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WO1998020017A1 - Nucleoside-5'-triphosphates modifies - Google Patents

Nucleoside-5'-triphosphates modifies Download PDF

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Publication number
WO1998020017A1
WO1998020017A1 PCT/RU1997/000348 RU9700348W WO9820017A1 WO 1998020017 A1 WO1998020017 A1 WO 1998020017A1 RU 9700348 W RU9700348 W RU 9700348W WO 9820017 A1 WO9820017 A1 WO 9820017A1
Authority
WO
WIPO (PCT)
Prior art keywords
modified
nucleoside
ppm
triphosphates
sπeκτρ
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/RU1997/000348
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English (en)
Russian (ru)
Inventor
Natalia Borisovna Dyatkina
Andrey Alexandrovich Arzumanov
Elena Anatolievna Shirokova
Maxim Vladimirovich Jasko
Ludmila Alexandrovna Alexandrova
Lyubov Semenovna Victorova
Ludmila Evgenievna Goryunova
Robert Shalvovich Bibilashvili
Alexander Antonovich Krayevsky
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.)
S & T Science And Technology Inc
Original Assignee
S & T Science And Technology 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
Application filed by S & T Science And Technology Inc filed Critical S & T Science And Technology Inc
Publication of WO1998020017A1 publication Critical patent/WO1998020017A1/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
    • 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

Definitions

  • the process of converting nukleoside in the human body which corresponds to the 5'-process, takes about 1.5-2 hours. During this time, the virus that has passed into the cell is accelerated in the form of a human virus by integrating into the human gene. Is ⁇ lz ⁇ vanie in ⁇ aches ⁇ ve le ⁇ a ⁇ s ⁇ venny ⁇ ⁇ e ⁇ a ⁇ a- ⁇ v nu ⁇ le ⁇ zid 5'- ⁇ i ⁇ s ⁇ a ⁇ v with nem ⁇ di ⁇ itsi ⁇ vann ⁇ y ⁇ i ⁇ s ⁇ a ⁇ - n ⁇ y chas ⁇ yu nev ⁇ zm ⁇ zhn ⁇ due i ⁇ niz ⁇ y s ⁇ abiln ⁇ s ⁇ i ⁇ deys ⁇ viyu ⁇ e ⁇ men ⁇ v gid ⁇ liza and vsleds ⁇ vie e ⁇ g ⁇ niz ⁇ y s ⁇ s ⁇ bn ⁇ s ⁇ i ⁇ - ni ⁇ a ⁇ vnu ⁇ ⁇ le ⁇ i.
  • ⁇ thymine, adenine, uracyl, guanine, cytosine or uracil, substituted in the 5-position
  • ⁇ '" ⁇ réelle ⁇ , ⁇ gu ⁇ , ⁇ instrument ⁇ , ⁇ gu ⁇ , ⁇ instrument ⁇ , ⁇ gu ⁇ , ⁇ - ⁇ êt
  • New compounds are inhibitors or substrates of D-polymerase and anti-virus agents.
  • the new connections are activated by activating the corresponding modifying mononucleotide with only hub, ⁇ réelle ⁇ ⁇ ⁇
  • the structure of the claimed compounds is approved by the methods of UF-, YaN- and mass spectrometry.
  • transcriptase used the same way, but without a matrix.
  • the conditions of the reaction were selected depending on the properties of the corresponding D-polymer (inverse transplant).
  • the single-stranded D-phage ⁇ / ICS ⁇ (0.5 ⁇ k ⁇ ) was hybridized with a pin labeled 32 ⁇ ⁇ 5'-end (0.75 ⁇ k ⁇ ) in the following buffer: 10 m ⁇ supplemental ⁇ note- ⁇ ()) 5 exerc ⁇ ⁇ 1 2 , 40 exerc ⁇ ⁇ , 1 m ⁇ dietary (in the case of reverse transplant), 100 m ⁇ as a dilute ( ⁇ 7.2), 10 m ⁇ ⁇ 1 2 , 1 m ⁇ Ca ⁇ 1 2 and 1 m ⁇ Ca ⁇ 1 2 and 1 rate (in the case of the end of deoxynuscleletidyl transplantation), 10 m ⁇ ⁇ ris- ⁇ ( ⁇ 7.4), 6 m ⁇ ⁇ 1 2 and 0.4 m ⁇ dietitum (in the case of ⁇ - ⁇ polimerase and)), 10 8.5), 6 m ⁇ of ⁇ C1 2 and 0.4 m ⁇ of diet (in the case of D-polymerase b).
  • the dividing of the active activity of the mouse affected the mouse cells infected with the viral infection of the disease
  • Table 2 shows the results of the pressure suppression of the virus, expressed in the concentration of the studied compounds, which suppress the virus by 50 and 90%.
  • the speed of the disruption of the synthesized connections in the serial connection of the people was divided by adding 2.5 ⁇ l of 10 m of the total connection of 100% 47%.
  • the incubators were incubated at 37 ° C and after 2.5, 5, 10, 20, 30, 40, 60, min, 2, 3, 4, 5, 8, 12, hours, 2, 4, 7, and 14 days, We added responsibly 50 ⁇ l of water and 230 ⁇ l of methanol, shook and left for 30 min at -20 ° ⁇ .
  • Table 3 provides data on the speed of the hydrolysis of the reagent compounds in the undiluted plasma of a human being, which are stable in this condition. ⁇ note ⁇ , given Duration of compound retention at the third stage, and the EZH ⁇ , which denotes the degree of their hydropower.
  • Example 1 5 '- ( ⁇ -phenylamide-b, ⁇ -dibrous methylmethylenediamine-5-desoxymethyl-3' - azide-3'-deoxycythimidine.
  • the elution is driven by a linear buffer of ⁇ 4 ⁇ 0 3 , ⁇ 7.5 (0-> 0.4 ⁇ , the total volume is 600 ml) with ⁇ - ⁇ fensiv .
  • Subjects with material substance lick, is left to dissolve in 1 ml of water and applied to the tin (20 x 1.5 cm) with YSGUGEGRU ⁇ 18. Eliminates that is, it is only 2.2%. %.
  • Method 1 proceeds from the--protected 5'-disinfection-2 ', 2-desimesid-2' bis ( ⁇ ibu ⁇ ilamm ⁇ niyn ⁇ y) s ⁇ li ⁇ enil ⁇ v ⁇ g ⁇ e ⁇ i ⁇ a dib ⁇ mme ⁇ ilen- di ⁇ s ⁇ n ⁇ v ⁇ y ⁇ isl ⁇ y. ⁇ y ⁇ d mm ⁇ l 0.32, 64%.
  • Example 8 2 ', 3'-Dideoxy-4'-n ⁇ -4' - ( ⁇ -phenyl-b, ⁇ - dibrous-methyl-n-a-phenylphenylmethyl) -b-carbadenozin 1
  • the claimed modified nucleoside-5'-compounds are inhibitors of the immunodeficiency virus virus infection slaughter Canal leveka, the virus ieri of the genus ⁇ , the viruses of the herpes group and may find a name in medicine.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Virology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • AIDS & HIV (AREA)
  • General Chemical & Material Sciences (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

L'invention relève du domaine de la biologie moléculaire et de la virologie, et se rapporte plus particulièrement à de nouveaux nucléoside-5'-triphosphates qui ont été modifiés au niveau de P-α,β,ψ et du résidu de sucre, et qui répondent à la formule générale (I) dans laquelle B = thymine, adénine, uracile, guanine, cytosine ou uracile substitué en position 5; A = (II) tandis que R' = H, N3, SH, NH2, F, Cl, CN, NCO, NCS, NOH; R'' = H ou R' et R'' forment ensemble une liaison double; Z = O, CH2; R''' Alkyle, Aryle, OAlkyle, OAryle, NHAlkyle, NHAryle, O-Gly; X' = X'' = H, Br, F; ou encore X' = H, et X'' = F, Br, NH2, CH2NH2, NHAlk, NHAryle, ou encore X' = F et X'' = Br; ou encore X' = CH3 et X'' = NH2. Les nouveaux composés consistent en des inhibiteurs ou des substrats d'ADN polymérases et en des agents antiviraux; ils sont notamment capables d'inhiber la reproduction du virus de l'immunodéficience humaine dans la culture de lymphocytes chez l'homme. On obtient les nucléoside-5'-triphosphates modifiés par la condensation d'un mononucléotide modifié et activé au moyen de N,N'-carbonyldiimidazol, avec un triphosphate modifié. L'activité antivirale des nouveaux composés vis-à-vis du VIH est comparable à celle de l'azidothymidine.
PCT/RU1997/000348 1996-11-05 1997-11-05 Nucleoside-5'-triphosphates modifies Ceased WO1998020017A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU96121584 1996-11-05
RU96121584/04A RU2183213C2 (ru) 1996-11-05 1996-11-05 Модифицированные нуклеозид-5'-трифосфаты как антивирусные агенты

Publications (1)

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WO1998020017A1 true WO1998020017A1 (fr) 1998-05-14

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RU (1) RU2183213C2 (fr)
WO (1) WO1998020017A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7125857B2 (en) 1997-08-29 2006-10-24 The Regents Of The University Of California Modulators of DNA cytosine-5 methyltransferase and methods for use thereof
RU2293739C2 (ru) * 2002-07-26 2007-02-20 Закрытое акционерное общество "Производственно-коммерческая Ассоциация АЗТ" 5`-холинфосфат 3`-азидо-3`-дезокситимидина как антивирусный агент
US7285658B2 (en) 2002-02-28 2007-10-23 Biota, Inc. Nucleotide mimics and their prodrugs
EP2980095A1 (fr) 2004-03-04 2016-02-03 K.U.Leuven Research & Development Nucléotides de type phosphonates utiles en tant qu'ingrédients actifs dans des compositions pharmaceutiques pour le traitement d'infections virales et intermédiaires pour leur production

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2225808C2 (ru) * 2002-05-15 2004-03-20 Федеральное государственное унитарное предприятие "Летно-исследовательский институт им. М.М. Громова" Устройство для обеспечения посадки летательного аппарата в ночное время, универсальное, двойного применения (упла-уд)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU455958A1 (ru) * 1973-03-23 1975-01-05 Предприятие П/Я А-1758 Способ тимидин-5 " -дифосфата
EP0097376A1 (fr) * 1982-06-23 1984-01-04 Yamasa Shoyu Kabushiki Kaisha 5'-Alkyl ou alcénylphosphate nucléoside
GB2150570A (en) * 1983-05-24 1985-07-03 Stanford Res Inst Int Novel antiviral agents
DE3543346A1 (de) * 1984-12-07 1986-06-12 Boryung Pharmaceutical Co., Ltd., Seoul Neue nucleosidderivate und verfahren zu ihrer herstellung
WO1990006320A1 (fr) * 1988-11-30 1990-06-14 Kaellander Clas Fredrik Runess Substrat pour la detection de l'activite de polymerase
EP0398231A2 (fr) * 1989-05-15 1990-11-22 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Analogues nucléosides

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1548182A1 (ru) * 1987-12-29 1990-03-07 Институт молекулярной биологии АН СССР 5 @ -Фосфонаты 3 @ -азидо-2 @ ,3 @ -дидезоксинуклеозидов, вл ющиес специфическими ингибиторами вируса СПИД в культуре лимфоцитов человека Н9/ШВ

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU455958A1 (ru) * 1973-03-23 1975-01-05 Предприятие П/Я А-1758 Способ тимидин-5 " -дифосфата
EP0097376A1 (fr) * 1982-06-23 1984-01-04 Yamasa Shoyu Kabushiki Kaisha 5'-Alkyl ou alcénylphosphate nucléoside
GB2150570A (en) * 1983-05-24 1985-07-03 Stanford Res Inst Int Novel antiviral agents
DE3543346A1 (de) * 1984-12-07 1986-06-12 Boryung Pharmaceutical Co., Ltd., Seoul Neue nucleosidderivate und verfahren zu ihrer herstellung
WO1990006320A1 (fr) * 1988-11-30 1990-06-14 Kaellander Clas Fredrik Runess Substrat pour la detection de l'activite de polymerase
EP0398231A2 (fr) * 1989-05-15 1990-11-22 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Analogues nucléosides

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7125857B2 (en) 1997-08-29 2006-10-24 The Regents Of The University Of California Modulators of DNA cytosine-5 methyltransferase and methods for use thereof
US7138384B1 (en) 1997-08-29 2006-11-21 The Regents Of The University Of California Modulators of DNA cytosine-5 methyltransferase and methods for use thereof
US7285658B2 (en) 2002-02-28 2007-10-23 Biota, Inc. Nucleotide mimics and their prodrugs
US7598230B2 (en) 2002-02-28 2009-10-06 Biota Scientific Management Pty Ltd Nucleotide mimics and their prodrugs
US7807653B2 (en) 2002-02-28 2010-10-05 Biota Scientific Management Pty Ltd Nucleotide mimics and their prodrugs
EP1485395A4 (fr) * 2002-02-28 2011-04-13 Biota Scient Management Mimetiques nucleotidiques et leurs promedicaments
RU2293739C2 (ru) * 2002-07-26 2007-02-20 Закрытое акционерное общество "Производственно-коммерческая Ассоциация АЗТ" 5`-холинфосфат 3`-азидо-3`-дезокситимидина как антивирусный агент
EP2980095A1 (fr) 2004-03-04 2016-02-03 K.U.Leuven Research & Development Nucléotides de type phosphonates utiles en tant qu'ingrédients actifs dans des compositions pharmaceutiques pour le traitement d'infections virales et intermédiaires pour leur production

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RU2183213C2 (ru) 2002-06-10

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