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WO2004113360A1 - Phosphoramidates d'analogues de nucleosides utilises comme inhibiteurs de la reproduction du virus de l'immunodeficience humaine - Google Patents

Phosphoramidates d'analogues de nucleosides utilises comme inhibiteurs de la reproduction du virus de l'immunodeficience humaine Download PDF

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Publication number
WO2004113360A1
WO2004113360A1 PCT/RU2003/000514 RU0300514W WO2004113360A1 WO 2004113360 A1 WO2004113360 A1 WO 2004113360A1 RU 0300514 W RU0300514 W RU 0300514W WO 2004113360 A1 WO2004113360 A1 WO 2004113360A1
Authority
WO
WIPO (PCT)
Prior art keywords
phosphoromidates
virus
mmol
nucleoside analogues
iii
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/RU2003/000514
Other languages
English (en)
Russian (ru)
Inventor
Andrei Georgievich Pokrovsky
Tatyana Rudolfovna Pronyaeva
Nina Vladimirovna Fedyuk
Aleksandr Valerevich Shipitsin
Elena Anatolevna Shirokova
Natalya Fanisovna Zakirova
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gosudarstvenny Nauchny Tsentr Virusologii I Biotekhnologii 'vektor'
Institut Molekulyarnoy Biologii Im Vaengelgardta Ran
Original Assignee
Gosudarstvenny Nauchny Tsentr Virusologii I Biotekhnologii 'vektor'
Institut Molekulyarnoy Biologii Im Vaengelgardta Ran
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gosudarstvenny Nauchny Tsentr Virusologii I Biotekhnologii 'vektor', Institut Molekulyarnoy Biologii Im Vaengelgardta Ran filed Critical Gosudarstvenny Nauchny Tsentr Virusologii I Biotekhnologii 'vektor'
Publication of WO2004113360A1 publication Critical patent/WO2004113360A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • HIV human immunodeficiency virus
  • the peculiar mechanism of the action of the indicated connection includes the diffusion of its internal cells, an infected HIC. Further, it is encouraged to process and specifically block the synthesis of electronic components, which is catalyzed by in-line electronic transmissions.
  • ⁇ nal ⁇ gichnym ⁇ b ⁇ az ⁇ m deys ⁇ vuyu ⁇ d ⁇ ugie ⁇ iv ⁇ vi ⁇ usnye nu ⁇ le ⁇ zidy, ⁇ imenyaemye meditsins ⁇ y ⁇ a ⁇ i ⁇ e in the treatment of AIDS: 2 ', 3'-didez ⁇ sitsi ⁇ idin and 2', 3'didez ⁇ siin ⁇ zin ( ⁇ yziua, ⁇ .; ⁇ g ⁇ eg, ⁇ ⁇ YSh ⁇ ⁇ "those T ⁇ tgesy ⁇ gu a ⁇ su ⁇ a ⁇ s.
  • yavlyae ⁇ sya is ⁇ lz ⁇ vanie in ⁇ aches ⁇ ve ⁇ iv ⁇ vi ⁇ usn ⁇ g ⁇ ⁇ e ⁇ a ⁇ a ⁇ a ⁇ izv ⁇ dny ⁇ azid ⁇ -Z'-W 1 - dez ⁇ si ⁇ imidina, s ⁇ de ⁇ zhaschi ⁇ m ⁇ di ⁇ itsi ⁇ vannuyu ⁇ s ⁇ a ⁇ nuyu g ⁇ u ⁇ u 5'- ⁇ l ⁇ zhenii and imenn ⁇ ⁇ - ⁇ s ⁇ na ⁇ ⁇ (Pa ⁇ en ⁇ SP ⁇ ⁇ > 5043437, C 07 ⁇ ZH ⁇ 19/00, published on 08.27.1991), and also: ⁇ .B.
  • ⁇ - ⁇ facilities can be isolated and cleaned with standard methods, for example, extraction, planting, chimney plant, etc.
  • the invention is illustrated by the following material.
  • ⁇ a ⁇ ig. 1 Comparative measures of anti-HI action of compound of Formula I in relation to HI-1 ⁇ 4046 for simultaneous application with a virue have been introduced.
  • ⁇ a ⁇ ig. 2 Comparative measures of the anti-PHI action of the connection of the formula I when entering it after the addition of the virus have been introduced.
  • ⁇ a ⁇ ig. 3 the same, the anti-BIT action of the compound of Formula II on the same time as the introduction of the virus.
  • ⁇ a ⁇ ig. 4 - the same the antithesis of the compounding of formula III on a single application with virus.
  • the present invention is based on the following methods for obtaining these compounds and the results of biochemical tests.
  • the appliance was burnt (acid chloride), they were removed, the motherboard was evaporated and the separator was separated by a large silica gel (10 volts).
  • the yield of the standard compound is 0.87 mmol (82%, ⁇ ⁇ ), the product contains about 2 molt of the material for the molten dimult. For the return payment, a half of this was taken quantity.
  • the test was carried out on silica gel (5 g of ⁇ Options in cool), eluting with 3% methanol in cold. 117 mg of the target compound (0.264 mmol, 50%) were obtained.
  • the new plants were planted, planted, and the source was allocated, and the products were allocated similarly as previously described.
  • the study of inhibition of the production of HICP includes the cultivation of primary infected lymphoid cells of the ⁇ - line
  • the final concentration of the catalytic tubes in the medium makes up 0.0001-100 micrograms / ml, while there is a single flow for 4.
  • the frequency of the product is evaluated by adding its dilutions to the ⁇ -1640 medium of the ⁇ - cell suspension
  • Example 5 The study of the influence of the claimed compounds on the production of KIC-1 in the culture of the K-4 cell.
  • the plate is placed in a temperature of 37 ° C in an atmosphere of 5% ⁇ 2 .
  • they account for the concentration and life of the cells with an oiled method.
  • the group of dependencies on the availability of life of the device is not affected by the loss of life due to the loss of life due to the loss of business due to the loss of access to the device. Dispose of the devices to protect the infected cages from the virulent cytosynthesis.
  • Compounds II (3'-azide-2 ', 3'-dehydroxy-thymidine 5'-phosphoamide (methoxyamide)) and III (3'-azide-2', 3'-dehydroxymethydine, are azidothymidine, an identical and identical one when added in addition to HIH and when added in an alternative condition.

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

Abstract

La présente invention concerne de nouveaux dérivés biologiquement actifs de 5'-phosphate de 3'-azido-3'-désoxythymidine et de 2',3'-didésoxy-2',3'-didéhydrothymidine, lesquels dérivés peuvent être utilisés comme agents antiviraux, en premier lieu contre le virus de l'immunodéficience humaine (VIH). Cette invention permet de créer et d'utiliser de nouveaux composés qui restent stables sous l'action d'enzymes de déphosphorylation, qui peuvent pénétrer à l'intérieur d'une cellule et qui présentent une activité sélective dans l'inhibition de la biosynthèse de l'ADN, qui est catalysée par la transcriptase inverse du VIH. Ces résultats sont obtenus grâce aux nouveaux composés de cette invention, à savoir les phosphoramidates d'analogues de nucléosides comprenant un 5'-phosphodimorpholidate de 2',3'-didésoxy-2',3'-didéhydrothymidine (formule I) et les phosphoramidates de 3'-azido-3'-désoxythymidine (formules II et III), qui inhibent l'activité de reproduction du virus de l'immunodéficience humaine et qui sont représentés par les formules I, II et III.
PCT/RU2003/000514 2003-06-26 2003-11-21 Phosphoramidates d'analogues de nucleosides utilises comme inhibiteurs de la reproduction du virus de l'immunodeficience humaine Ceased WO2004113360A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2003119415 2003-06-26
RU2003119415/04A RU2243972C1 (ru) 2003-06-26 2003-06-26 Фосфорамидаты нуклеозидных аналогов - ингибиторы репродукции вируса иммунодефицита человека

Publications (1)

Publication Number Publication Date
WO2004113360A1 true WO2004113360A1 (fr) 2004-12-29

Family

ID=33538137

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/RU2003/000514 Ceased WO2004113360A1 (fr) 2003-06-26 2003-11-21 Phosphoramidates d'analogues de nucleosides utilises comme inhibiteurs de la reproduction du virus de l'immunodeficience humaine

Country Status (2)

Country Link
RU (1) RU2243972C1 (fr)
WO (1) WO2004113360A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012053917A1 (fr) 2010-10-19 2012-04-26 Instytut Chemii Bioorganicznej Pan Analogue nucléotidique, leur procédé de synthèse et utilisation, pro-nucléotide antiviral, composition pharmaceutique
US11642361B2 (en) 2007-03-30 2023-05-09 Gilead Sciences, Inc. Nucleoside phosphoramidate prodrugs
US11707479B2 (en) 2013-08-27 2023-07-25 Gilead Sciences, Inc. Combination formulation of two antiviral compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5233031A (en) * 1991-09-23 1993-08-03 University Of Rochester Phosphoramidate analogs of 2'-deoxyuridine
US6455513B1 (en) * 1995-03-13 2002-09-24 University College Cardiff Consultants Ltd. Chemical compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5233031A (en) * 1991-09-23 1993-08-03 University Of Rochester Phosphoramidate analogs of 2'-deoxyuridine
US6455513B1 (en) * 1995-03-13 2002-09-24 University College Cardiff Consultants Ltd. Chemical compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHIPITSYN A.V. ET AL.: "Phosphorodiamides as prodrugs for antiviral nucleosides", NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, vol. 22, no. 5-8, 2003, pages 963 - 966, XP008071902, DOI: doi:10.1081/NCN-120022696 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11642361B2 (en) 2007-03-30 2023-05-09 Gilead Sciences, Inc. Nucleoside phosphoramidate prodrugs
US12121529B2 (en) 2007-03-30 2024-10-22 Gilead Sciences, Inc. Nucleoside phosphoramidate prodrugs
WO2012053917A1 (fr) 2010-10-19 2012-04-26 Instytut Chemii Bioorganicznej Pan Analogue nucléotidique, leur procédé de synthèse et utilisation, pro-nucléotide antiviral, composition pharmaceutique
US9206209B2 (en) 2010-10-19 2015-12-08 Instytut Chemii Bioorganicznej Pan Nucleotide analogue, method of synthesis of nucleotide analogue, use of nucleotide analogue, antiviral pro-nucleotide, pharmaceutical composition
US11707479B2 (en) 2013-08-27 2023-07-25 Gilead Sciences, Inc. Combination formulation of two antiviral compounds

Also Published As

Publication number Publication date
RU2243972C1 (ru) 2005-01-10

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