化合物及其用途
US20240034724A1 (en) 2022-07-01 2024-02-01 Gilead Sciences, Inc. Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection
JP2025526212A (ja) 2022-07-21 2025-08-13 アンティバ バイオサイエンシズ インコーポレイテッド Ｈｐｖ感染症及びｈｐｖ誘発性新生物の治療用の組成物及び剤形
WO2024044477A1 (en) 2022-08-26 2024-02-29 Gilead Sciences, Inc. Dosing and scheduling regimen for broadly neutralizing antibodies
US20240226130A1 (en) 2022-10-04 2024-07-11 Gilead Sciences, Inc. 4'-thionucleoside analogues and their pharmaceutical use
WO2024196814A1 (en) 2023-03-17 2024-09-26 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methods for treatment of age-related macular degeneration
WO2024220624A1 (en) 2023-04-19 2024-10-24 Gilead Sciences, Inc. Dosing regimen of capsid inhibitor
WO2024249592A1 (en) 2023-05-31 2024-12-05 Gilead Sciences, Inc. Quinazolinyl-indazole derivatives as therapeutic compounds for hiv
WO2024249573A1 (en) 2023-05-31 2024-12-05 Gilead Sciences, Inc. Solid forms of compounds useful in the treatment of hiv
WO2025029247A1 (en) 2023-07-28 2025-02-06 Gilead Sciences, Inc. Weekly regimen of lenacapavir for the treatment and prevention of hiv
WO2025042394A1 (en) 2023-08-23 2025-02-27 Gilead Sciences, Inc. Dosing regimen of hiv capsid inhibitor
US20250127801A1 (en) 2023-10-11 2025-04-24 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
WO2025080863A1 (en) 2023-10-11 2025-04-17 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
US20250120989A1 (en) 2023-10-11 2025-04-17 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
WO2025137245A1 (en) 2023-12-22 2025-06-26 Gilead Sciences, Inc. Solid forms of hiv integrase inhibitors
US12357577B1 (en) 2024-02-02 2025-07-15 Gilead Sciences, Inc. Pharmaceutical formulations and uses thereof
WO2025184609A1 (en) 2024-03-01 2025-09-04 Gilead Sciences, Inc. Antiviral compounds
WO2025184447A1 (en) 2024-03-01 2025-09-04 Gilead Sciences, Inc. Pharmaceutical compositions comprising hiv integrase inhibitors
WO2025184452A1 (en) 2024-03-01 2025-09-04 Gilead Sciences, Inc. Solid forms of hiv integrase inhibitors
CN118652277A (zh) * 2024-08-19 2024-09-17 成都工业学院 一种用于治疗癌症疾病的化合物的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999005150A1 (en) * 1997-07-25 1999-02-04 Gilead Sciences, Inc. Nucleotide analog composition and synthesis method
US5977089A (en) * 1996-07-26 1999-11-02 Gilead Sciences, Inc. Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability

Family Cites Families (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CS233665B1 (en) 1983-01-06 1985-03-14 Antonin Holy Processing of isomere o-phosphonylmethylderivative of anantiomere racemic vicinal diene
CS263951B1 (en) 1985-04-25 1989-05-12 Antonin Holy 9-(phosponylmethoxyalkyl)adenines and method of their preparation
CS263952B1 (en) 1985-04-25 1989-05-12 Holy Antonin Remedy with antiviral effect
CS264222B1 (en) 1986-07-18 1989-06-13 Holy Antonin N-phosphonylmethoxyalkylderivatives of bases of pytimidine and purine and method of use them
US5650510A (en) 1986-11-18 1997-07-22 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Antiviral phosphonomethoxyalkylene purine and pyrimidine derivatives
US5057301A (en) 1988-04-06 1991-10-15 Neorx Corporation Modified cellular substrates used as linkers for increased cell retention of diagnostic and therapeutic agents
US5053215A (en) * 1988-05-26 1991-10-01 University Of Florida NMR-assayable ligand-labelled trifluorothymidine containing composition and method for diagnosis of HSV infection
US5744600A (en) 1988-11-14 1998-04-28 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Phosphonomethoxy carbocyclic nucleosides and nucleotides
US5688778A (en) 1989-05-15 1997-11-18 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Nucleoside analogs
JP2648516B2 (ja) 1989-07-27 1997-09-03 ダイセル化学工業株式会社 立体異性体の分離法
US5624898A (en) * 1989-12-05 1997-04-29 Ramsey Foundation Method for administering neurologic agents to the brain
JP2925753B2 (ja) 1990-02-23 1999-07-28 ダイセル化学工業株式会社 光学異性体の分離方法
ATE124050T1 (de) * 1990-04-20 1995-07-15 Acad Of Science Czech Republic Chirale 2-(phosphonomethoxy)propyl-guanine als antivirale agentien.
US5302585A (en) 1990-04-20 1994-04-12 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Use of chiral 2-(phosphonomethoxy)propyl guanines as antiviral agents
SK280313B6 (sk) 1990-04-24 1999-11-08 �Stav Organick� Chemie A Biochemie Av �R N-(3-fluór-2-fosfonylmetoxypropyl)deriváty purínov
US5627165A (en) * 1990-06-13 1997-05-06 Drug Innovation & Design, Inc. Phosphorous prodrugs and therapeutic delivery systems using same
US5177064A (en) 1990-07-13 1993-01-05 University Of Florida Targeted drug delivery via phosphonate derivatives
CS387190A3 (en) 1990-08-06 1992-03-18 Ustav Organicke Chemie A Bioch (2r)-2-/di(2-propyl)phosphonylmethoxy/-3-p-toluenesulfonyloxy -1- trimethylacetoxypropane and process for preparing thereof
AU653552B2 (en) 1990-08-10 1994-10-06 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Novel process for the preparation of nucleotides
ES2118069T3 (es) 1990-09-14 1998-09-16 Acad Of Science Czech Republic Profarmacos de fosfonatos.
US5827819A (en) * 1990-11-01 1998-10-27 Oregon Health Sciences University Covalent polar lipid conjugates with neurologically active compounds for targeting
US5208221A (en) * 1990-11-29 1993-05-04 Bristol-Myers Squibb Company Antiviral (phosphonomethoxy) methoxy purine/pyrimidine derivatives
CZ284678B6 (cs) 1991-05-20 1999-01-13 Ústav Organické Chemie A Biochemie Avčr Di(2-propyl)estery 1-fluor-2-fosfonomethoxy-3-p -toluensulfonyloxypropanů, způsob jejich přípravy a použití
JP3010816B2 (ja) 1991-08-22 2000-02-21 ダイセル化学工業株式会社 光学分割における光学異性体と溶媒との回収方法、溶媒の循環使用方法、および光学異性体の再利用方法
US5498752A (en) 1991-08-22 1996-03-12 Daicel Chemical Industries, Ltd. Process for recovering optical isomers and solvent, process for using solvent by circulation and process for reusing optical isomers in optical resolution
HU225970B1 (en) 1991-10-11 2008-01-28 Acad Of Science Czech Republic Antiviral acyclic phosphonomethoxyalkyl-substituted alkenyl purine and pyrimidine derivatives, and pharmaceutical preparations containing them
US6057305A (en) 1992-08-05 2000-05-02 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Antiretroviral enantiomeric nucleotide analogs
IL106998A0 (en) * 1992-09-17 1993-12-28 Univ Florida Brain-enhanced delivery of neuroactive peptides by sequential metabolism
US6413949B1 (en) * 1995-06-07 2002-07-02 D-Pharm, Ltd. Prodrugs with enhanced penetration into cells
US5656745A (en) * 1993-09-17 1997-08-12 Gilead Sciences, Inc. Nucleotide analogs
DE69435319D1 (de) 1993-09-17 2010-12-16 Gilead Sciences Inc Nukleotidanaloge
US5798340A (en) * 1993-09-17 1998-08-25 Gilead Sciences, Inc. Nucleotide analogs
AU690587B2 (en) * 1993-09-17 1998-04-30 Gilead Sciences, Inc. Method for dosing therapeutic compounds
GB9505025D0 (en) 1995-03-13 1995-05-03 Medical Res Council Chemical compounds
US5977061A (en) 1995-04-21 1999-11-02 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic N6 - substituted nucleotide analagues and their use
CA2222048A1 (en) * 1995-05-26 1996-11-28 Polska Akademia Nauk Compositions and methods for the synthesis of organophosphorus derivatives
BR9612317A (pt) 1995-12-29 2000-10-31 Gilead Sciences Inc Análogos nucleotìdeos.
US5717095A (en) * 1995-12-29 1998-02-10 Gilead Sciences, Inc. Nucleotide analogs
US5874577A (en) * 1996-04-03 1999-02-23 Medichem Research, Inc. Method for the preparing 9-12-(Diethoxyphosphonomethoxy)ethyl!adenine and analogues thereof
JP4033494B2 (ja) * 1996-07-26 2008-01-16 ギリヤド サイエンシーズ， インコーポレイテッド ヌクレオチドアナログ
US5739314A (en) 1997-04-25 1998-04-14 Hybridon, Inc. Method for synthesizing 2'-O-substituted pyrimidine nucleosides
PT996430E (pt) 1997-07-25 2003-03-31 Gilead Sciences Inc Composicoes de analogos nucleotidicos
US5935946A (en) 1997-07-25 1999-08-10 Gilead Sciences, Inc. Nucleotide analog composition and synthesis method
EP1037649B1 (en) * 1997-12-17 2009-09-30 Enzon, Inc. Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents
BR9907736A (pt) * 1998-01-23 2000-10-17 Newbiotics Inc Agentes terapêuticos catalisados por enzima
US6169078B1 (en) * 1998-05-12 2001-01-02 University Of Florida Materials and methods for the intracellular delivery of substances
JP2002518521A (ja) * 1998-06-20 2002-06-25 ワシントン・ユニバーシティ 医用画像解析、診断および治療のための膜透過性ペプチド錯体
US6169879B1 (en) * 1998-09-16 2001-01-02 Webtv Networks, Inc. System and method of interconnecting and using components of home entertainment system
GB9821058D0 (en) † 1998-09-28 1998-11-18 Univ Cardiff Chemical compound
TWI230618B (en) * 1998-12-15 2005-04-11 Gilead Sciences Inc Pharmaceutical compositions of 9-[2-[[bis[(pivaloyloxy)methyl]phosphono]methoxy]ethyl]adenine and tablets or capsules containing the same
WO2000047591A1 (en) † 1999-02-12 2000-08-17 Glaxo Group Limited Phosphoramidate, and mono-, di-, and tri-phosphate esters of (1r, cis)-4-(6-amino-9h-purin-9-yl)-2-cyclopentene-1-methanol as antiviral agents
CZ304886B6 (cs) 2000-07-21 2015-01-07 Gilead Sciences, Inc. Prekurzory léčiv na bázi fosfonátových analogů nukleotidů a způsoby jejich výběru a přípravy
CA2425610A1 (en) * 2000-10-13 2002-04-18 University Of Lausanne Intracellular delivery of biological effectors by novel transporter peptide sequences
US20020119433A1 (en) * 2000-12-15 2002-08-29 Callender Thomas J. Process and system for creating and administering interview or test

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5977089A (en) * 1996-07-26 1999-11-02 Gilead Sciences, Inc. Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability
WO1999005150A1 (en) * 1997-07-25 1999-02-04 Gilead Sciences, Inc. Nucleotide analog composition and synthesis method

Also Published As

Publication number Publication date
US20080227754A1 (en) 2008-09-18
UA75889C2 (uk) 2006-06-15
EP2682397A1 (en) 2014-01-08
BRPI0112646B8 (pt) 2021-05-25
FR16C0013I2 (fr) 2016-09-09
NO336718B1 (no) 2015-10-26
HRP20160074A8 (hr) 2016-07-29
KR100767432B1 (ko) 2007-10-17
CA2725819A1 (en) 2002-01-31
JP2011140506A (ja) 2011-07-21
AP2003002724A0 (en) 2003-06-30
EE200300029A (et) 2004-10-15
PL213214B1 (pl) 2013-01-31
CN1291994C (zh) 2006-12-27
US20050159392A1 (en) 2005-07-21
EA004926B1 (ru) 2004-10-28
KR20030022295A (ko) 2003-03-15
PL360490A1 (en) 2004-09-06
EP2682397B1 (en) 2017-04-19
NO20030270D0 (no) 2003-01-20
SI1301519T1 (sl) 2015-07-31
NZ523438A (en) 2005-02-25
JP2004504402A (ja) 2004-02-12
HRP20160074B1 (hr) 2021-09-03
NZ536942A (en) 2006-03-31
HUS1900027I1 (hu) 2021-03-29
LTPA2016009I1 (lt) 2016-04-25
CN100402539C (zh) 2008-07-16
CY2016008I2 (el) 2016-12-14
HK1243711A1 (en) 2018-07-20
US20050124585A1 (en) 2005-06-09
IS2985B (is) 2017-09-15
WO2002008241A3 (en) 2002-08-29
IL153658A0 (en) 2003-07-06
US20050009043A1 (en) 2005-01-13
EP1301519B1 (en) 2015-02-25
AU2001282941C1 (en) 2016-12-22
IS6689A (is) 2003-01-17
PT2682397T (pt) 2017-05-31
US20040018150A1 (en) 2004-01-29
NO20120466L (no) 2003-03-20
PT1301519E (pt) 2015-06-11
US20030219727A1 (en) 2003-11-27
MXPA03000587A (es) 2004-04-05
CN1706855A (zh) 2005-12-14
BG66037B1 (bg) 2010-11-30
HK1054238A1 (en) 2003-11-21
NZ535408A (en) 2006-09-29
ZA200210271B (en) 2003-12-31
NO20030270L (no) 2003-03-20
US20020119443A1 (en) 2002-08-29
LT2682397T (lt) 2017-06-12
ES2627903T3 (es) 2017-08-01
JP2009062383A (ja) 2009-03-26
KR20060105807A (ko) 2006-10-11
AU2005225039B2 (en) 2008-09-25
CA2416757C (en) 2011-02-15
DK2682397T3 (da) 2017-06-19
BG107572A (bg) 2003-11-28
US20050124583A1 (en) 2005-06-09
EA200300188A1 (ru) 2003-06-26
DK1301519T4 (da) 2021-12-20
US7803788B2 (en) 2010-09-28
ES2536972T5 (es) 2022-04-06
ES2536972T3 (es) 2015-06-01
HUP0301307A2 (hu) 2003-09-29
CZ304886B6 (cs) 2015-01-07
CA2416757A1 (en) 2002-01-31
AU2001282941B2 (en) 2006-04-27
DK1301519T3 (en) 2015-05-26
JP4651264B2 (ja) 2011-03-16
US20050124584A1 (en) 2005-06-09
HUS000494I2 (hu) 2021-03-29
NO20131717L (no) 2003-03-20
US20060024659A1 (en) 2006-02-02
CN1443189A (zh) 2003-09-17
HRP20030047A2 (en) 2007-08-31
SI2682397T1 (sl) 2017-08-31
OA12393A (en) 2006-04-18
NO20150909L (no) 2003-03-20
AU2005225039A1 (en) 2005-11-10
CY2016008I1 (el) 2016-12-14
JP5063554B2 (ja) 2012-10-31
AP1466A (en) 2005-09-22
HRP20030047B1 (hr) 2016-02-26
BRPI0112646B1 (pt) 2017-10-17
CA2725819C (en) 2015-09-22
LTC1301519I2 (lt) 2023-02-27
HRP20160074A2 (hr) 2016-03-11
EE05366B1 (et) 2010-12-15
BE2016C018I2 (cs) 2020-08-20
BR0112646A (pt) 2003-06-24
HUP0301307A3 (en) 2005-12-28
HU230960B1 (hu) 2019-06-28
NL300803I2 (cs) 2016-06-30
KR100749160B1 (ko) 2007-08-14
US7390791B2 (en) 2008-06-24
EP1301519B2 (en) 2021-11-10
TR200300055T2 (tr) 2004-12-21
NO2016006I1 (no) 2016-04-19
AU8294101A (en) 2002-02-05
JP2010174033A (ja) 2010-08-12
LU93029I2 (fr) 2016-06-14
NO2023006I1 (no) 2023-02-03
NO2016006I2 (no) 2016-04-19
WO2002008241A2 (en) 2002-01-31
EP3235823A1 (en) 2017-10-25
FR16C0013I1 (fr) 2016-05-27
JP5111551B2 (ja) 2013-01-09
EP1301519A2 (en) 2003-04-16
CA2893174A1 (en) 2002-01-31
CY1119411T1 (el) 2018-03-07
CZ2003413A3 (cs) 2003-12-17

Similar Documents

Publication Publication Date Title
CZ304734B6 (cs) Způsob přípravy 9-[2-(fosfonomethoxy)propyl]adeninu a 9-[2-(fosfonomethoxy)ethyl]adeninu
US8846896B2 (en) Methods of preparing substituted nucleotide analogs
CN108738321B (zh) GalNAc簇亚磷酰胺
FI90429B (fi) Menetelmä uusien terapeuttisesti käyttökelpoisten adenosiinijohdannaisten valmistamiseksi ja välituotteita
CN101657462A (zh) 卡培他滨的制备方法及其中间体
GB2134907A (en) Isomeric o-phosphonylmethyl derivatives of enantiomeric and racemic vicinal diols and method of preparing them
WO2014033688A1 (en) A process for the preparation of (r)-9-[2-(phosphonometh-oxy)propyl]adenine (pmpa)
EP0521923B1 (en) Process for producing nucleosides, and analogs therof
EP3131910B1 (en) Use of a 1,3,5-triazin-2-yl phosphoramidate compound in the synthesis of sofosbuvir
EP2181102A1 (en) Process for controlled crystal size in 1,2-substituted 3,4-dioxo-1-cyclobutene compounds
CZ293546B6 (cs) Způsob štěpení racemátů ketaminu
JP2012533618A (ja) フルオロシチジン誘導体の製造プロセス
HUP0200839A2 (en) Novel synthesis and crystallization of piperazine ring-containing compounds and pharmaceutical compositions containing them
JP3884779B2 (ja) ２’，３’−ジデヒドロ−２’，３’−ジデオキシヌクレオシド類の大量製造法
JP3901321B2 (ja) リボフラビン−５’−リン酸またはそのナトリウム塩の製造法
WO2008065490A2 (en) Process for the preparation of atazanavir
KR101247653B1 (ko) 아데포비어 디피복실 제조방법
KR101195631B1 (ko) ９-［２-(포스포노메톡시)에틸］아데닌의 개선된 제조방법
KR20060132910A (ko) 스퐁고신의 합성
TW202426003A (zh) 用於製備奈拉濱(nelarabine)或其鹽及中間體之方法
EP1018509A1 (en) A process for preparing 4-amino-1,2,4-triazolin-5-ones
EP4373494A1 (en) Methods for preparing bisphosphocins
WO2014126954A1 (en) Regioselective synthesis of substituted pyrimidines
CN107759483B (zh) 一种甲氨基取代的环戊烷甲酸烷基酯的制备方法
EP3848381A1 (en) Method for producing glycoside compound

Legal Events

Date Code Title Description
MK4A Patent expired

Effective date: 20210720