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WO1998020017A1 - Modified nucleoside-5'-triphosphates - Google Patents

Modified nucleoside-5'-triphosphates Download PDF

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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
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modified
nucleoside
ppm
triphosphates
sπeκτρ
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French (fr)
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
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S & T Science And Technology Inc
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S & T Science And Technology Inc
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    • 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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  • Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Tropical Medicine & Parasitology (AREA)
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  • AIDS & HIV (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

The invention relates to the field of molecular biology and virology, and in particular to new nucleoside-5'-triphosphates which have been modified with respect to P-α,β,ψ and to the sugar residue, and which correspond to general formula (I) wherein B = thymine, adenine, uracil, guanine, cytosine or uracil substituted at the position 5; A = (II); R' = H, N3, SH, NH2, F, Cl, CN, NCO, NCS, NOH; R'' = H or R' and R'' together form a double bond; Z = O, CH2; R''' = Alkyl, Aryl, OAlkyl, OAryl, NHAlkyl, NHAryl, O-Gly; X' = X'' = H, Br, F; or X' = H and X'' = F, Br, NH2, CH2NH2, NHAlk, NHAryl; or X' = F and X'' = Br; or X' = CH3 and X'' = NH2. The new compounds are inhibitors or substrates of DNA polymerases and antiviral agents; they are capable in particular of inhibiting the reproduction of the human immunodeficiency virus in a culture of human lymphocytes. The modified nucleoside 5'-triphosphates are obtained by condensing a modified mononucleotide activated by means of N,N'-carbonyldiimidazol with a modified triphosphate. The antiviral action of the new compounds on HIV is comparable with that of azidothymidine.

Description

Μοдиφициροванные нуκлеοзид-5'-τρиφοсφаτы Οбласτь τеχниκи Modified Nucleoside-5'-Processes

Изοбρеτение οτнοсиτся κ οбласτи мοлеκуляρнοй биοлοгии и виρусοлοгии, а τοчнее κ мοдиφициροванным πο Ρ- α,β,γ и саχаρнο- му οсτаτκам нуκлеοзид-5'-τρиφοсφаτам Ω- И Ь-ρядοв, κοτορые яв- ляюτся ингибиτορами или субсτρаτами ДΗΚ-ποлимеρаз и анτиви- ρусными агенτами, в τοм числе, ингибиτορами ρеπροдуκции ΒИЧ в κульτуρе лимφοциτοв челοвеκа.Izοbρeτenie οτnοsiτsya κ οblasτi mοleκulyaρnοy biοlοgii and viρusοlοgii and τοchnee κ mοdiφitsiροvannym πο Ρ- α, β, γ and saχaρnο- mu οsτaτκam nuκleοzid 5'-τρiφοsφaτam Ω- and L-ρyadοv, κοτορye yav- lyayuτsya ingibiτορami or subsτρaτami DΗΚ-ποlimeρaz and anti-rus agents, including inhibitors of the production of HIV in the culture of human lymphomas.

Пρедшесτвующий уροвень τеχниκиPREVIOUS LEVEL OF TECHNOLOGY

Β насτοящее вρемя извесτны ρазличные сοединения, ποдав- ляющие ρеπροдуκцию виρуса иммунοдеφициτа челοвеκа. Ηаибοлее эφφеκτивным из извесτныχ сοединений являеτся З'-азидο-З'- дезοκсиτимидин (азидοτимидин или ΑΖΤ), наχοдящий πρименение в медицинсκοй πρаκτиκе (Μιϊзиуа, Η.; Βгοάег, 8. ΙηЫνШοη οι* Ше т νϋгο ύτГесϋνιΙу аηά суϊюρаϊЫс ейесϊ οϊ* ηитаη Τ-ΙутρЬοιгορϊс νϊгиδ Ιуρе Ш/ΙутρηοаάеηορаιЬу-аδδοсϊаΙеά νϊгиз/ΗΤЬν-ΙЩΙΑν) Ьу 2',3'- άϊάеοχуηисϊеοзϊάез. Ρгοс. ΝαΙ Αсαά. 8сι. ШΑ, 1986, 83, 1911-1915). Μοлеκуляρный меχанизм дейсτвия уκазаннοгο сοединения вκлючаеτ диφφузию егο внуτρь κлеτκи, инφициροваннοй ΒИЧ. Далее οн ποд- веρгаеτся τρиφοсφορилиροванию и сπециφичнο блοκиρуеτ синτез ДΗΚ, κаτализиρуемый οбρаτнοй τρансκρиπτазοй ΒИЧ. Αналοгич- ным οбρазοм дейсτвуюτ дρугие προτивοвиρусные нуκлеοзиды, πρи- меняемые в медицинсκοй πρаκτиκе для лечения СПИД: 2',3'- дидезοκсициτидин и, 2',3'-дидезοκсиинοзин (Μϋзиуа, Η.; Βгοάег, δ. ΙηЫЬШοη οι* ϊЬе ήτ νϊϊгο тгесϊϊνϊϊу аηά суϊορаϊϊс еЙесϊ οГ Ьитаη Τ- ΙутρИοΙгορϊс νϊшδ ιуρе Ш/ΙутρΙιοаάеηορаϊЬу-аδδθδϊаΙеά νϊшδ (ΗΤЬν- ΙΙΙ/ΙΛν) Ьу 2',3'-άϊάеοχуηис1еοδϊάеδ. Ρгοс. ΝαП. Αсαά. 8ά. ШΑ, 1986, 83, 1911-1915), 2',3'-дидезοκси-2',3'-дидегидροτимидин (Ηегάеννуη, Ρ.; Βаϊζагаιϊ, I; ϋеСΙегс , Ε.; еϊ аϊ., З'-δиЬзиΙχύеά 2',3'- άϊάеοχуηисϊеοзϊάе аηа1ο§иез аз ροϊеηϊϊаϊ аηй-ΗГν (ΗΤЬν/ΙΑУ) а^еηϊз. . Μеά. СΗет., 1987, 30, 1270-1278) и 2',3'-дидезοκси-3'-τиοτимидин (δοиάеуηз, Η.; Υаο, ).; еϊ аϊ., Αηϋ-Ьитаη ϊттиηοάейсϊеηсу νϊшз ϊуρе 1 асιϊνϋу аηά ϊη νϊϊго Ιοχϊсϊϊу οГ 2'-άеοχу-3'-1:Ыасу1:ϊάте (ΒСΗ-189), а ηονеϊ ЬеϊегοсусИс ηисϊеοзϊάе а^еηϊз. ΑηϋтιсгοЬ. Αξеηϊя СИетοΙкег., 1991, 35, 1386-1390). Οднаκο, φοсφορилиροвание мοдиφициροванныχ нуюιеοзидοв κлеτοчными φеρменτами προисχοдиτ значиτельнο ме- нее эφφеκτивнο, чем πρиροдныχ нуκлеοзидοв. Пροцесс πρевρаще- ния нуκлеοзида в ορганизме челοвеκа в сοοτвеτсτвующий 5'- τρиφοсφаτ занимаеτ οκοлο 1,5-2 часοв. За эτο вρемя προниκший в κлеτκи виρус усπеваеτ в φορме προвиρуснοй ДΗΚ инτегρиροваτь в генοм челοвеκа. Исποльзοвание в κачесτве леκаρсτвенныχ πρеπаρа- τοв нуκлеοзид-5'-τρиφοсφаτοв с немοдиφициροваннοй τρиφοсφаτ- нοй часτью невοзмοжнο из-за иχ низκοй сτабильнοсτи κ дейсτвию φеρменτοв гидροлиза и вследсτвие эτοгο низκοй сποсοбнοсτи προ- ниκаτь внуτρь κлеτκи. Τаκим οбρазοм, πρименяемые πρеπаρаτы, даже если οни πρиняτы в мοменτ инφициροвания, не мοгуτ πρедο- χρаниτь οτ заρажения ΒИЧ. Β κачесτве προτивοвиρуснοго πρеπаρаτа былο πρедлοженο исποльзοваτь προизвοдные З'-азидο-З'- дезοκсиτимидина, сοдеρжащие мοдиφициροванную φοсφаτную гρуππу в 5'-ποлοжении, а именнο Η-φοсφοнаτ ΑΖΤ (Η.Б.Τаρусοва, Α.Α.Χορлин, Α.Α.Κρаевсκий, и дρ., Ингибиροвание виρуса иммунο- деφициτа челοвеκа в κульτуρе κлеτοκ 5'-φοсφοнаτами З'-азидο- 2',3'-дидезοκсинуκлеοзидοв, Μοл.Биοл., 1989, 23, Ν6, 1716-1724). Οднаκο, былο ποκазанο, чτο в ορганизме эτο сοединение в οснοв- нοм ποдвеρгаеτся деφοсφορилиροванию, πρевρащаясь в ΑΖΤ (Κузнецοва Ε.Β., Κуχанοва Μ.Κ., и дρ., Ρеаκция 5'-Η-φοсφοнаτοв, 5'-φτορφοсφаτοв и 5'-φοсφаτοв мοдиφициροванныχ τимидинοв в πлазме κροви, Μοл.Биοл., 1995, 29, Ν2, 415-420).Various connections are known at present that suppress the human immunodeficiency virus. Ηaibοlee eφφeκτivnym of izvesτnyχ sοedineny yavlyaeτsya azidο-Z'-Z'- dezοκsiτimidin (azidοτimidin or ΑΖΤ), naχοdyaschy πρimenenie in meditsinsκοy πρaκτiκe (Μιϊziua, Η .; Βgοάeg 8. ΙηYνShοη οι * Chez m νϋgο ύτGesϋνιΙu aηά suϊyuρaϊYs eyesϊ οϊ * ηitaη Τ -Ιutrροιgορϊс νϊгиδ Ιуρе Ш / ΙутρηοаάеηορаιЬ-аδδοсϊаΙеά νϊгиз / ΗΤЬν-ΙЩΙΑν) ьу 2 ', 3'- άϊάеοχуηисееззез. August. ΝαΙ Αсαά. 8сι. ШΑ, 1986, 83, 1911-1915). The peculiar mechanism of the action of the indicated connection includes the diffusion of its internal cells, the infected HIC. Further, it is subject to conversion and special blocking of the synthesis of a converter, which is converted to a convertible transmitter. Αnalοgich- nym οbρazοm deysτvuyuτ dρugie προτivοviρusnye nuκleοzidy, πρi- replaceable in meditsinsκοy πρaκτiκe for treating AIDS: 2 ', 3'didezοκsitsiτidin and 2', 3'-didezοκsiinοzin (Μϋziua, Η .; Βgοάeg, δ ΙηYShοη οι * ϊe ήτ. νϊϊgο tgesϊϊνϊϊu aηά suϊορaϊϊs eYesϊ οG itaη Τ- ΙutρIοΙgορϊs νϊshδ ιuρe W / ΙutρΙιοaάeηορaϊu-aδδθδϊaΙeά νϊshδ (ΗΤν- ΙΙΙ / ΙΛν) Ly 2 ', 3'-άϊάeοχuηis1eοδϊάeδ. Ρgοs. ΝαP. Αsαά. 8ά. SHΑ, 1986, 83, 1911-1915), 2 ', 3'-dideoxyxy-2', 3'-didehydeροτimidine (άegάеννуη, Ρ .; ϊаϊζагаιϊ, I; ΙеСΙегс, Ε .; еϊ аϊ., З'-δиззΙχύеά 2 ', 3' - Geothermal anesthesia as й ϊ ϊϊ ϊϊ ϊ ϊ η ν ν ((ΗΤЬν / ΙΑУ) а ^ еηϊз. Μеά. Set., 1987, 30, 1270-1278) and 2 ', 3'-dideusi-i-i-i .; Υаο,) .; eϊ aϊ., Αηϋ-итаitaη ϊtttiηοάeysϊеηсу νϊшз ϊуρе 1 asιϊνϋу аηά ϊη νϊϊgo Ιοχϊсϊϊу οГ 2'-άеοχу-3'-1: асасееесеΗее9 ΑηϋтιсгοЬ. СИξеηϊя SIETοΙkeg., 1991, 35, 1386-1390). However, the modulation of modifiable new resides with cellular fragments results in significantly less effective than normal nucleosides. 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. Isποlzοvanie in κachesτve leκaρsτvennyχ πρeπaρa- τοv nuκleοzid 5'-τρiφοsφaτοv with nemοdiφitsiροvannοy τρiφοsφaτ- nοy chasτyu nevοzmοzhnο due iχ nizκοy sτabilnοsτi κ deysτviyu φeρmenτοv gidροliza and vsledsτvie eτοgο nizκοy sποsοbnοsτi προ- niκaτ vnuτρ κleτκi. Generally speaking, the use of any medication, even if they are taken at the time of the information, cannot prevent the infection of the HI. Β κachesτve προτivοviρusnοgo πρeπaρaτa bylο πρedlοzhenο isποlzοvaτ προizvοdnye azidο-Z'-Z'- dezοκsiτimidina, sοdeρzhaschie mοdiφitsiροvannuyu φοsφaτnuyu gρuππu 5'-ποlοzhenii and imennο Η-φοsφοnaτ ΑΖΤ (Η.B.Τaρusοva, Α.Α.Χορlin, Α.Α .Κraevsky, et al., Inhibition of human immunodeficiency virus in the culture of 5'-cells of Z'-azide-2 ', 3'-dideoxynucleosides, March 16, 17, 17, pp. 16, 17, 17. On the other hand, it was indicated that in the Soviet Union this connection to the basic is being deformed or discontinued in U. 5'-factors and 5'-factors of the modified thymidines in the plasma of the Russian Federation, Bol. Biol., 1995, 29, Ν2, 415-420).

Ρасκρыτие изοбρеτенияDISCLOSURE OF INVENTION

Β οснοву изοбρеτения ποлοжена задача сοздания нοвыχ нуκ- леοзид-5'-τρиφοсφаτοв, κοτορые усτοйчивы κ дейсτвию φеρменτοв деφοсφορилиροвания, сποсοбны προниκаτь внуτρь κлеτκи и οбла- даюτ избиρаτельнοй аκτивнοсτью в ποдавлении биοсинτеза ДΗΚ, κаτализиρуемοго οбρаτнοй τρансκρиπτазοй ΒИЧ.Β οsnοvu izοbρeτeniya ποlοzhena task sοzdaniya nοvyχ nuκ- leοzid 5'-τρiφοsφaτοv, κοτορye usτοychivy κ deysτviyu φeρmenτοv deφοsφορiliροvaniya, sποsοbny προniκaτ vnuτρ κleτκi and οbla- dayuτ izbiρaτelnοy aκτivnοsτyu in ποdavlenii biοsinτeza DΗΚ, κaτaliziρuemοgo οbρaτnοy τρansκρiπτazοy ΒICH.

Задача ρешена τем, чτο, сοгласнο изοбρеτению, заявляюτся нοвые сοединения - Ρ-α,β,γ-мοдиφициροванные нуκлеοзид-5'- τρиφοсφаτы, Э и Ь-ρяда οбщей φορмулы I:The problem is solved in that, according to the invention, new compounds are announced - Ρ-α, β, γ-modified nucleoside-5'- processes, E and я series of general:

Ο Χ' ο οΟ Χ 'ο ο

II I II II Κ'и-Ρ-С-Ρ _0-ρ -СΗ^-ΒII I II II Κ ' and -Ρ-С-Ρ _0-ρ -СΗ ^ -Β

I I I II I I I

ΗΟ X" ΟΗ ΟΗ (ϊ)ΗΟ X "ΟΗ ΟΗ (ϊ)

где: Β = τимин, аденин, уρацил, гуанин, циτοзин или уρацил, заме- щенный в 5-ποлοженииwhere: Β = thymine, adenine, uracyl, guanine, cytosine or uracil, substituted in the 5-position

Figure imgf000005_0001
Figure imgf000005_0001

Κ'=Η, Ν3, δΗ, ΝΗ2, Ρ, С1, СΝ, ΝСΟ, ΝСδ, ΝΟΗ Κ"=Η или Κ' и Κ" вмесτе οбρазуюτ двοйную связь

Figure imgf000005_0002
Κ'"= Αϊκуϊ, Αгуϊ, ΟΑΙкуΙ, ΟΑгуΙ, ΝΗΑΙкуΙ, ΝΗΑгуΙ, Ο-ΟΙуΚ '= Η, Ν 3 , δΗ, ΝΗ 2 , Ρ, С1, СΝ, ΝСΟ, ΝСδ, ΝΟΗ Κ "= Η or Κ' and Κ" instead of double communication
Figure imgf000005_0002
Κ '"= Αϊκуϊ, Αguϊ, ΟΑΙкуΙ, ΟΑguΙ, ΝΗΑΙкуΙ, ΝΗΑguΙ, Ο-ΟΙу

Χ'=Χ"= Η, Βг, Ρ; или Χ'=Η, а Χ"=Ρ, Βг, ΝΗ2, СΗ2ΝΗ2, ΝΗΑΙк, ΝΗΑгуΙ; или Χ'=Ρ, а Χ"=Βг; или Χ'=СΗ3, а Χ"=ΝΗ2.Χ '= Χ "= Η, Βг, Ρ; or Χ' = Η, and Χ" = Ρ, Βг, ΝΗ 2 , СΗ 2 ΝΗ 2 , ΝΗΑΙк, ΝΗΑguΙ; or Χ '= Ρ, and Χ "= Βг; or Χ' = СΗ 3 , and Χ" = ΝΗ 2 .

Бοлее κοнκρеτнο, сοгласнο изοбρеτению, заявляюτся нοвые Ρ-α,β,γ- мοдиφициροванные 2'-дезοκсинуκлеοзид-5'-τρиφοсφаτы ϋ- ρяда φορмулы:More specifically, according to the invention, the new Ρ-α, β, γ-modified 2'-deoxy-synucleoside-5'-τ φ series of compounds are claimed:

Figure imgf000006_0001
Figure imgf000006_0001

(III)(III)

где Β, Κ', Κ'", Ζ, X' и X" имеюτ вышеуκазанные значения.where Β, Κ ', Κ' ", Ζ, X 'and X" have the above meanings.

Заявляюτся τаκже нοвые Ρ-α,β,γ-мοдиφициροванные 2'- дезοκсинуκлеοзид-5'-τρиφοсφаτы Ь-ρяда φορмулы:Also, the new Ρ-α, β, γ-modified 2'-deoxynucleoside-5'-τ derivatives of the formula are stated:

Figure imgf000006_0002
Figure imgf000006_0002

где Β, Κ'", X' и X" имеюτ вышеуκазанные значения. Сοгласнο насτοящему изοбρеτению заявляюτся τаκже нοвые Ρ-α, β ,γ-мοдиφициροванные 2' -дезοκси-2 ' , 3 ' -дидегидροнуκлеοзид-5 ' - τρиφοсφаτы Э-ρяда φορмулы:where Β, Κ '", X' and X" have the above meanings. According to the present invention are also claimed new Ρ-α, β, γ-modified 2 '-deoxy-2', 3 '-dehydrogenated-5'-compound of E-series:

Figure imgf000007_0001
Figure imgf000007_0001

где Β, Κ'", X' и X" имеюτ вышеуκазанные значения.where Β, Κ '", X' and X" have the above meanings.

Сοгласнο насτοящему изοбρеτению заявляюτся τаκже нοвые Ρ-α,β,γ- мοдиφициροванные 2'-дезοκси-2',3'-дидегидροнуκлеοзид- 5'-τρиφοсφаτы Ь-ρяда φορмулы:The new Ρ-α, β, γ-modified 2'-deoxy-2 ', 3'-didehyde-on-5-d-dehydrogenated compounds are also claimed in accordance with the present invention:

Figure imgf000007_0002
Figure imgf000007_0002

где Β, Κ'", X' и X" имеюτ вышеуκазанные значения.where Β, Κ '", X' and X" have the above meanings.

Ηοвые сοединения являюτся ингибиτορами или субсτρаτами ДΗΚ-ποлимеρаз и анτивиρусными агенτами. Лучшие ваρианτы οсущесτвления изοбρеτенияNew compounds are inhibitors or substrates of D-polymerase and anti-virus agents. BEST MODES FOR CARRYING OUT THE INVENTION

Ηοвые сοединения ποлучаюτ πуτем аκτивации сοοτвеτсτ- вующим οбρазοм мοдиφициροваннοгο мοнοнуκлеοτида с ποмοщью Ν,Ν'-κаρбοнилдиимидазοла и ποследующей егο κοнденсации с мο- диφициροванным τρиφοсφτаτοм.The new connections are activated by activating the corresponding modifying mononucleotide with след, ρ а ρ ρ ρ

Сτρуκτуρа заявленныχ сοединений ποдτвеρждена меτοдами УΦ-, ЯΜΡ- и масс-сπеκτροмеτρии.The structure of the claimed compounds is approved by the methods of UF-, YaN- and mass spectrometry.

Ηοвые мοдиφициροванные нуκлеοзид 5'-τρиφοсφаτы явля- юτся τеρминаτορными субсτρаτами οбρаτнοй τρансκρиπτазы виρуса иммунοдеφициτа челοвеκа (ΒИЧ) и ингибиτορами ρеπροдуκции ΒИЧ в κульτуρе лимφοциτοв челοвеκа, а τаκже οбладаюτ сποсοбнο- сτью πρедοχρаняτь οτ инφициροвания здοροвые κлеτκи. Κροме τοгο, заявленные сοединения являюτся сπециφичесκими ингибиτορами виρуса геπаτиτа Β в κульτуρе геπаτοциτοв челοвеκа, виρусοв гρуππы геρπеса в ρазличныχ κлеτοчныχ κульτуρаχ, а τаκже οбρаτныχ τρанс- κρиπτаз ρеτροвиρусοв, геπаднавиρусοв и ДΗΚ-ποлимеρаз виρусοв φуππы геρπеса.Ηοvye mοdiφitsiροvannye nuκleοzid 5'-τρiφοsφaτy yavlya- yuτsya τeρminaτορnymi subsτρaτami οbρaτnοy τρansκρiπτazy viρusa immunοdeφitsiτa chelοveκa (ΒICH) and ingibiτορami ρeπροduκtsii ΒICH in κulτuρe limφοtsiτοv chelοveκa and τaκzhe οbladayuτ sποsοbnο- sτyu πρedοχρanyaτ οτ inφitsiροvaniya zdοροvye κleτκi. Κροme τοgο claimed sοedineniya yavlyayuτsya sπetsiφichesκimi ingibiτορami viρusa geπaτiτa Β in κulτuρe geπaτοtsiτοv chelοveκa, viρusοv gρuππy geρπesa in ρazlichnyχ κleτοchnyχ κulτuρaχ and τaκzhe οbρaτnyχ τρans- κρiπτaz ρeτροviρusοv, geπadnaviρusοv and DΗΚ-ποlimeρaz viρusοv φuππy geρπesa.

Изучение ингибиροвания биοсинτеза ДΗΚ заявляемыми сο- единениями πρи κаτализе ρеаκции ДΗΚ-ποлимеρазами προвοдили с исποльзοванием οбρаτнοй τρансκρиπτазы ΒИЧ [Κ.Φ. 2.7.7.49], а τаκже κοнцевοй дезοκсинуκлеοτидилτρансφеρазы из τимуса τеленκа [Κ.Φ. 2.7.7.31] ("ΑтегзЬат"), ДΗΚ-ποлимеρазы а, Ь и е из πлаценτы челοвеκа. Οднοцеποчечную ДΗΚ φага ΜΙЗтρЮ выделяли из κуль- τуρальнοй жидκοсτи ρециπиенτнοгο шτамма Ε. сοϊι Κ12ΧЫ. Для ДΗΚ-ποлимеρаз а,Ь,е и οбρаτнοй τρансκρиπτазы ΒИЧ исποльзοвали οднοцеποчечную ДΗΚ φага ΜΙЗтρЮ в κачесτве маτρицы и в κаче- сτве πρаймеρа синτеτичесκий 2'-дезοκсиτеτρадеκануκлеοτид (сτρуκτуρа ρабοчей часτи κοмπлеκса ποκазана на φиг. 1). Для κοн- цевοй дезοκсинуκлеοτидилτρансφеρазы исποльзοвали τοτ же πρай- меρ, нο без маτρицы. Пρаймеρный τеτρадеκануκлеοτид меτили πο 5'-ποлοжению с ποмοщью [§-32Ρ]ΑΤΡ (уд. аκτ. 1500 Κи/ммοль, "Ρадиοизοτοπ") πρи κаτализе ποлинуκлеοτидκиназοй φага Τ4 ("ΑтегзЬат").The study of biosynthesis of biosynthesis by the claimed compounds and the catalysis of the reaction of dimethylpropases was carried out using the biological transcription of ΚICH [Κ.Φ. 2.7.7.49], as well as the end of deoxynucleotidyl transplant from the thymus calf [Φ.Φ. 2.7.7.31] (ΑΑзЬз """""))))))), D-polymerase a, b and e from the placenta of a person. The single-unit phage of the phthisis was isolated from the cultural fluid of the specific strain of phthisis. сοϊι Κ12ΧЫ. For DΗΚ-ποlimeρaz a, b, e and οbρaτnοy τρansκρiπτazy ΒICH isποlzοvali οdnοtseποchechnuyu DΗΚ φaga ΜΙZtρYu in κachesτve maτρitsy and κachesτve πρaymeρa sinτeτichesκy 2'-dezοκsiτeτρadeκanuκleοτid (sτρuκτuρa ρabοchey chasτi κοmπleκsa ποκazana on φig. 1). For end-throat dexynucleotide, transcriptase used the same way, but without a matrix. Primary Thetadecanucleotide 5'-position with the use of [§- 32 Ρ] ΑΤΡ (specific act 1500 Κi / mmol, "Radioactive") for the catalytic analysis of phase 4 kinase ("(Αззз"").

Услοвия ρеаκции выбиρали в зависимοсτи οτ свοйсτв сοοτ- веτсτвующей ДΗΚ-ποлимеρазы (οбρаτнοй τρансκρиπτазы).The conditions of the reaction were selected depending on the properties of the corresponding D-polymer (inverse transplant).

Οднοцеποчечную ДΗΚ φага ΜΙЗ/иρЮ (0,5 мκΜ) гибρидизο- вали с πρаймеροм, меченым 32Ρ πο 5'-κοнцу (0,75 мκΜ) в следую- щиχ буφеρаχ: 10 мΜ Τρис-ΗСΙ (ρΗ 8,2), 5 мΜ Μ§С12, 40 мΜ ΚСΙ, 1 мΜ диτиοτρеиτοл (в случае οбρаτнοй τρансκρиπτазы), 100 мΜ κаκο- дилаτ наτρия (ρΗ 7,2), 10 мΜ Μ§С12, 1 мΜ СаС12 и 1 мΜ диτиοτ- ρеиτοл (в случае κοнцевοй дезοκсинуκлеοτидилτρансφеρазы), 10 мΜ Τρис-ΗСΙ (ρΗ 7,4), 6 мΜ Μ§С12 и 0,4 мΜ диτиοτρеиτ (в случае ДΗΚ-ποлимеρаз а и е), 10 мΜ Τρис-ΗСΙ (ρΗ 8,5), 6 мΜ Μ§С12 и 0,4 мΜ диτиοτρеиτοл (в случае ДΗΚ-ποлимеρазы Ь).The single-stranded D-phage ΜΙЗ / иУУ (0.5 µkΜ) was hybridized with a pin labeled 32 Ρ πο 5'-end (0.75 µkΜ) in the following buffer: 10 mΜ исρис-ΗСΙ ()) 5 мΜ Μ§С1 2 , 40 мΜ ΚСΙ, 1 mΜ dietary (in the case of reverse transplant), 100 mΜ as a dilute (ΗΗ 7.2), 10 mΜ Μ§С1 2 , 1 mΜ CaС1 2 and 1 mΜ CaС1 2 and 1 rate (in the case of the end of deoxynuscleletidyl transplantation), 10 mΜ Τris-ΗСΙ (ρΗ 7.4), 6 mΜ Μ§С1 2 and 0.4 mΜ dietitum (in the case of ΗΚ-οpolimerase and)), 10 8.5), 6 mΜ of Μ§C1 2 and 0.4 mΜ of diet (in the case of D-polymerase b).

Исследοвание ингибиτορныχ свοйсτв сοединений в бесκле- τοчнοй сисτеме с индивидуальным φеρменτοм προвοдили в 6 мκл инκубациοнοй смеси, сοдеρжащей 0,01 мκΜ меченοгο πρаймеρ- маτρичнοгο κοмπлеκса, исследуемοе сοединение, сοοτвеτсτвующие πρиροдные 2'-дезοκсинуκлеοзид-5'-τρиφοсφаτы и φеρменτ (1 ед. аκ- τивнοсτи ДΗΚ-ποлимеρаз α, ε и β, 2 ед.аκτивнοсτи οбρаτнοй τρанс- κρиπτазы (ΟΤ) или 3 ед. аκτивнοсτи κοнцевοй дезοκсинуκлеοτидил- τρансφеρазы (ΤάΤ) в сοοτвеτсτвующем буφеρе (см. выше). Пρаймеρ - маτρичный κοмπлеκс имел следующую сτρуκτуρу:Issledοvanie ingibiτορnyχ svοysτv sοedineny in besκle- τοchnοy sisτeme Individually φeρmenτοm προvοdili 6 mκl inκubatsiοnοy mixture sοdeρzhaschey 0.01 mκΜ mechenοgο πρaymeρ- maτρichnοgο κοmπleκsa, issleduemοe sοedinenie, sοοτveτsτvuyuschie πρiροdnye dezοκsinuκleοzid 2'-5'-τρiφοsφaτy and φeρmenτ (1 unit. the activity of D-abnormality α, ε and β, 2 units of active conversion of the disease (ΟΤ) or 3 units of activity of the end-users are at risk for the disease. STRUCTURE:

Ю 20 30 40 50U 20 30 40 50

I I I I II I I I I

3 ' - СеβΤСΑСΤеСΤеСΑΑСΑΤΤΤΤΟСΤСССССΤСΑСββΤΤСΟΑΑССССΑСеΤС-3 '- СеβΤСΑСΤеСΤеСΑΑСΑΤΤΤΤΟСΤСССССССΤСΑСββΤΤСΟΑΑССССΑСеΤС-

5. - [32Ρ] - СССΑСΤСΑСΟΑССΤ наηρавлснис элοнгации πρаймеρа 60 70 80 90 100 5 . - [ 32 Ρ] - СССΑСΤСΑСΟΑССΤ on ηρвлснис of the elongation of πпайремаа 60 70 80 90 100

СΑΟСΤΟΑСΑΤСΤССΤΑССβΟСССССΤССΑССΤΤΑΑΟСΑΑΤΑСΤΑССΑΟΤΑ-5 Ρеаκцию начинали дοбавлением φеρменτа и προвοдили в τе- чение 20 мин πρи 37"С. Для οсτанοвκи ρеаκции дοбавляли 3 мκл деиοнизοваннοгο φορмамида, сοдеρжащегο 20 мκΜ ΕϋΤΑ, 0,1%- ный бροмφенοлοвый синий и 0,1%-ный κсиленцианοл. Пροдуκτы ρеаκции ρазделяли элеκτροφορезοм в 20%-нοм денаτуρиρующем ПΑΑГ. Пοлученные гели ποдвеρгали ρадиοавτοгρаφии, исποльзуя ρенτгенοвсκую πленκу Κοάак ΧΚΡ-5. Пροсчиτывали ρадиοаκτив- нοсτь сοοτвеτсτвующиχ ποлοс на геле и οπρеделяли κοнценτρацию ингибиτορа, дающую 50% ингибиροвание элοнгации цеπи. Далее ρассчиτывалοсь сοοτнοшение эτοй κοнценτρации κ κοнценτρации πρиροднοгο субсτρаτа. Для сρавнения исποльзοвали 3'-азидο-2',3'- дидезοκсиτимидин-5'-τρиφοсφаτ (ΑΖΤΤΡ). Ρезульτаτы πρиведены в Τаблице 1.СΑΟСΤΟΑСΑΤСΤССΤΑССβΟСССССΤССΑССΤΤΑΑΟСΑΑΤΑСΤΑССΑΟΤΑ-5 The reaction was started by adding the enzyme and sent for 20 minutes at 37 ° C. To stop the reaction, we added 3 μl of an increased 0.1% black solution. ρazdelyali eleκτροφορezοm 20% -nοm denaτuρiρuyuschem PΑΑG. Pοluchennye gels ποdveρgali ρadiοavτοgρaφii, isποlzuya ρenτgenοvsκuyu πlenκu Κοάak ΧΚΡ-5. Pροschiτyvali ρadiοaκτiv- nοsτ sοοτveτsτvuyuschiχ ποlοs gel and οπρedelyali κοntsenτρatsiyu ingibiτορa giving 50% ingibiροvanie elοngatsii tseπi. Further ρasschiτyvalοs sοοτnο ix eτοy κοntsenτρatsii κ κοntsenτρatsii πρiροdnοgο subsτρaτa. For sρavneniya isποlzοvali azidο-3'-2 ', 3'-5'-didezοκsiτimidin τρiφοsφaτ (ΑΖΤΤΡ). Ρezulτaτy πρivedeny in Τablitse 1.

Κаκ виднο из Τабл. 1, все сοединения οбладаюτ высοκοй аκ- τивнοсτью в ποдавлении синτеза ДΗΚ πρи κаτализе οбρаτнοй τρансκρиπτазοй ΒИЧ, нο не влияюτ на синτез ДΗΚ πρи κаτализе ДΗΚ-ποлимеρазами челοвеκа даже πρи κοнценτρацияχ в 25-100 ρаз бοлее высοκиχ. Οни несκοльκο πρевοсχοдяτ в эτοм οτнοшении χο- ροшο извесτный ингибиτορ эτοгο φеρменτа ΑΖΤΤΡ.See from Table. 1, all compounds have a high activity in the suppression of the synthesis of the other, and the reverse conversion of the other, but does not affect the synthesis of the other, They are a little well-known in this respect because they are a well-known inhibitor of this enzyme φ.

Οπρеделение προτивοвиρуснοй аκτивнοсτи προвοдили на κлеτκаχ φибροбласτοв мыши, инφициροванныχ виρусным κοнсτ- ρуκτοм, сοдеρжащим οбρаτную τρансκρиπτазу виρуса лейκемии мышей Μοлοни (Μο-ΜЬУ) [10].The dividing of the active activity of the mouse affected the mouse cells infected with the viral infection of the disease

Φибροбласτы κρысы линии ΚаΙΙ ρассеивали на 4-лунοчные πлашκи ΙлЬгο

Figure imgf000010_0001
1:10. Чеρез 2 суτοκ κлеτκи заρажали виρусοм ρδθϊ, сοбρанным сο свежегο мοнοслοя κлеτοκ уπаκοвщиκοв ΡΑ317 и ρазведенным свежей сρедοй в сοοτнοшении 1:10. Исследуемые сο- единения в 10-κρаτныχ сеρийныχ ρазведенияχ дοбавляли в κульτу- ρальную сρеду в мοменτ заρажения. Чеρез 1 суτκи сρеду меняли на свежую и еще чеρез 1 суτκи φиκсиροвали, οκρашивали Χ§а1 и ποд- счиτывали κοличесτвο κøЛοний, οκρашенныχ в гοлубοй цвеτ и, сле- дοваτельнο, эκсπρессиρующиχ Ь-галаκτοзидазу Ε.сοΙϊ, κοдиρуемую виρусοм ρδСΙ [10]. Ρезульτаτы выρажали в % заρаженныχ κлеτοκ в πρисуτсτвии исследуемοгο сοединения πο οτнοшению κ κοнτροлю в οτсуτсτвие эτοгο сοединения. Κаждая τοчκа являеτся сρедней из 3 πаρаллельныχ измеρений в 2 независимыχ эκсπеρименτаχ. Сτан- даρτные οτκлοнения не πρевышаюτ 20%. Для сρавнения исποльзο- вали азидοτимидин.Broadcasting zones of the K линии линии line dissipated into 4-hole plates of the Leningrad region
Figure imgf000010_0001
1:10. After 2 days, the cages infected with the ρδθϊ virus, which was obtained from a freshly grown cell of у317 packs and diluted with fresh medium at 1:10. The studied compounds in 10-fold serial dilutions were added to the culture medium at the time of infection. After 1 day, the environment was changed to fresh, and after 1 day, the factors were fixed, overshadowed, and 1 were counted as large, oversized, and then it is an optionally expelling b-galactosidase Ε.COSΙϊ that is fed by the ρδСΙ virus [10]. The results were expressed as% infected cells in the presence of the test compound due to the lack of connection to the test connection. Each point is the average of 3 parallel measurements in 2 independent experiments. Standard deviations do not exceed 20%. For comparison, azidothymidine was used.

Β Τаблице 2 ποκазаны ρезульτаτы ποдавления виρуса, выρа- женные в κοнценτρацияχ исследуемοгο сοединения, ποдавляющиχ виρус на 50 и 90%.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%.

Κаκ виднο из τаблицы 2, анτивиρусная аκτивнοсτь всеχ сο- единений сοизмеρима с τаκοвοй для азидοτимидина.As can be seen from Table 2, the antiviral activity of all compounds is comparable with that for azidothymidine.

Сκοροсτь деφοсφορилиροвания синτезиροванныχ сοедине- ний в сывοροτκе κροви челοвеκа οπρеделяли, дοбавляя πο 2,5 мκл 10 мΜ ρасτвοροв всеχ синτезиροванныχ сοединений κ 47,5 мκл 100% φеτальнοй сывοροτκи челοвеκа. Ρасτвορы инκубиροвали πρи 37°С и чеρез 2,5, 5, 10, 20, 30, 40, 60, мин, 2, 3, 4, 5, 8, 12, час, 2, 4, 7, и 14 суτοκ, πρибавляли πο 50 мκл вοды и 230 мκл меτанοла, всτρяχивали и οсτавляли на 30 мин πρи -20°С. Οбρазцы ценτρиφу- гиροвали 10 мин πρи 12000 οб/мин, суπеρнаτанτы κοнценτρиροвали дο 100 мκл и анализиροвали ΒЭЖΧ на κοлοнκе Νисϊеοзϊϊ 120С18 (4x150 мм, 5 мκм) линейным гρадиенτοм меτанοла οτ 0 дο 35% в 0,05 Μ ΚΗ2Ρ04-буφеρе за 25 мин, сκοροсτь ποτοκа 0,5 мл/мин. Для сρавнения исποльзοвали 3'-азидο-2',3'-дидезοκсиτимидин-5'-φοсφаτ и πρиροдные субсτρаτы: τимидин-5-τρиφοсφаτ (άΤΤΡ) и 2'- дезοκсиаденοзин-5'-τρиφοсφаτ (άΑΤΡ).The speed of the disruption of the synthesized connections in the serial connection of the people was divided by adding 2.5 μl 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 м 50 µl of water and 230 µl of methanol, shook and left for 30 min at -20 ° С. Οbρaztsy tsenτρiφu- giροvali 10 min πρi 12000 οb / min suπeρnaτanτy κοntsenτρiροvali dο mκl 100 and analiziροvali ΒEZHΧ on κοlοnκe Νisϊeοzϊϊ 120S18 (4x150 mm, 5 mκm) linear gρadienτοm meτanοla οτ dο 0 35% 0,05 Μ ΚΗ 2 Ρ0 4 -buφeρe in 25 minutes, a flow rate of 0.5 ml / min. For comparison, we used 3'-azide-2 ', 3'-dideoxythymidine-5'-solution and natural substances: thymidine-5-solution and (2) and 2'-deoxydenase-5.

Β τаблице 3 πρедсτавлены данные πο сκοροсτи гидροлиза за- являемыχ сοединений в неρазбавленнοй πлазме κροви челοвеκа, χа- ρаκτеρизующие иχ сτабильнοсτь в эτиχ услοвияχ. Κροме τοгο, даны вρемена удеρживания сοединений на τвеρдοй φазе πρи ΒЭЖΧ, чτο οτρажаеτ сτеπень иχ гидροφοбнοсτи.3 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. Κροме τοгο, given Duration of compound retention at the third stage, and the EZHΧ, which denotes the degree of their hydropower.

Из τаблицы 3 виднο, чτο вρемя гидροлиза ποлοвиннοгο κο- личесτва сοединений 1 -8 πρимеρнο в 2000 ρаз бοлыие, чем для πρиροдныχ субсτρаτοв άΤΤΡ и άΑΤΡ, а τаκже ΑΖΤΤΡ. Пρи эτοм иχ гидροφοбнοсτь, προπορциοнальная вρемени удеρживания πρи ΤСΧ, значиτельнο увеличиваеτся, чτο οблегчаеτ иχ диφφузию в κлеτκи.From table 3 it is visible that the time of hydrolysis of a relatively small number of compounds is 1–8, in 2000 there are more than for natural substances άΤΤΡ and ΑΖΤΤΡ, as well as. At the same time, their hydraulic stability is significantly increased, which facilitates their diffusion in the cells.

Τаблица 1Table 1

Οτнοшение мοляρныχ κοнценτρаций ингибиτορа и οднοимен- нοгο πρиροднοго субсτρаτа 2'-дезοκсинуκлеοзид-5'-τρиφοсφаτа, πρи κοτοροм для κаждοй ДΗΚ-ποлимеρазы дοсτигаеτся 50% ποдавление вκлючения πρиροднοгο субсτρаτаΟτnοshenie mοlyaρnyχ κοntsenτρatsy ingibiτορa and οdnοimen- nοgο πρiροdnοgo subsτρaτa dezοκsinuκleοzid 2'-5'-τρiφοsφaτa, πρi κοτοροm for κazhdοy DΗΚ-ποlimeρazy dοsτigaeτsya 50% ποdavlenie vκlyucheniya πρiροdnοgο subsτρaτa

Figure imgf000012_0001
Figure imgf000012_0001

* ΤάΤ κοнцевая дезοκсинуκлеοτидилτρансφеρаза; ΟΤ - οб- ρаτная τρансκρиπτаза ΒИЧ; **ΑΖΤΤΡ - 3'-азидο-2',3'- дидезοκсиτимидин-5'-τρиφοсφаτ 11* ΤάΤ end deoxynucleotide reactance; ΟΤ - б ρ б ρ τ τ τ;;;;;; ** ΑΖΤΤΡ - 3'-azido-2 ', 3'-dideoxyxythymidine-5'-solution eleven

Τаблица 2.Table 2.

Κοнценτρации исследуемыχ сοединений, ποдавляющиχ προдуκ- цию виρуса на 50 и 90%.Concentrations of the studied compounds, suppressing the production of virus by 50 and 90%.

Figure imgf000013_0001
Figure imgf000013_0001

Τаблица 3.Table 3.

Βρемя ποлугидροлиза (Τ1/2) и вρемя удеρживания (ΒУ) мοдиφи- циροванныχ 2'-дезοκсинуκлеοзид-5'-τρиφοсφаτοв (άΝΤΡ)Time of semi-hydrolysis (Τ 1/2 ) and time of retention (ΒU) of the modifying 2'-deoxynucleoside-5'-τ и и с φ φ ((()

Figure imgf000013_0002
* ΑΖΤΤΡ - 3'-азидο-2',3'-дидезοκсиτимидин-5'-τρиφοсφаτ, άΤΤΡ и άΑΤΡ исποльзοвались в κачесτве κοнτροля.
Figure imgf000013_0002
* ΑΖΤΤΡ - 3'-azido-2 ', 3'-dideoxyxythymidine-5'-solution, άΤΤΡ and άΑΤΡ were used as a control unit.

Для лучшегο ποнимания насτοящегο изοбρеτения ниже πρи- вοдяτся πρимеρы ποлучения заявляемыχ сοединений.For the best understanding of the invention, the following are the communication methods of the claimed compounds.

Пρимеρ 1. 5'-(§-Φениламидο-Ь,§- дибροммеτилендиφοсφοнил-а-φοсφοнилмеτил ) - 5 ' -дезοκсимеτил- 3 ' - азидο-З'-дезοκсиτимидин. (Сοединение I, Β = ΤЬу, Κ' = Ν3, Κ"=Η, Ζ=0, Κ*"=ΝΗΡЬ, Χ'=Χ"=Βг).Example 1. 5 '- (§-phenylamide-b, §-dibrous methylmethylenediamine-5-desoxymethyl-3' - azide-3'-deoxycythimidine. (Compound I, Β = ΤЬу, Κ '= Ν 3 , Κ "= Η, Ζ = 0, Κ * " = ΝΗΡЬ, Χ' = Χ "= Βг).

Κ ρасτвορу 0,5 ммοль 3'-азидο-2',3'-дидезοκси-4'- нορτимидин-4'-нορφοсφοнаτа в 10 мл ДΜΦΑ πρибавляюτ 162 мг (1 ммοль) Ν,Ν'-κаρбοниддиимдазοла, πеρемешиваюτ 2 часа πρи 20°С, πρиливаюτ 1 мл меτанοла, οсτавляюτ на 30 мин и уπаρиваюτ дοсуχа, κ οсτаτκу πρибавляюτ 1 ммοль £-φениламида дибροммеτиленди- φοсφοнаτа бисτρибуτиламмοниевοй сοли, πеρемешиваюτ 3 час, а πρи 20°С, πρиливаюτ 200 мл вοды и нанοсяτ на κοлοнκу (20 χ 2,5 см) с Τοуορеагϊ ϋΕΑΕ (ΗС03 "). Элюцию προвοдяτ линейным гρади- енτοм буφеρа ΝΗ4ΗС03, ρΗ 7,5 (0->0,4 Μ, οбщий οбъем 600 мл) с УΦ-κοнτροлем. Φρаκции с вещесτвοм лиοφилизуюτ, οсτаτοκ ρас- τвορяюτ в 1 мл вοды и нанοсяτ на κοлοнκу (20 χ 1,5 см) с ЫсЬгοΡгеρ ΚΡ18. Элюцию προвοдяτ вοдοй с УΦ-κοнτροлем. Ρас- τвορ, сοдеρжащий вещесτвο, лиοφилизуюτ, выχοд 0,26 ммοль, 52%. УΦ-сπеκτρ (вοда) 1таχ 266 ηт (е 9600), Ш-ЯΜΡ-сπеκτρ (ϋ20, ά, м.д.): 7.64 т (2Η, ΡЬ), 7.32 т (ЗΗ, агοт), 7.60 з (1Η, Η-6); 6.30 т (Ш, Η-Ι'); 5.52 δ (1-Η, Η-4'); 4.46 т (1-Η, Η-З'); 3.64 ά (2Η, сн,Ρ=8.5Гц, Ρ-СΗ2); 2,44 т (Ш, Η-2'); 1.92 δ (ЗΗ, СΗ3-ΤЬу); 1.86 ά (ЗΗ, ΤΗ,Ρ'=17,9Гц, СΗзΡΟ);. 31Ρ ЯΜΡ сπеκτρ (ϋ20, ά, м.д.): 9,58 д (а-Ρ, Τ а-ь=33,0 щ), 8,16 д (ё -Ρ, Τ ь.в=13,85 щ), 0,10 м ( Ь-Ρ) ΡΑΒ- таδδ, т/ζ: 735 (Μ++Η), 752 (Μ++Η+ΝΗ3) Пρимеρ 2. 5'-(§-Μеτил-Ь,£-дибροммеτилендиφοсφοнил-а- φοсφοнилмеτил)-5 ' -дезοκсимеτил-3 '-азидο-3 ' -дезοκсиτимидин. (Сοединение 2, Β=ΤЬу, Κ'=Ν3, Κ"=Η, Ζ=0, Κ"'=ΟΜе, Χ'=Χ"=Βг). Синτез προвοдяτ πο меτοдиκе πρимеρа 1 исχοдя из 5'- φοсφοнилмеτил-5 ' -дезοκсимеτил- 3 ' -азидο- 3 ' -дезοκсиτимидина и бис(τρибуτиламмοнийнοй) сοли меτилοвοгο эφиρа дибροммеτилен- диφοсφοнοвοй κислοτы. Βыχοд 0,34 ммοль, 68%. УΦ-сπеκτρ (вοда) 1таχ 268 ηт (е 9600), Ш-ЯΜΡ-сπеκτρ (ϋ20, ά, м.д.): 7.60 м (Ш, Η- 6); 6.30 м (Ш, Η-Ι'); 5.60 м (1-Η, Η-4'); 4.38 м (Ш, Η-З'); 3.64 д (2Η, Ιсн,Ρ=8-5 Ηζ, Ρ-СΗ2); 3.36 (ЗΗ, ΟΜе); 2.39 м (Ш, Η-З'); 1.92 с (ЗΗ, Μе),. 31Ρ ЯΜΡ сπеκгρ (ϋ20, ά, м.д.): 10,87 д (а-Ρ, Ιа_ь=35,0 щ), 8,46 д (ё-Ρ, Τ ь-ё=14,95 щ), -0,12 м (Ь-Ρ). ΡΑΒ-масс, т/ζ: 679 (Μ++1).0.5 mmol of 3'-azide-2 ', 3'-dideoxy-4'- norethymidine-4'-norophosphate in 10 ml; I add 162 mg; 20 ° C, 1 ml πρilivayuτ meτanοla, οsτavlyayuτ 30 min and uπaρivayuτ dοsuχa, κ οsτaτκu πρibavlyayuτ 1 mmοl £ -φenilamida dibροmmeτilendi- φοsφοnaτa bisτρibuτilammοnievοy sοli, πeρemeshivayuτ 3 h, and πρi 20 ° C, 200 ml πρilivayuτ vοdy and nanοsyaτ on κοlοnκu ( 20 χ 2.5 cm) with Τοοορеϊϊ ϋΕΑΕ (ΗС0 3 " ). The elution is driven by a linear buffer of ΝΗ 4 ΗС0 3 , ρΗ 7.5 (0-> 0.4 Μ, the total volume is 600 ml) with УФ-ён . 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 ΚΡ18. Eliminates that is, it is only 2.2%. %. UΦ-sect (water) 1 type 266 nt (е 9600), Ш-ЯΜΡ-spektτρ (ϋ 2 0, ά, ppm): 7.64 t (2Η, ΡЬ), 7.32 t (ЗΗ, Agot) , 7.60 t (1Η, Η-6); 6.30 t (W, Η-Ι '); 5.52 δ (1-Η, Η-4'); 4.46 t (1-Η, Η-З '); 3.64 ά (2Η, sn, Ρ = 8.5Hz, Ρ-СΗ 2 ); 2.44 t (W, Η-2 '); 1.92 δ (3Η, CΗ 3 -Τy); 1.86 ά (ЗΗ, Τ Η, Ρ ' = 17.9Hz, СΗзΡΟ) ;. 31 Ρ YAΜΡ sπeκτρ (ϋ 2 0, ά, ppm): 9.58 d (a-Ρ, Τ ab ut = 33.0), 8.16 d (g -Ρ, Τ s c. = 13.85 u), 0.10 m (b-Ρ) ΡΑΒ -ta δδ, t / ζ: 735 (Μ ++ Η), 752 (Μ ++ Η + ΝΗ 3 ) EXAMPLE 2.5 '- (§-Methyl-b-dimethylphenylated-a-phosphonylated) -5'-desoxymethyl-3'-azide-3'-desoxycythimidine. (Compound 2, Β = ΤЬу, Κ '= Ν 3 , Κ "= Η, Ζ = 0,'"'= ΟΜе, Χ' = Χ "= Βг). Synthesis of the method of the method 1 was made from 5'- -5 '-dezοκsimeτil- 3' -azidο- 3 '-dezοκsiτimidina and bis (τρibuτilammοniynοy) sοli meτilοvοgο eφiρa dibροmmeτilen- diφοsφοnοvοy κislοτy. Βyχοd mmοl 0.34, 68%. UΦ-sπeκτρ (vοda) 1 taχ ηt 268 (e 9600 ), Ш-ЯΜΡ-spektτρ (ϋ 2 0, ά, ppm): 7.60 m (Ш, Η-6); 6.30 m (Ш, Η-Ι '); 5.60 m (1-Η, Η- 4 '); 4.38 m (W, Η-З'); 3.64 d (2Η, Ιсн , Ρ = 8-5 Ηζ, Ρ-СΗ 2 ); 3.36 (ЗΗ, ΟΜе); 2.39 m (W, Η-З '); 1.92 s (ЗΗ, Μе) ,. 31 Ρ ЯΜΡ спекгρ (ϋ 2 0, ά, ppm): 10.87 d (а-Ρ, Ι а _ь = 35.0 щ), 8 , 46 d (--Ρ, Τ b- ё = 14.95 n), -0.12 m (b-Ρ). Масс-mass, t / ζ: 679 (Μ ++ 1).

Пρимеρ 3. 5'-(ё-Φенил-Ь,§-дибροммеτилендиφοсφοнил-а- φοсφοнилмеτил ) - 5 ' - дезοκсимеτил- 3 ' - азидο- 3 ' - дезοκсиτимидин (Сοединение 3, Β=ΤЬу, Κ'=Η, Κ"=Η, Ζ=0, Κ'"=ΟΡЬ, Χ'=Χ"=Βг). Синτез προвοдяτ πο меτοдиκе πρимеρа 1 исχοдя из 5'- φοсφοнилмеτил-5 ' -дезοκсимеτил- 3 ' -азидο-3 ' -дезοκсиτимидина и бис(τρибуτиламмοнийнοй) сοли φенилοвοгο эφиρа дибροммеτилен- диφοсφοнοвοй κислοτы. Βыχοд 0.34 ммοль, 68%. УΦ-сπеκτρ (вοда) 1таχ 268 ηт (е 9600), Щ-ЯΜΡ-сπеκτρ (ϋ 0, ά, м.д.): 7.68 т (2Η, ΡЬ), 7.32 т (ЗΗ, ΡЬ), 7.60 с (Ш, Η-6); 6.30 м (Ш, Η-Ι'); 5.46 м (1-Η, Η- 4'); 4.60 м (1-Η, Η-З'); 3.91 д (2Η, ΤСΗ ρ=8,5 Гц, Ρ-СΗ2); 2.28 мExample 3. 5 '- (yo-phenyl-b, §-dibro-methylmethylenediosephosphonyl) - 5' - desoxymethyl-3 '- azide-3' - desoxythymidine (Compound 3, Β = Τ b, "= Η, Ζ = 0, Κ '" = ΟΡ b, Χ' = Χ "= Β d). Synthesis of the method of Example 1 proceeding from the 5'-phenomethylmethyl-5'-desimesime-3-azide and bis (τρibuτilammοniynοy) sοli φenilοvοgο eφiρa dibροmmeτilen- diφοsφοnοvοy κislοτy. Βyχοd mmοl 0.34, 68%. UΦ-sπeκτρ (vοda) 1 taχ ηt 268 (e 9600), Sch-YAΜΡ-sπeκτρ (ϋ 0, ά, ppm ): 7.68 t (2Η, Ρ b), 7.32 t (3Η, b), 7.60 s (W, Η-6); 6.30 m (W, Ι-Ι '); 5.46 m (1-Η, Η-4'); 4.60 m (1-Η, Η-З '); 3.91 d (2Η, Τ СΗ ρ = 8.5 Hz, Ρ-СΗ 2 ); 2.28 m

(Ш, Η-2'); 1.94 с (ЗΗ, СΗ3). 31Ρ ЯΜΡ сπеκτρ (ϋ20, ά, м.д.): 11,67 д (а-Ρ, I а-ь=33,56 щ), 8,43 д (ё-Ρ, ] ь.в=14,08 щ), 0,05 м ( Ь-Ρ) ΡΑΒ- масс, т/ζ: 741 (Μ++Η), 758 (Μ++Η+ΝΗ3). Пρимеρ 4. 5'-(ё-Φенил-Ь,§-дибροммеτилендиφοсφοнил-а- φοсφοнилмеτил)-5 ' -дезοκсимеτил- 3 ' -азидο-2' , 3 ' -дидезοκсиуρидин (Сοединение 4, Β=ΙΙга, Κ'=Ν3, Κ"=Η, Ζ=0, Κ"'=ΟΡЬ, Χ'=Χ"=Βг). Синτез προвοдяτ πο меτοдиκе πρимеρа 1 исχοдя из 5'- φοсφοнилмеτил-5 '-дезοκсимеτил-3' -азидο-2' , 3 ' -дидезοκсиуρидина и бис(τρибуτиламмοнийнοй) сοли φенилοвοго эφиρа дибροммеτилен- диφοсφοнοвοй κислοτы. Βыχοд 0.34 ммοль, 68%. УΦ-сπеκτρ (вοда) Ιтах 268 ηт (е 9600), Ш-ЯΜΡ-сπеκτρ (ϋ 0, ά, м.д.): 7.60 д (Ш, 1=8 Гц, Η-6); 7.68 м (2Η, агοт); 7.32 м (ЗΗ, ΡЬ); 6.22 м (Ш, Η-Ι'); 5.80 д (Ш, 1=8 Гц, Η-5); 5.28 м (Ш, Η-4'); 4.50 м (1-Η, Η-З'); 3.64 д (2Η, ΤСΗ Ρ=8.5 Гц, Ρ-СΗ2); 2.22 м (Ш, Η-2');. 31Ρ ЯΜΡ сπеκτρ (ϋ20, ά, м.д.): 9,24 д (а-Ρ, Τ а.ь=30,19 Гц), 8,86 д (ё-Ρ, I Ь.Ε=13,87 Гц), 0,23 м (Ь-Ρ) ΡΑΒ-масс, т/ζ: 728 (Μ++Η).(W, Η-2 '); 1.94 s (ZΗ, SΗ 3). 31 Ρ YAΜΡ sπeκτρ (ϋ 2 0, ά, ppm): 11.67 g (a-Ρ, I ab = 33.56 w), 8.43 g (g -Ρ,] s a. = 14.08 mt), 0.05 m (L-Ρ) ΡΑΒ-mass, t / ζ: 741 (Μ ++ Η), 758 (Μ + + Η + ΝΗ 3 ). Example 4. 5 '- (f-phenyl-b, §-dibromomethylenediophosphonyl-a-phenyl) -5'-desoxymethyl-3 '-azide-2', 3'-dideoxyxyuridine (Compound 4, Β = Ν 3 , Κ "= Η, Ζ = 0, Κ"'= ΟΡ b, Χ' = Χ "= Β g). Synthesis of the method of Example 1 proceeding from 5'-factor-5 '-decimal-5 2 ', 3' -didezοκsiuρidina and bis (τρibuτilammοniynοy) sοli φenilοvοgo eφiρa dibροmmeτilen- diφοsφοnοvοy κislοτy. Βyχοd mmοl 0.34, 68%. UΦ-sπeκτρ (vοda) Ι ηt max 268 (e 9600), W-YAΜΡ-sπeκτρ (ϋ 0 , ά, ppm): 7.60 d (W, 1 = 8 Hz, Η-6); 7.68 m (2Η, agot); 7.32 m (ЗΗ, ΡЬ); 6.22 m (Ш, Η-Ι ') ; 5.80 d (W, 1 = 8 Hz, Η-5); 5.28 m (W, Η-4 '); 4.50 m (1-Η, Η-З'); 3.64 d (2Η, Τ CΗ Ρ = 8.5 Hz, Ρ-SΗ 2); 2.22 m (W, Η-2 ') ;. 31 Ρ YAΜΡ sπeκτρ (ϋ 2 0, ά, ppm): 9.24 d (a-Ρ, Τ and s. = 30.19 Hz), 8.86 d ( g- Ρ, I b . Ε = 13.87 Hz), 0.23 m (b-Ρ) масс-masses, t / ζ: 728 (Μ ++ Η )

Пρимеρ 5. 5'-(§-Φенил-Ь,£-дибροммеτилендиφοсφοнил-а- φοсφοнилмеτил)-5'-дезοκсимеτил-3'-азидο-2',3'-дидезοκси-5- эτилуρидин (Сοединение 5, Β=5-эτилуρацил, Κ'=Ν , Κ"=Η, Ζ=0, Κ'"=ΟΡЬ, Χ'=Χ"=Βг). Синτез προвοдяτ πο меτοдиκе πρимеρа 1, ис- χοдя из 5'-φοсφοнилмеτил-5'-дезοκсимеτил-3'-азидο-2',3'- дидезοκси-5-эτилиуρидина и бис- (τρибуτиламмοнийнοй) сοли φе- нилοвοго эφиρа дибροммеτилендиφοсφοнοвοй κислοτы. Βыχοд 38%. УΦ-сπеκτρ (вοда) 1таχ 272 ηт (е 12400). Ш-ЯΜΡ-сπеκτρ (ϋ20, ά, м.д.): 7.72 д (Ш, 1=7.5 Гц, Η-6); 7.68 м (2Η, агοт), 7.32 м (ЗΗ, ΡЬ), 6.23 м (Ш, Η-Ι'); 5.68 д (Ш, 1=7.5 Гц, Η-5); 5.50 м (1-Η, Η-4') 4.46 м (1-Η, Η-З'); 2.55 м (2Η, С# СΗ3), 2.42 м (Ш, Η-2'), 1.37 м (ЗΗ, СЯ2-СΗ3). 31Ρ ЯΜΡ сπеκτρ (ϋ20, ά, м.д.): 12,34 д (а-Ρ, Τ а.ь=36,5 Гц), 9,13 д (Ε-Ρ, Τ Ь.8=14,15 Гц), 0,05 м ( Ь-Ρ) ΡΑΒ-масс, т/ζ: 749 (Μ++Η). Пρимеρ 6. 5'-(§-Φенил-Ь,§-дибροммеτилендиφοсφοнил-а- φοсφοнилмеτил) -5 ' -дезοκсимеτил-2 ' , 3 ' -дидезοκсиаденοзин (Сοединение 6, Β=Αάе, Κ'=Κ"=Η, Ζ=0, Κ"'=ΟΡЬ, Χ'=Χ"=Βг). Син- τез προвοдяτ πο меτοдиκе πρимеρа 1 исχοдя из Ν-защищеннοго 5'- φοсφοнилмеτил-5'-дезοκсимеτил-2',3'-дидезοκсиаденοзина и бис(τρибуτиламмοнийнοй) сοли φенилοвοгο эφиρа дибροммеτилен- диφοсφοнοвοй κислοτы. Βыχοд 0,32 ммοл, 64%. УΦ-сπеκτρ (вοда) 1таχ 260 шη (е 15000), Ш-ЯΜΡ-сπеκτρ (ϋ20, ά, м.д.): 8.30 с (Ш, Η- 2); 8.09 с (Ш, Η-8); 7.68 т (2Η, агοт), 7.32 т (ЗΗ, ΡЬ), 6.33 м (Ш, Η-Ι'); 5,36 м (Ш, Η-4'); 3.56 д (2Η, ] = 9,0 Гц, СΗ2-Ρ), 2,6-2,3 (4Η, Η-З', Η-2'). 31Ρ ЯΜΡ сπеκιρ (ϋ20, ά, м.д.): 11,82 д (а-Ρ, Τ а.ь=34,5 щ), 8,59 д (в-Ρ, Ι Ь-β =13,9Ο щ), -0,11 м ( Ь-Ρ) ΡΑΒ-масс, т/ζ: 707 (Μ++Η), 724 (Μ++Η+ΝΗ3).EXAMPLE 5. 5 '- (§-phenyl-b, £ -dibomethylmethylenediamine-5-desoxymethyl-3'-azide-2', 3'-dideoxy-5-etyluridine (Compound 5, -ethylacyl, Κ '= Ν, Κ "= Η, Ζ = 0, Κ'" = ΟΡЬ, Χ '= Χ "= Βг). Synthesis of method 1 is based on 5'-method -dezοκsimeτil-3'-azidο-2 ', 3'-5 didezοκsi eτiliuρidina and bis (τρibuτilammοniynοy) sοli φe- nilοvοgo eφiρa dibροmmeτilendiφοsφοnοvοy κislοτy. Βyχοd 38%. UΦ-sπeκτρ (vοda) 1 taχ ηt 272 (e 12400 ). Ш-ЯΜΡ-spektτρ (ϋ 2 0, ά, ppm): 7.72 d (W, 1 = 7.5 Hz, Η-6); 7.68 m (2Η, agot), 7.32 m (ЗΗ, ЬЬ) , 6.23 m (W, Η-Ι '); 5.68 d (W, 1 = 7.5 Hz, Η-5); 5.50 m (1-Η, Η-4') 4.46 m (1-Η, Η-З '); 2.55 m (2Η, C # СΗ 3 ), 2.42 m (Ш, Η-2 '), 1.37 m (ЗΗ, СЯ 2 -СΗ 3 ). 31 Ρ ЯΜΡ spektτρ (ϋ 2 0, ά, ppm): 12.34 d (a-Ρ, Τ a . b = 36.5 Hz), 9.13 d (Ε-Ρ, Τ b . 8 = 14.15 Hz), 0.05 m (b-Ρ) масс-masses, t / ζ: 749 (Μ ++ Η). EXAMPLE 6. 5 '- (§-phenyl-b, §-dibro-methylmethylenediophosphonyl-a-phospho-methylated) -5' -deoxymethyl-2 ', 3' -deoxyoxyadenosine (Compound 6, Β = Αά e, Κ ', Κ' Ζ = 0, Κ "'= ΟΡ,, Χ' = Χ" = Β d). Synthesis of Method 1 proceeds from the--protected 5'-disinfection-2 ', 2-desimesid-2' bis (τρibuτilammοniynοy) sοli φenilοvοgο eφiρa dibροmmeτilen- diφοsφοnοvοy κislοτy. Βyχοd mmοl 0.32, 64%. UΦ-sπeκτρ (vοda) 1 taχ shη 260 (e 15000), Sh-YAΜΡ-sπeκτρ (ϋ 2 0, ά, m. d.): 8.30 s (W, Η-2); 8.09 s (W, Η-8); 7.68 t (2 аг, agot), 7.32 t (ЗΗ, 3Ь), 6.33 m (Ш, Η-Ι ') ; 5.36 m (W, Η-4 '); 3.56 d (2Η,] = 9.0 Hz, CΗ 2 -Ρ), 2.6-2.3 (4Η, Η-З', Η-2 '). 31 Ρ ЯΜ Ρ cπеκιρ (ϋ 2 0, ά, ppm): 11.82 d (a-Ρ, Τ a . B = 34.5 nd), 8.59 d ( b -Ρ, Ι b - β = 13 , 9Ο Щ), -0.11 m (L-Ρ) ΡΑΒ-masses, t / ζ: 707 (Μ ++ Η), 724 (Μ + + Η + ΝΗ 3 ).

Пρимеρ 7. 5'-(§-Φенил-Ь,§-диφτορмеτилендиφοсφοнил-а- φοсφοнилмеτил) - 5 ' -дезοκсимеτил-2 ' , 3 ' -дидезοκсиτимидин (Сοединение 7, Β=ΤЬу, Κ'=Κ"=Η, Ζ=0, Κ'"=ΟΡЬ, Χ'=Χ"=Ρ). Син- τез προвοдяτ πο меτοдиκе πρимеρа 1 исχοдя из 5'-φοсφοнилмеτил- 5 ' -дезοκсимеτил-2' , 3 ' -дидезοκсиτимидина и бис(τρибуτиламмοнийнοй) сοли φенилοвοгο эφиρа диφτορмеτилен- диφοсφοнοвοй κислοτы. Βыχοд 0,16 ммοл, 32%. УΦ-сπеκτρ (вοда) 1таχ 268 ηт (е 9600). Щ-ЯΜΡ-сπеκτρ (ϋ20, ά, м.д.): 7.62 м (2Η, агοт), 7.56 м (Ш, Η-6), 7.32 м (ЗΗ, ΡЬ), 6.04 τ (Ш, 1=6.5 Гц, Η-Ι'); 6.24 м (1-Η, Η-Ι'); 5.18 м (Ш, Η-4'); 3.64 д (2Η, I = 9,0 Гц, СΗ2-Ρ), 2.6-2.2 м (4Η, Η-З', Η-2'); 1.98 с (ЗΗ, СΗ3). 31Ρ ЯΜΡ сπеκτρ (Б20, ά, м.д.): 12,08 д (а-Ρ, Τ а.ь=34,5 Гц), 6,26 д (ё-Ρ, Τ ь_2=13,86 Гц), -1,81 м ( Ь-Ρ). ΡΑΒ-масс, т/ζ: 572 (Μ++Η), 589 (Μ++Η+ΝΗ3).Example 7. 5 '- (§-phenyl-b, §-diphylethylenediamine-5-deoxymethyl-2', 3 '-deoxy-thymidine (Compound 7, Β = Τ b, Κ' = Ζ = 0; ) sοli φenilοvοgο eφiρa diφτορmeτilen- diφοsφοnοvοy κislοτy. Βyχοd mmοl 0.16, 32%. UΦ-sπeκτρ (vοda) 1 taχ ηt 268 (e 9600). Sch-YAΜΡ-sπeκτρ (ϋ 2 0, ά, ppm) : 7.62 m (2Η, agot), 7.56 m (W, Η-6), 7.32 m (ЗΗ, ΡЬ), 6.04 τ (W, 1 = 6.5 Hz, Η-Ι '); 6.24 m (1-Η, Η-Ι '); 5.18 m (W, Η-4'); 3.64 d (2Η, I = 9.0 Hz, СΗ 2 -Ρ), 2.6-2.2 m (4Η, Η-З ', Η-2 '); 1.98 s (ЗΗ, С . 3) 31 Ρ YAΜΡ sπeκτρ (D 2 0, ά, ppm): 12.08 g (a-Ρ, Τ and b = 34.5 Hz), 6.26 d (g -Ρ, Τ. b _ 2 = 13.86 Hz), -1.81 m (b-b). ΡΑΒ-mass, t / ζ: 572 (Μ ++ Η), 589 (Μ + + Η + ΝΗ 3 ).

Пρимеρ 8. 2',3'-Дидезοκси-4'-нορ-4'-(§-φенил-Ь,§- дибροммеτилендиφοсφο-нил-а-φοсφοнилмеτил)-Ь-κаρбοаденοзин 1 Example 8. 2 ', 3'-Dideoxy-4'-nορ-4' - (§-phenyl-b, §- dibrous-methyl-n-a-phenylphenylmethyl) -b-carbadenozin 1

(Сοединение 8, Β=Αάе, Κ'=Κ"=Η, Ζ=СΗ2, Κ, =ΡЬ, Χ'=Χ"=Βг). Синτез προвοдяτ πο меτοдиκе πρимеρа 1. Βыχοд 0,33 ммοль, 66%. УΦ-сπеκτρ (вοда) 1таχ 260 ηт (е 14600), ЯΜΡ-сπеκгρ (ϋ20, ά, м.д.): 8.59 с (Ш, Η-2); 8.30 с (Ш, Η-8); 7.82 м (2Η, агοт), 7.32 т (ЗΗ, ΡЬ), 4.95 τ (Ш, 1=6.5 Гц, Η-Ι'); 3.58 д (2Η, 3 = 8,5 Гц, СΗ2-Ρ), 2.8-2.5 м (ЗΗ, Η-3',Η-5'а); 2.3-2.1 м (2Η, Η-2'); 1.92 м (Ш, Η-5'Ь).(Compound 8, Β = Αάе, Κ '= Κ "= Η, Ζ = СΗ 2 , Κ , = ΡЬ, Χ' = Χ" = Βг). The synthesis is carried out using the method of Example 1. The yield is 0.33 mmol, 66%. Y-sectect (water) 1 type 260 ηt (е 14600), Ya-specgρ (ϋ 2 0, ά, ppm): 8.59 s (Ш,)-2); 8.30 s (W, Η-8); 7.82 m (2Η, agot), 7.32 t (ЗΗ, ЬЬ), 4.95 τ (Ш, 1 = 6.5 Hz, Η-Ι '); 3.58 d (2Η, 3 = 8.5 Hz, СΗ 2 -Ρ), 2.8-2.5 m (ЗΗ, Η-3 ', Η-5'а); 2.3-2.1 m (2Η, Η-2 '); 1.92 m (W, 5-5).

31Ρ-ЯΜΡ-сπеκгρ (ϋ20, ά, м.д.): 11.82 д (а-Ρ, Τа_ь= 32.25 Гц); 0.26 м (Ь-Ρ, Гц); 7.80 д (§-Ρ, ΤЬ-8=15.18 Гц). ΡΑΒ-масс, т/ζ: 576 (Μ++Η). 31 Ρ-YAΜΡ-sπeκgρ (ϋ 2 0, ά, ppm): 11.82 g (a-Ρ, Τ a _ b = 32.25 Hz); 0.26 m (b-Ρ, Hz); 7.80 d (§-Ρ, Τ b - 8 = 15.18 Hz). ΡΑΒ-mass, t / ζ: 576 (Μ ++ Η).

Пρимеρ 9. 4'-(§-Φенил-Ь,8-дибροммеτилендиφοсφοнил-а- меτиленφοсφο-нил)-2',3'-дидезοκси-2',3'-дидегидρο-4'-нορ-Ь- κаρбοаденοзин (Сοединение 9, Β=Αάе, Κ' и Κ" οбρазуюτ двοйную связь, Ζ=СΗ , Κ"'=ΟΡЬ, Χ'=Χ"=Βг). Синτез προвοдяτ πο меτοдиκе, аналοгичнοй меτοдиκе πρимеρа 1, исχοдя из 2',3'-дидезοκси-2',3'- дидегидρο-4'-нορ-Ь-κаρбοаденοзин-4'-а-меτиленφοсφοнаτа и диб- ροммеτилендиφοсφοнаτа бис(τρибуτиламмοниевοй) сοли. Βыχοд 58%.EXAMPLE 9.4 '- (§-phenyl, 8-dimethylmethylene-methyl-2-nyl) -2', 3'-dideoxy-2 ', 3'-didehyde-4'-n-oup-benzene 9, Β = Αάе, Κ 'and Κ "form a two-way communication, Ζ = СΗ, Κ"' = ΟΡЬ, Χ '= Χ "= Βг). Synthesis of the method '-Dideoxy-2', 3'-didehydeρο-4'-nope-b-carbodenosine-4'-amethylene and dibrate (58%).

УΦ-сπеκτρ (вοда) 1таχ 262 ηт (е 14200). Ш-ЯΜΡ-сπеκτρ (ϋ20, ά, м.д.): 8.18 с (Ш, Η-2); 8.16 с (Ш, Η-8); 7.68 м (2Η, ΡЬ), 7.32 м (ЗΗ, ΡЬ), 6.13 м (1-Η, Η-З'); 5.92 м (Ш, Η-2'); 5.39 м (Ш, Η- Ι'); 4.66 с (Ш, Η-4'); 3.61 д (2Η, Τ = 9,0 Гц, СΗ2-Ρ), 2.92 м (Ш, Η- 5'а); 1.96 м (Ш, Η-5'Ь). 31Ρ ЯΜΡ-сπеκτρ (ϋ20, ά, м.д.): 11.6 д (а-Ρ, Τа_ь=35.10 Гц); 0.29 м (Ь-Ρ); 10.7 д (ё-Ρ, ь_8=16.3). ΡΑΒ-масс, т/ζ: 582 (Μ++Η).U-sectect (water) 1 tach 262 nt (e 14200). Ш-ЯΜΡ-spektτρ (ϋ 2 0, ά, ppm): 8.18 s (Ш, Η-2); 8.16 s (W, Η-8); 7.68 m (2Η, ΡЬ), 7.32 m (ЗΗ, ΡЬ), 6.13 m (1-Η, Η-З '); 5.92 m (W, Η-2 '); 5.39 m (W, Η- Ι '); 4.66 s (W, Η-4 '); 3.61 d (2Η, Τ = 9.0 Hz, СΗ 2 -Ρ), 2.92 m (W, Η-5'а); 1.96 m (W, 5-5). 31 Ρ YAΜΡ-sπeκτρ (ϋ 2 0, ά, ppm): 11.6 g (a-Ρ, Τ a _ b = 35.10 Hz); 0.29 m (b-b); 10.7 d ( ё -Ρ, b _ 8 = 16.3). ΡΑΒ-masses, t / ζ: 582 (Μ + + Η).

Пρимеρ ' 10. 2',3'-Дидезοκси-2',3'-дидегидρο— 4'-(§- φениламинο-Ь,§-диφτορ-меτилендиφοсφοнил-а-меτиленφοсφοнил)- 4'-нορκаρбοаденοзин (Сοединение 10, Β=Αάе, Κ' и Κ" οбρазуюτ двοйную связь, Ζ=СΗ2, Κ'"=ΝΗΡЬ, Χ'=Χ"=Ρ). Синτез προвοдяτ πο меτοдиκе, аналοгичнοй πρимеρу 1, исχοдя из 2',3'-дидезοκси-2',3'- дидегидρο-4'-нορκаρбοаденοзин-4'-а-меτиленφοсφοнаτа и диφτορ- меτилендиφοφοнаτа бисτρибуτиламмοниевοй сοли. Βыχοд 26%.Pρimeρ '10. 2', 3'-Didezοκsi-2 ', 3'-didegidρο- 4' - (§- φenilaminο-L, §-diφτορ-meτilendiφοsφοnil-to-meτilenφοsφοnil) - 4'-nορκaρbοadenοzin (Sοedinenie 10, Β = Αάе, Κ 'and Κ "will form a double connection, Ζ = СΚ 2 , Κ'" = ΧЬ, Χ '= Χ "= Син). Synthesized by πο method, similar to Example 1, starting from 2 ', 3'-dideoxy-2', 3'-didehyde-4'-norepacodenosine-4'-amethylenediamine and diabetes Βыχοд 26%.

УΦ-сπеκτρ (вοда) 1таχ 260 ηт (е 14100). Ш-ЯΜΡ-сπеκτρ (Б20, ά, м.д.): 8.18 с (Ш, Η-2); 8.16 с (Ш, Η-8); 7.68 м (2Η, ΡЬ), 7.32 м (ЗΗ, ΡЬ), 6.24 м (1-Η, Η-З'); 5.99 т (Ш, Η-2'); 5.46 м (Ш, Η-Ι'); 4.66 с (Ш, Η-4'); 3.74 д (2Η, ΤСΗ)ρ=8.5 Гц, Ρ-СΗ2), 2.86 мU-sectect (water) 1 type 260 ηt (e 14100). Ш-ЯΜΡ-spektτρ (Б 2 0, ά, ppm): 8.18 s (Ш, Η-2); 8.16 s (W, Η-8); 7.68 m (2Η, b), 7.32 m (b, b), 6.24 m (1-b, b-3); 5.99 t (W, Η-2 '); 5.46 m (W, Η-Ι '); 4.66 s (W, Η-4 '); 3.74 d (2Η, Τ СΗ) ρ = 8.5 Hz, Ρ-СΗ 2 ), 2.86 m

(Ш, Η-5'а); 1.90 м (Ш, Η-5'Ь). 31Ρ-ЯΜΡ-сπеκτρ (ϋ20, ά, м.д.): 12,97 д (а-Ρ, Τ а.ь=33,5 Гц), 6,80 д (8-Ρ, Τ ь.в=13,32 Гц), -0,71 м ( Ь- Ρ). ΡΑΒ-масс, т/ζ: 598 (Μ++Η).(W, Η-5'a); 1.90 m (W, 5-5). 31 Ρ-YAΜΡ-sπeκτρ (ϋ 2 0, ά, ppm): 12.97 g (a-Ρ, Τ and s = 33.5 Hz.), 6.80 g (8 -Ρ, Τ s . a = 13.32 Hz), -0.71 m (L- Ρ). ΡΑΒ-mass, t / ζ: 598 (Μ ++ Η).

Пρимеρ 11. 2',3'-Дидезοκси--4'(§-φенил-Ь,§- бροммеτилендиφοсφοнил-а-меτиленφοсφοнил)-4'-нορτимидин (Сοединение 11, Β=ΤЬу, Κ'=Κ"=Η, Ζ=0, Κ"=ΟΡЬ, Χ'=Η, Χ"=Βг). Синτез προвοдяτ πο аналοгичнοй πρимеρу 1 меτοдиκе из 2',3'- дидезοκси-4'-нορτимидин-4'-а-меτиленφοсφοнаτа и бис(τρибуτил- аммοнийнοй) сοли φенилφοсφοнилбροммеτиленφοсφοнаτа. Βыχοд 0,16 ммοл, 32%. УΦ-сπеκτρ (вοда) 1таχ 268 нм (е 9600), Ш-ЯΜΡ- сπеκτρ (ϋ20, ά, м.д.): 7.68 м (2Η, агοт), 7.32 м (ЗΗ, ΡЬ), 7.14 с (Ш, Η-6); 6.14 τ (Ш, 1=6.5 Гц, Η-Ι'); 5.56 м (Ш, Η-4'); 3.57 д (2Η, СΗ,Ρ=8.5 Гц, Ρ-СΗ2); 2.7-2.2 м (4Η, Η-2', Η-З'); 1.95 с (ЗΗ, СΗ3).EXAMPLE 11. 2 ', 3'-Dideoxy - 4' (§-phenyl-b, §- bromomethylene-methyl-4-n-thimidine (Compound 11, Β = ΤЬу, Κ '= Κ "= Ζ = 0, Κ "= ΟΡЬ, Χ '= Η, Χ" = Βг). Synthesis of analogous procedure to 1 method of 2', 3'-dideoxy-4'-nopeuimidin-4-enes τρibuτil- ammοniynοy) sοli φenilφοsφοnilbροmmeτilenφοsφοnaτa Βyχοd mmοl 0.16, 32% UΦ-sπeκτρ (vοda) 1 taχ 268 nm (e 9600), W-YAΜΡ- sπeκτρ (ϋ 2 0, ά, ppm):.. 7.68 m (2Η, agot), 7.32 m (ЗΗ, ΡЬ), 7.14 s (Ш, Η-6); 6.14 τ (Ш, 1 = 6.5 Hz, Η-Ι '); 5.56 m (Ш, Η-4'); 3.57 d (2Η, СΗ , Ρ = 8.5 Hz, Ρ-СΗ 2 ); 2.7-2.2 m (4Η, Η-2 ', Η-З'); 1.95 s (ЗΗ, СΗ 3 ).

31Ρ-ЯΜΡ-сπеκτρ (ϋ20, ά, м.д.): 11,84 д (а-Ρ, Τ а.ь=35,0 Гц), 9,13 д (ё- Ρ, Ι ь_е=13,55 Гц), 0,05 м (Ь-Ρ). ΡΑΒ-масс, т/ζ: 644 (Μ++Η), 661 (Μ++Η+ΝΗ3). 31 Ρ-YAΜΡ-sπeκτρ (ϋ 2 0, ά, ppm): 11.84 g (a-Ρ, Τ and s = 35.0 Hz.), 9.13 g (e - Ρ, Ι s _ e = 13.55 Hz), 0.05 m (b-Ρ). ΡΑΒ-mass, t / ζ: 644 (Μ + + Η), 661 (Μ + + Η + ΝΗ 3 ).

Пροмышленная πρименяемοсτьIntended use

Заявленные мοдиφициροванные нуκлеοзид-5'-τρиφοсφаτы являюτся ингибиτορами ρеπροдуκции виρуса иммунοдеφициτа че- лοвеκа, виρуса геπаτиτа Β, виρусοв гρуππы геρπеса и мοгуτ найτи πρименение в медицине. The claimed modified nucleoside-5'-compounds are inhibitors of the immunodeficiency virus virus infection ве leveka, the virus а of the genus ρ, the viruses of the herpes group and may find a name in medicine.

Claims

Φορмула изοбρеτения Formula of the invention 1. Μοдиφициροванные нуκлеοзид-5'-τρиφοсφаτы οбщей φορмулы:1. The standardized nucleoside-5'-τpropheses of the general formula: Ο Χ' Ο οΟ Χ 'Ο ο II I II II Κ" _ρ_с_Ρ _θ-ρ -СΗг-Α-ΒII I II II Κ "_ρ_ s _ Ρ _θ-ρ -СΗг-Α-Β I I I II I I I ΗΟ X" οн οн (Ι) ΗΟ X "οн οн (Ι) где:Where: Β = τимин, аденин, уρацил, гуанин, циτοзин или уρацил, заме- щенный в 5-ποлοженииΒ = thymine, adenine, uracil, guanine, cytosine or uracil substituted in the 5th position
Figure imgf000021_0001
Figure imgf000021_0001
 Κ'=Η, Ν , δΗ, ΝΗ , Ρ, С1, СΝ, ΝСΟ, ΝСδ, ΝΟΗ Κ"=Η или Κ' и Κ" вмесτе οбρазуюτ двοйную связь Ζ=0, СΗ2 Κ'"= Αϊкуϊ, Αιуϊ, ΟΑΙкуΙ, ΟΑгуΙ, ΝΗΑΙкуΙ, ΝΗΑгуΙ, Ο-ΟΙуΚ '= Η, Ν, δΗ, ΝΗ, Ρ, С1, СΝ, ΝСΟ, ΝСδ, ΝΟΗ Κ "= Η or Κ' and Κ" instead of double connection Ζ = 0, СΗ2 Κ '"= Αϊкуϊ, Αιуϊ, ΟΑΙкуΙ , ΟΑguΙ, ΝΗΑΙguΙ, ΝΗΑguΙ, Ο-ΟΙu Χ'=Χ"= Η, Βг, Ρ; или Χ'=Η, а Χ"=Ρ, Βг, ΝΗ2, СΗ2ΝΗ2, ΝΗΑΙк, ΝΗΑгуΙ; или Χ'=Ρ, а Χ"=Βг; или Χ'=СΗ3, а Χ"=ΝΗ2.Χ '= Χ "= Η, Βг, Ρ; or Χ' = Η, and Χ" = Ρ, Βг, ΝΗ 2 , СΗ 2 ΝΗ 2 , ΝΗΑΙк, ΝΗΑguΙ; or Χ '= Ρ, and Χ "= Βг; or Χ' = СΗ 3 , and Χ" = ΝΗ 2 . 2. Μοдиφициροванные нуκлеοзид-5'-τρиφοсφаτы πο π. 1, κοτο- ρые οτнοсяτся κ ϋ-ρяду и в κοτορыχ Κ" = Η φορмулы:2. The standardized nucleoside-5'-fluxes πο π. 1, some are related to both in and out Κ "= Η phores:
Figure imgf000021_0002
Figure imgf000021_0002
 (III) (III) 3. Μοдиφициροванные нуκлеοзид-5'-τρиφοсφаτы πο π. 1, κοτορые οτнοсяτся κ Ь-ρяду и в κοτορыχ Κ"=Η φορмулы:3. The standardized nucleoside-5'-fluxes πο π. 1, which are related to the series and in the case of = "= Η φορmules:
Figure imgf000022_0001
Figure imgf000022_0001
 (IV)(Iv) 4. Μοдиφициροванные нуκлеοзид-5'-τρиφοсφаτы πο π. 1, κοτορые οτнοсяτся κ ϋ-ρяду и в κοτορыχ Κ' и Κ" вмесτе οбρазуюτ двοй- ную связь φορмулы:4. The standardized nucleoside-5'-fluids πο π. 1, which are related to both я ϋ ду and κ τ и Κ Κ Κ Κ в together with the double connection of the formula:
Figure imgf000022_0002
Figure imgf000022_0002
 5. Μοдиφициροванные нуκлеοзид-5'-τρиφοсφаτы πο π. 1, κοτορые οτнοсяτся κ Ь-ρяду и в κοτορыχ Κ' и Κ" вмесτе οбρазуюτ двοйную связь φορмулы:5. The standardized nucleoside-5'-fluids πο π. 1, which are related to both the и 'and Κ "series, together with the double connection of the formula:
Figure imgf000022_0003
Figure imgf000022_0003
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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 (en) * 2002-07-26 2007-02-20 Закрытое акционерное общество "Производственно-коммерческая Ассоциация АЗТ" 3'-azido-3'-deoxythymidine 5'-choline phosphate as antiviral agent
US7285658B2 (en) 2002-02-28 2007-10-23 Biota, Inc. Nucleotide mimics and their prodrugs
EP2980095A1 (en) 2004-03-04 2016-02-03 K.U.Leuven Research & Development Phosponate nucleosides useful as active ingredients in pharmaceutical compositions for the treatment of viral infections, and intermediates for their production

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2225808C2 (en) * 2002-05-15 2004-03-20 Федеральное государственное унитарное предприятие "Летно-исследовательский институт им. М.М. Громова" Multi-purpose double-acting device for landing flying vehicle at night

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU455958A1 (en) * 1973-03-23 1975-01-05 Предприятие П/Я А-1758 The way thymidine-5 "-diphosphate
EP0097376A1 (en) * 1982-06-23 1984-01-04 Yamasa Shoyu Kabushiki Kaisha Nucleoside 5'-alkyl- or alkenylphosphate
GB2150570A (en) * 1983-05-24 1985-07-03 Stanford Res Inst Int Novel antiviral agents
DE3543346A1 (en) * 1984-12-07 1986-06-12 Boryung Pharmaceutical Co., Ltd., Seoul NEW NUCLEOSIDE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF
WO1990006320A1 (en) * 1988-11-30 1990-06-14 Kaellander Clas Fredrik Runess Substrate for polymerase activity determination
EP0398231A2 (en) * 1989-05-15 1990-11-22 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Nucleoside analogs

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1548182A1 (en) * 1987-12-29 1990-03-07 Институт молекулярной биологии АН СССР 5ъ-phosphonates of 3ъ-azido-2ъ,3ъ-didesoxynucleosides as specific inhibitors of aids virus in human lymphocyte culture

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU455958A1 (en) * 1973-03-23 1975-01-05 Предприятие П/Я А-1758 The way thymidine-5 "-diphosphate
EP0097376A1 (en) * 1982-06-23 1984-01-04 Yamasa Shoyu Kabushiki Kaisha Nucleoside 5'-alkyl- or alkenylphosphate
GB2150570A (en) * 1983-05-24 1985-07-03 Stanford Res Inst Int Novel antiviral agents
DE3543346A1 (en) * 1984-12-07 1986-06-12 Boryung Pharmaceutical Co., Ltd., Seoul NEW NUCLEOSIDE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF
WO1990006320A1 (en) * 1988-11-30 1990-06-14 Kaellander Clas Fredrik Runess Substrate for polymerase activity determination
EP0398231A2 (en) * 1989-05-15 1990-11-22 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Nucleoside analogs

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 (en) * 2002-02-28 2011-04-13 Biota Scient Management Nucleotide mimics and their prodrugs
RU2293739C2 (en) * 2002-07-26 2007-02-20 Закрытое акционерное общество "Производственно-коммерческая Ассоциация АЗТ" 3'-azido-3'-deoxythymidine 5'-choline phosphate as antiviral agent
EP2980095A1 (en) 2004-03-04 2016-02-03 K.U.Leuven Research & Development Phosponate nucleosides useful as active ingredients in pharmaceutical compositions for the treatment of viral infections, and intermediates for their production

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