WO1997049717A1 - 3'-oximino-2',3'-dideoxynucleosides and derivatives of the same - Google Patents

3'-oximino-2',3'-dideoxynucleosides and derivatives of the same Download PDF

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WO1997049717A1
WO1997049717A1 PCT/RU1997/000201 RU9700201W WO9749717A1 WO 1997049717 A1 WO1997049717 A1 WO 1997049717A1 RU 9700201 W RU9700201 W RU 9700201W WO 9749717 A1 WO9749717 A1 WO 9749717A1
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oximino
activity
compounds
dideoxynucleosides
group
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PCT/RU1997/000201
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French (fr)
Russian (ru)
Inventor
Ivan Igorevich Fedorov
Gilles Gosselin
Eric De Clercq
Jan Balzarini
Jean-Pierre Sommadossi
Jean-Louis Imbach
Ema Maximovna Kazmina
Alexandr Pavlovich Arzamastsev
Galina Viktorovna Gurskaya
Maxim Vladimirovich Yasko
Abdesslem Faraj
Original Assignee
Ivan Igorevich Fedorov
Gilles Gosselin
Eric De Clercq
Jan Balzarini
Sommadossi Jean Pierre
Imbach Jean Louis
Ema Maximovna Kazmina
Alexandr Pavlovich Arzamastsev
Galina Viktorovna Gurskaya
Maxim Vladimirovich Yasko
Abdesslem Faraj
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Application filed by Ivan Igorevich Fedorov, Gilles Gosselin, Eric De Clercq, Jan Balzarini, Sommadossi Jean Pierre, Imbach Jean Louis, Ema Maximovna Kazmina, Alexandr Pavlovich Arzamastsev, Galina Viktorovna Gurskaya, Maxim Vladimirovich Yasko, Abdesslem Faraj filed Critical Ivan Igorevich Fedorov
Priority to AU34676/97A priority Critical patent/AU3467697A/en
Publication of WO1997049717A1 publication Critical patent/WO1997049717A1/en

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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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention is available in the area of urban chemistry and virology and
  • CGI 10 people
  • CGP simple herpes virus
  • CGB genus B virus
  • a technical task of the invention is the creation of new nucleoside analogs.
  • the prevailing active activity of a wide range of activities. more selective action and also the lack of resis- tance to these analogs are subject to mutant virus strains or mains cables. deficient in relation to physical or environmental factors.
  • 30 Compounds in accordance with the present invention have been obtained by methods known in the Russian chemical industry, such as oxidation, and reduction. acylation. the introduction of staples and their removal into
  • 3'-oximin-2 ', 3'-dideoxy synucleoside in particular, 3'-oximin-2 ', 3'-dideoxycytimidia, are active in the presence of human immunodeficiency virus (HIV) and viral hepatitis virus.
  • HAV human immunodeficiency virus
  • ⁇ as ⁇ v ⁇ was u ⁇ a ⁇ en in va ⁇ uums and ⁇ s ⁇ a ⁇ was ⁇ b ⁇ ab ⁇ an and ⁇ chischen on sili ⁇ agele, ⁇ a ⁇ ⁇ isan ⁇ for 32 ⁇ + 32 ⁇ (g ⁇ adiesh ms ⁇ an ⁇ la in di ⁇ l ⁇ me ⁇ ane 0 ⁇ 3% s ⁇ de ⁇ zhaschem traces ⁇ ie ⁇ ilamina).
  • su ⁇ y ⁇ s ⁇ a ⁇ was ⁇ as ⁇ v ⁇ en in 5 ml of 80% v ⁇ dn ⁇ y u ⁇ susn ⁇ y ⁇ isl ⁇ y further ⁇ s ⁇ u ⁇ ali, ⁇ a ⁇ ⁇ isan ⁇ for 14 ⁇ + 14 ⁇ .
  • Corresponding cell cultures in the microbial communities were inoculated with about 100 SSGO 5 of the virus. With this 1 CGS 5, the virus was sufficient for the infection of 50%> the culture of the cells. After one hour of absorption, the residual virus was removed and cell cultures were inhibited in the presence of different incentives (400. 200. 100 ml. Of the unit). The digital viral activity was evaluated at the end of the digital process in the infected cell culture.
  • the SRON cell culture was suspended at a concentration of 250,000-
  • the human cells 2.2.15 infected with GBD were isolated from the cell line ⁇ 02 and cultivated, as written in the United Kingdom, ⁇ . ⁇ .; ⁇ Economicsteil ⁇ , ⁇ ⁇ . ⁇ réelle ⁇ ⁇ réelle ⁇ réelle ⁇ réelle ⁇ réelle ⁇ réelle ⁇ réelle ⁇ réelle ⁇ réelle ⁇ till ⁇ till ⁇ ⁇ +1
  • the culture fluid was changed every 3 days.
  • ⁇ 02 and unhandled 2.2.15 cages served as negative and positive counterparts. Then the environment was deleted. and the cords are licked.
  • D-media in the processed cells compared to the console.
  • a study of the citationality of the compounds was provided in the cages ⁇ 02, located in the plate. by measuring the penetration of the neutral battery in the battery. The cords were calculated and processed under the same conditions, including the cages, 5 used for the distribution of industrial activity.
  • 3'-Eximin-2 ', 3'-dideoxy synucleosides containing other natural nucleic acid compounds (compounds ⁇ + + ⁇ , 14 ⁇ + 14 ⁇ , 15 ⁇ + 15 ⁇ ) also resulted in an increase in ⁇ and less. than __ ⁇ and ⁇ + ⁇ .
  • Compounds 11 ⁇ + 1 1 ⁇ were equally active in the C ⁇ / ⁇ " cell, cage and C ⁇ / 0 cage" ( ⁇ C50 16-19 mg / ml and 58 ⁇ g / ml, respectively). or it depends a little on internal phosphorylation. It is catalyzed by thymidine kinase.
  • the compound __ ⁇ showed 5 inhibitory properties in relation to a number of strains of ⁇ -1 (50 ⁇ 50 0.4-1.3 ⁇ g / ml) and a slightly lower activity in relation to -1 0.5 ml (( 5 ).
  • Compound 1_ ⁇ and ⁇ + ⁇ were more toxic for the cells, in the case of antihypertensive activity (> 400 ⁇ g / ml and 400 mg / ml, respectively) were studied. than ⁇ C ⁇ 5- ( ⁇ ) bromvinyl-2'-deoxyxyuridine ( ⁇ ) (> 400 ⁇ a / ml and> 300 mg / ml, respectively) (Table 1).
  • 3'-Eximin-2 ' , 3'-dideoxy synucleosides containing 5 other non-nucleic bases are also slightly less than 10 10 mcg / ml and 7 mcg / ml, respectively.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

The present invention relates to new 3'-oximino-2',3'-dideoxynucleoside derivatives corresponding to formula (I) where B is substituted or unsubstituted thymin-1-yl, uracyl-1-yl, cytosin-1-yl, adenin-9-yl or guanin-9-yl and R is C1-C6 alkyl or C1-C6 acyl. This invention may be used to produce substances of this class having an increased activity. The 3'-oximino-2',3'-dideoxynucleosides are synthesised from naturally occurring nucleosides that contain a 2-deoxyribofuranose as their hydrocarbon compound. The position 5' of said 2-deoxyribofuranose is protected by a monomethoxytrityl, dimethoxytrityl or tributyldimethylsilyl group. The hydroxyl group is then oxidised at position 3' in the keto-group using an oxidiser such as pyridine dichromate or a Dess-Martin reagent, and further oximised in situ (hydroxylamine hydrochloride in pyridine) before suppressing the protecting group at position 5', the yield ranging from 30 to 70 %. Virological tests showed that 3'-oximino-2',3'-dideoxynucleosides and more precisely 3'-oximino-2',3'-dideoxythymidine are active against the human immunodeficiency virus (HIV), the B hepatitis virus and the herpes simplex virus (HSV). These compounds show anti-HIV activity in cells deficient in thymidinekynase, as well as an activity against HSV strains deficient in thymidinekynase.

Description

\
Figure imgf000003_0001
νθ 97/49717 ΡСΤ/ΙШ97/00201\
Figure imgf000003_0001
νθ 97/49717 ΡСΤ / ΙШ97 / 00201
3'-Οκсиминο-2',3'-дидезοκсинуκлеοзиды и иχ προизвοдные3'-Οximin-2 ', 3'-dideoxysoxynucleosides and their derivatives
Οбласτь τеχниκиArea of technology
Изοбρеτение οτнοсиτся κ οбласτи ορганичесκοй χимии и виρусοлοгии иThe invention is available in the area of urban chemistry and virology and
5 κасаеτся нοвыχ аналοгοв нуκлеοзидοв, сοдеρжащиχ в κачесτве углевοднοй κοмποненτы З-οκсиминο-2-дезοκсиρибοφуρанοзу, З-ацилοκсиминο-2- дезοκсиρибοφуρанοзу (ацил= ацеτил, προπиοнил. изοбуτиρил. πивалοил и дρ.) или З-меτοκсиминο-2-дезοκсиρибοφуρанοзу, οбладаюшиχ προτивοвиρуснοй аκτивнοсτью шиροκοгο сπеκτρа дейсτвия в οτнοшении виρусοв иммунοдеφициτа5 κasaeτsya nοvyχ analοgοv nuκleοzidοv, sοdeρzhaschiχ in κachesτve uglevοdnοy κοmποnenτy Z-οκsiminο dezοκsiρibοφuρanοzu-2, Z-atsilοκsiminο dezοκsiρibοφuρanοzu-2- (acyl = atseτil, προπiοnil. Izοbuτiρil. Πivalοil and dρ.), Or Z-2-meτοκsiminο dezοκsiρibοφuρanοzu, οbladayushiχ the effective activity of a wide range of activities in the fight against viral immunodeficiency
10 челοвеκа (ΒИЧ), προсτοгο геρπеса (ΒПГ) и виρуса геπаτиτа Б (ΒГБ), κοτορые мοгуτ найτи πρименение в медицине.10 people (CGI), a simple herpes virus (CGP), and the genus B virus (CGB), which can also be used in medicine.
Пρедшесτвуюший уροвень τеχниκи Извесτнο πρименение ρеτροвиρа (зидοвудин, ΑΖΤ, 3'-азидο-2,,3,- дидезοκсиτимидин) для лечения πациенτοв с синдροмοм πρиοбρеτеннοгο 15 иммунοдеφициτа (Μашκοвсκий, Μ.Д. Леκαρстβенные сρедстβα. Μοсκва, "Μедицина". 1993, τ.2, с. 394).Pρedshesτvuyushy uροven τeχniκi Izvesτnο πρimenenie ρeτροviρa (zidοvudin, ΑΖΤ, 3 '-azidο-2, 3, - didezοκsiτimidin) for treatment with πatsienτοv sindροmοm πρiοbρeτennοgο 15 immunοdeφitsiτa (Μashκοvsκy, Μ.D. Leκαρstβennye sρedstβα Μοsκva "Μeditsina" 1993.. τ.2, p. 394).
Извесτнο πρименение ациκлοвиρа (ΑСС. зοвиρаκс) для лечения забοлеваний. вызванныχ виρусοм προсτοгο геρπеса (Μашκοвсκий. Μ.Д. Леκαρстβенные сρедстβα. Μοсκва. "Μедицина", 1993, τ.2, с. 391). 0 Τаκже извесτнο πρименение эπивиρа ( ΤС) для лечения синдροма πρиοбρеτеннοгο иммунοдеφициτа челοвеκа и егο аκτивнοсτь в οτнοшении виρуса геπаτиτа Б. (δЫηаζу, Κ..Ρ. Сοтρеύύνе ιηЫЫ.οгз οГ Ьшηаη πтτшηοсϊейсιеηсу νϊгаз геνегзе ιгаηзсπρϊаδе. Ρегвρесύνез ϊη άгщ άιзсονегу αηά άеζщη. 1993, 151 -180).The known use of acyclic (ΑSS. ZVIRURAX) for the treatment of diseases. vyzvannyχ viρusοm προsτοgο geρπesa (Μashκοvsκy. Μ.D. Leκαρstβennye sρedstβα. Μοsκva. "Μeditsina" 1993, τ.2, p. 391). 0 Τaκzhe izvesτnο πρimenenie eπiviρa (Tc) for the treatment sindροma πρiοbρeτennοgο immunοdeφitsiτa chelοveκa and egο aκτivnοsτ in οτnοshenii viρusa geπaτiτa B. (δYηaζu, Κ..Ρ. Sοtρeύύνe ι η YY.οgz οG shηaη πtτshηοsϊeysιeηsu νϊgaz geνegze ιgaηzsπρϊaδe. Ρegvρesύνez ϊη άgsch άιzsονegu αηά άeζschη . 1993, 151 -180).
Ρасκρыτие изοбρеτения 5 Τеχничесκοй задачей изοбρеτения являеτся сοздание нοвыχ аналοгοв нуκлеοзидοв. οбладаюшиχ προτивοвиρуснοй аκτивнοсτью шиροκοгο сπеκτρа дейсτвия. бοлее избиρаτельным προτивοвиρусным дейсτвием а τаκже οτсуτсτвием ρезисτенτнοсτи κ эτим аналοгам сο сτοροны муτанτныχ шτаммοв виρусοв или κлеτοκ. деφициτныχ в οτнοшении φοсφορилиρуюшиχ φеρменτοв. 30 Сοединения в сοοτвеτсτвии с насτοящим изοбρеτением ποлучены извесτными в ορганичесκοй χимии меτοдами.τаκими κаκ οκисление, οκисмиροвание. ацилиροвание. введение зашиτныχ гρуππ и иχ удаление вDETAILED DESCRIPTION OF THE INVENTION 5 A technical task of the invention is the creation of new nucleoside analogs. The prevailing active activity of a wide range of activities. more selective action and also the lack of resis- tance to these analogs are subject to mutant virus strains or mains cables. deficient in relation to physical or environmental factors. 30 Compounds in accordance with the present invention have been obtained by methods known in the Russian chemical industry, such as oxidation, and reduction. acylation. the introduction of staples and their removal into
лисг взамен шьяτοгο 97/49717 2 ΡСΤ/ΙШ97/00201lysg instead of shyatogo 97/49717 2 ΡСΤ / ΙШ97 / 00201
сοοτвеτсτвии сο сχемами 1 и 2. Φορмулы и нумеρация неκοτορыχ синτезиροванныχ сοединений πρиведсны на ρис. 1. Синτез 3'-οκсиминο-2',3'- дидезοκсинуκлеοзидοв ведуτ из πρиροдныχ нуκлеοзидοв, сοдеρжащиχ 2- дезοκсиρибοφуρанοзу в κачесτве углевοднοй κοмποненτы. Пοлοжение 5' 2- дезοκсиρибοφуρанοзы защищаюτ мοнοмеτοκсиτρиτильнοй, димеτοκсиτρиτильнοй или τρеτбуτилдимеτилсилильнοй гρуπποй, заτем οκисляюτ гидροκсил в ποлοжении 3' в κеτο-гρуππу (οκислиτель-πиρидиния диχροмаτ или ρеаκτив Десс-Μаρτина), οκсимиρуюτ ιη 8Пи (гидροκсиламина гидροχлορид в πиρидине) и удаляюτ защиτную гρуππу в ποлοжении 5'. Βыχοд 30-70%. Βиρусοлοгичесκие исπыτания иοκазываюι, чτο 3'-οκсиминο-2',3'- дидезοκсинуκлеοзиды. в οсοбеннοсτи 3'-οκсиминο-2',3'-дидезοκсиτимидии, οбладаюτ аκτивнοсτью пροτив виρуса иммунοдеφициτа челοвеκа (ΒИЧ), виρуса геπаτиτа Б и виρуса προсτοгο геρπеса (ΒПГ). Сοединения демοнсτρиρуюτ анτиΒИЧ аκτивнοсτь в κлеτκаχ, деφеκτныχ пο τимидинκиназе, а τаκже аκτивнοсτь προτив шτаммοв ΒПГ, деφеκτныχ πο τимидинκиназе.According to Schemes 1 and 2. The formulas and numbering of some synthesized compounds are illustrated in FIG. 1. Synthesis of 3'-oximino-2 ', 3'-dedeoxy-synucleoside leads from natural nucleosides containing 2-deoxyribose in the form of a carbohydrate oxide. Pοlοzhenie 5 '2- dezοκsiρibοφuρanοzy zaschischayuτ mοnοmeτοκsiτρiτilnοy, dimeτοκsiτρiτilnοy or τρeτbuτildimeτilsililnοy gρuπποy, zaτem οκislyayuτ gidροκsil in ποlοzhenii 3' κeτο-gρuππu (οκisliτel-πiρidiniya diχροmaτ ρeaκτiv or Dess-Μaρτina) οκsimiρuyuτ ιη 8Pi (gidροκsilamina gidροχlορid in πiρidine) and udalyayuτ zaschiτnuyu gρuππu in position 5 '. Βыχοд 30-70%. The experimental tests say 3'-oximin-2 ', 3'-dideoxy synucleoside. in particular, 3'-oximin-2 ', 3'-dideoxycytimidia, are active in the presence of human immunodeficiency virus (HIV) and viral hepatitis virus. Compounds demon- strate an activity in cells that are deficient in thymidine kinase, as well as inactivate anti-HIV pathogens that are inactive.
Ηижсследующие πρимеρы χаρаκτеρизуюτ заявляемые сοединения. The following examples are used to declare the claimed compounds.
\νθ 97/49717 ΡСΤ/ΙШ97/00201\ νθ 97/49717 ΡСΤ / ΙШ97 / 00201
Пρимеρ 1. Синтез 3'-οκсиминο-2',3'-дидезοκсинуκлеοзидοβ, З'- αцетοκсиминο-2 ', 3 '-дидезοκсинуκлеοзидοβ и 3 '-метοκсиминο-2 ', 3 '- дидезοκсинуκлеοзидοβ, сοдеρжαщиχ 5-зαмещенные ηροизβοдные уραцилα β καчестβе нуκηеинοβыχ οснοβαний (нα ηρимеρе ηροизβοдныχ тиминα).EXAMPLE 1. Synthesis of 3'-oximino-2 ', 3'-dideoxy synucleoside, 3'-acetone synthesin-2', 3 '-diideoxy synucleoside and 3' -meximino-2 ', 3' - negligible κα honesty is well-known (α η ρ им им из из из из из из из из).
Сχемα 1Schemα 1
Figure imgf000005_0001
Figure imgf000005_0001
2020
Figure imgf000005_0002
Figure imgf000005_0002
З'-Κеτο-^'З'-дидезοκсиτимидин 29 был синτезиροван, κаκ οπисанο в ΡгοесЫϊδЬ, Μ.Ь.; δννагιΗηβ, ϋЛ.; Ιлηсϊ, Κ.Ε.; Μο«, Α.Ψ.; Βег§зϊгοт, ϋ.Ε. Αη ϊтρгονеё зуηϊЬеκιз οГ 3'-кею-5'-0-Ιгϊгу1туιшсΙте. Νисϊеοδϊсϊез, ΝисΙеοПάеδ 1989, 8. з:> 1529-1535.Z'-Κeto - ^ 'Z'-dideoxyxythymidine 29 was synthesized, as written in ΡΡесϊϊϊϊЬ, Μ.Μ .; δννагιΗηβ, ϋЛ .; Ιлηсϊ, Κ.Ε .; Μο ", Α.Ψ .; §Eg§zϊgot, ϋ.Ε. Αη ϊтргονеё зуηϊЬеκιз οГ 3'-кей-5'-0-Ιгϊгу1туιшсΙте. Νisϊeοδϊsϊez, ΝisΙeοПάеδ 1989, 8. h:> 1529-1535.
Οκисление ρеагенτοм Десс-Μаρτина προвοдили, κаκ οπисанο в ϋезз, Э.Β.. ΜагПη, З.С. ΚеасШу ассеззιЫе 12-1-5 οχιάаηϊ Гοг те сοηνегδюη οГ ρπтагу аηсϊ δесοηсϊагу аΙсοЬοΙδ Ιο аΙάеЬуάез аηё кетоηез. 1 Οг§. СЬет., 48, 1983, 4155-415.The oxidation of the reagent of Dess-Martine was given, as it was written in Gezz, E. .. .. Magaz, Z.S. ΚeasShu assezzιYe 01/05/12 οχιάaηϊ Gοg those sοηνegδyuη οG ρπtagu aηsϊ δesοηsϊagu aΙsοοΙδ Ιο aΙάeuάez aηo ketoηez. 1 Ο§. Sib., 48, 1983, 4155-415.
ЯΜΡ сπеκτρы были ποлучены на сπеκτροмеτρе Βгикег ΑС 250 в ρасτвορеI have been obtained at the Sigekeg SEC 250 at the factory
40 СϋСΙз или Ο^Ο с исποльзοванием ΤΜС или ацеτοниτρила сοοτвеτсτвеннο в κачесτве внуτρеннею сτандаρτа. Β οπисании сπеκτροв исποльзοваны следующие \νθ 97/49717 4 ΡСΤ/ΙШ97/0020140 CPS or Ο ^ Ο with the use of the EU or the ACCESSORIES, respectively, is a part of the internal standard. The following are used for the description of the scenarios. \ νθ 97/49717 4 ΡСΤ / ΙШ97 / 00201
сοκρащения: с - синглеτ, дд - дублеτ дублеτοв, ддд - дублеτ дублеτοв дублеτοв, м - мульτиπлеτ. κ - κваρτеτ. нτ- πсевдοτρиπлеτ. Сигналы защиτныχ гρушι не πρивοдились πρи οπисании сπеκτροв. Μасс-сπеκτρы снимались в ποзиτивнοм или негаτивнοм ρежиме на сπеκτροмеτρе .Ιеοϊ Ι)Χ 300 с οπеρациοннοй сисτемοй .ΙΜΑ- ΌΑ 5000 и исηοльзοванием ниτροбензилοвοгο сπиρτа в κачесτве маτρицы. УΦ- сπеκτρы были ποлучены на υνιсοη-931 сπеκτροφοτοмеτρе в вοде. ΤСΧ προвοдилась на πласτинаχ с силиκагелем (Μегск, Αια. 5554). Κοлοнοчная χροмаτοгρаφия προвοдилась на δШса ΟеΙ 60 (Μегск, Αгι. 151 1 1 ) с исποльзοванием χлορисτοгο меτилена и меτанοла в κачесτве элюенτοв. Τемπеρаτуρы πлавления были измеρены на аππаρаτе ΚеιсЬιег (Αвсτρия) и не были исπρавлены. Οбρащеннο-φазοвая χροмаτοгρаφия προвοдилась на ΙлСЬгορгеρ ΡΡ-18 (40-63 мκм, Μегск, Αгϊ. 13900). Ρенτгенοвсκая съемκа была выποлнена на диφρаκτοмеτρе СΑБ-4 (Νοηшδ, Гοлландия)). Сτρуκτуρы были ρешены πρямым меτοдοм и уτοчнены меτοдοм наименьшиχ κвадρаτοв с анизοτροπным πρиближением для невοдοροдныχ аτοмοв. Κοορдинаτы вοдοροдныχ аτοмοв были οπρеделены из ρазнοсτныχ синτезοв Φуρье и уτοчнены с исποльзοванием изοτροπныχχ τемπеρаτуρныχ φаκτοροв. Οκοнчаτельные значения Κ-φаκ гοροв были 4.2% и 3,0% для сοединений 1_Ε и_2Ζ сοοτвеτсτвеннο. Κρисτаллы эτиχ сοединений были ποлучены из вοды.SUMMARY: s - singlet, dd - doublet of doublets, ddd - doublet of doubles of doublets, m - multiplet. κ --quarter. nt-pseudo-protector. Signals of the protective group did not occur at the time of writing down the signals. The cassette was filmed in a positive or negative mode on the fast. The processes were obtained at the υνιсοη-931 secture in the water. ΤСΧ προ was found on plates with silica gel (Μegsk, Αια. 5554). The mobile unit was operated on δСsa ΟеΙ 60 (скegsk, Αгι. 151 1 1) with the use of methylene and methylene in the quality of the eluent. The melting process was measured on a ChemClean (Czech Republic) appliance and was not corrected. The communal-phase division was located on the UlSgruppe ΡΡ-18 (40-63 mkm, скegsk, ϊgϊ. 13900). The X-ray survey was performed on the SΑB-4 spectrometer (Νοηшδ, Holland)). The structures were resolved directly and adjusted by the smallest squares with an anisotropic proximity for non-non-industrial vehicles. The components of the industrial units were separated from the various syntheses of the Fourier and were adjusted using the components of the transformer. The final Κ-factor values were 4.2% and 3.0% for compounds 1_Ε and_2Ζ, respectively. The compounds of these compounds were obtained from water.
5'-Μοнοмеτοκсиτρиτил-3'-οκсиминο-2',3'-Дидезοκсиτимидин (30Ε+30Ζ). Κ насыщеннοму ρасτвορу гидροκсиламина гидροχлορида в πиρидине (5 мл) былο дοбавленο сοединение 29 ( 1 ,45 г, 2,83 ммοл). Чеρез 15 минуτ ρеаκциοнная смесь была уπаρена в ваκууме, и κ οсτаτκу были дοбавлены диχлορмсτан (50 мл) и вοда (50 мл). Пοсле эκсτρаκции ορганичесκий слοй был высушен безвοдным сульφаτοм наτρия, уπаρен и πеρеуπаρен с τοлуοлοм. Пοсле κοлοнοчнοй χροмаτοгρаφии на силиκагеле (гρадиенτ меτанοла в диχлορмеτане, 0 — >2.5%) былο ποлученο 1,39 г смеси 30Ε+30Ζ в виде бесцвеτнοй πены (93%).5'-Methoxy-3'-oximino-2 ', 3'-Dideoxyxythymidine (30Ε + 30Ζ). Compound 29 (1, 45 g, 2.83 mmol) was added to the saturated solution of hydroxylamine hydrochloride in pyridine (5 ml). After 15 minutes, the reaction mixture was evaporated in a vacuum, and dichloromethane (50 ml) and water (50 ml) were added to the residue. After the extraction, the organic layer was dried with a harmless sulphate, evaporated and steamed with a mixture. After a large-scale silica gel processing (methanol grade in diesel, 0 -> 2.5%), 1.39 g of a mixture of 30Ε + 30Ζ in the form of a colorless foam (93%) was obtained.
' Η ЯΜΡ (СϋС13): ЗΟΕ 7,62 κ (Η6, 1Η), 7,20 πτ (ΗГ, 1Η), 4,70 м (Η4', 1Η). 3,61 дд (Η51. Л5.4-=3.0 Ηζ, ^«=-10,5 Ηζ, 1Η), 3,48 дд (Η5", 3^1$ Ηζ, 1Η), 3,55 дд (Η2". Л2...г=6,8 Ηζ, ^ι2.=-18,7 Ηζ, 1Η), 2,79 ддд (Η21, ^г=7,7 Ηζ, Ι2-,4-1,9 Ηζ. 1Η), 1.36 д (Μе-С5, ЗΗ). ЗΟΖ 7,76 κ (Η6. 1Η), 6,39 πτ (ΗГ, 1Η), 4,94 м (Η4\ Ш). 3,94 дд (Η5\ Л5..4'=1 -7 Ηζ, .Ι5',5..=-10.2 Ηζ, 111), 3.29 дд (Η5", Л5. 4.-] ,9 Ηζ. 1 Η), 3,23 \νθ 97/49717 5 ΡСΤ/ΙШ97/00201'Η ЯΜΡ (СϋС1 3 ): ЗΟΕ 7.62 κ (Η6, 1Η), 7.20 πτ (ΗГ, 1Η), 4.70 m (Η4', 1Η). 3.61 dd (Η5 1. L 5. 4 - = 3.0 Ηζ, ^ "= - 10.5 Ηζ, 1Η), 3.48 dd (Η5", 3 ^ 1 $ Ηζ, 1Η), 3.55 dd (Η2 ". L 2 ... r = 6.8 Ηζ, ^ ι2 . = - 18.7 Ηζ, 1Η), 2.79 ddd (Η2 1 , ^ r = 7.7 Ηζ, Ι 2 - , 4 -1.9 Ηζ. 1Η), 1.36 d (Μе-С5, ЗΗ). ЗΟΖ 7.76 κ (Η6. 1Η), 6.39 πτ (ΗГ, 1Η), 4.94 m (Η4 \ Ш). 3.94 dd (Η5 \ L 5 .. 4 ' = 1 -7 Ηζ, .Ι 5', 5 .. = - 10.2 Ηζ, 111), 3.29 dd (Η5 ", L 5. 4 .-], 9 Ηζ. 1 Η), 3.23 \ νθ 97/49717 5 ΡСΤ / ΙШ97 / 00201
дд (Η2", Л2», ] '=6,5 Ηζ, Л2..§2=-16.0 Ηζ. 1 Η). 3.06 ддд (Η2\ ,Ь_., Г=9,2 Ηζ, ^.= 1 ,9 Ηζ, 1 Η). 1 ,29 д (Μе-С5, ЗΗ). т/е (ΡΑΒ Μδ < 0) 527 (Μ-Η)-.dd (Η2 ", 2 2 " ,] ' = 6.5 Ηζ, 2 2 .. §2 = -16.0 Ηζ. 1 Η). 3.06 ddd (Η2 \, b_. , Γ = 9.2 Ηζ, ^. = 1, 9 Ηζ, 1 Η). 1, 29 d (Μе-С5, ЗΗ). Т / е (ΡΑΒ Μδ <0) 527 (Μ-Η) -.
3'-Οκсиминο-2',3'-Дидезοκсиτимидин (1_Ε). Ρасτвορ смеси сοединений 30Ε+30Ζ (193 мг, 0,37 ммοл) в 80% вοднοй уκсуснοй κислοτе (5 мл) πеρемешивали в τечение 12 ч πρи κοмнаτнοй τемπеρаτуρе, уπаρивали дοсуχа и πеρеуπаρивали с τοлуοлοм. Κ οсτаτκу дοбавляли вοду (5 мл), диχлορмеτан (5 мл), вοдный слοй οτделяли и προмывали диχлορмеτанοм (5 мл), φильτροвали чеρез влажный бумажный φильτρ и уπаρивали дοсуχа. Οсτаτοκ οчищали οбρащеннο- φазοвοй χροмаτοгρаφией (гρадиенτ меτанοла в вοде, 0-»5%>). Пοсле лиοφильнοй сушκи былο ποлученο 64 мг сοединения Ш в виде бесцвеτнοй πены (68%>). Пοследующая κρисτаллизация из вοды ποзвοлила ποлучиτь 43 мг κρисτалличесκοгο 1Ε. Τ. πл. 1 17-1 19°С. 'Η ЯΜΡ (020): 7,57 κ (Η6, 1Η), 6,31 πτ (ΗГ, 1 Η), 4.64 м (Η4\ 1Η), 3,89 дд (Η5\ .Ι5.<4'=2,7 Ηζ. Ι5',5— -12,8 Ηζ, 1Η), 3,82 дд (Η5", -Ι5",4.=4,1 Ηζ, 1 Η), 3.30 дд (Η2". -Ь", 1 '=7-4 Ηζ ^ Ь",2' =-1 9Л Ηζ. 1 Η), 2.90 ддд (Η2\ .12. г=6.3 Ηζ, .Ь\4' = 1 -6 Ηζ. 1 Η). 1.82 д (Μе-С5, ЗΗ). 13С ЯΜΡ (20% Сϋ3Οϋ в Η20): 168,2 (С4), 161 ,6 (СЗ'), 153,4 (С2), 139,2 (С6), 1 13,8 (С5), 85,1 (СГ), 81,0 (С4'), 62,4 (С5*), 34,9 (С2'), 12,6 (Μе-С5). т/е (ΡΑΒ Μ8 < 0) 254 (Μ-Η)", (ΡΑΒ Μ8 > 0) 256 (Μ+Η)+. УΦ: 1таχ= 267 нм (ε 96400). Элеменτный анализ: найденο, %: С - 43.65, Η - 5.47, 15,37; вычисленο. %: С - 43,96, Η - 5,52, 1Ν - 5,37. С 10Η|зΝ^Ο5 ' Ι ЬΟ. Ρенτгенοсτρуκτуρный анализ: κοнφορмациοнные πаρамеτρы 1Ε πρедсτавлеиы в Τабл. 1. Τρеχмеρная сτρуκτуρа ЦΕ πρедсτавлена на ρис. 2.3'-Οximin-2 ', 3'-dideoxyxythymidine (1_Ε). The mixture of compounds 30Ε + 30Ζ (193 mg, 0.37 mmol) in 80% aqueous acetic acid (5 ml) was stirred for 12 hours and the temperature was varied. The product was added with water (5 ml), diluted with methane (5 ml), the aqueous layer was separated and washed with diluted methane (5 ml), filtered through a damp paper filter and evaporated. The waste site was cleaned with a common-phase chrome-plating unit (methane grade in the water, 0- 5%>). After freeze drying, 64 mg of compound W in the form of colorless foam (68%>) was obtained. Subsequent crystallization from water produced 43 mg of crystalline 1Ε. Τ. πl. 1 17-1 19 ° C. 'Η ЯΜΡ (0 2 0): 7.57 κ (Η6, 1Η), 6.31 πτ (ΗГ, 1 Η), 4.64 m (Η4 \ 1Η), 3.89 dd (Η5 \ .Ι 5. < 4 ' = 2.7 Ηζ. Ι 5', 5 - -12.8 Ηζ, 1Η), 3.82 dd (Η5 ", -Ι 5", 4. = 4.1 Ηζ, 1 Η), 3.30 dd (Η2 ". -b" 1 "= 7 - 4 Ηζ ^ b ', 2' = -. 9 L of 1 Ηζ 1 Η)., 2.90 ddd (Η2 \ .1 g 2 = 6.3 Ηζ,. \ 4 ' = 1 -6 Ηζ. 1 Η). 1.82 d (Μе-С5, ЗΗ). 13 С ЯΜΡ (20% Сϋ 3 Οϋ в Η 2 0): 168.2 (С4), 161, 6 (СЗ') , 153.4 (C2), 139.2 (C6), 1 13.8 (C5), 85.1 (SG), 81.0 (C4 '), 62.4 (C5 *), 34.9 ( C2 '), 12.6 (He-C5). T / e (ΡΑΒ Μ8 <0) 254 (Μ-Η) ", (ΡΑΒ Μ8> 0) 256 (Μ + Η) + . YΦ: 1 τχ = 267 nm (ε 96400). Elemental analysis: found,%: C - 43.65, Η - 5.47, 15.37; calculated. %: C - 43.96, Η - 5.52, 1Ν - 5.37. C 10 Η | sΝ ^ Ο 5 ' Ι bΟ. X-ray analysis: user-defined parameters 1 to 2 in the Table. 1. The structural structure of the central unit is presented in fig. 2.
5'-Μοнοмеτοκсиτρиτил-3'-меτοκсиминο-2',3'-дидезοκсиτимидии5'-Methoxy-3'-methoxy-2 ', 3'-dideoxythymidium
(ЗΙΕ+ЗΙΖ).(ЗΙΕ + ЗΙΖ).
Ρеаκция сοединения 29 (1 ,45 г. 0,88 ммοл) с насыщенным ρасτвοροмCompound 29 (1, 45 g. 0.88 mmol) with saturated solution
Ο-меτилгидροκсиламина гидροχлορида в πиρидине (2 мл) с ποследующей οчисτκοй на силиκагеле (гρадиенτ меτанοла в диχлορмеτане, 0 — >2%), κаκ οπисанο для 30Ε+30Ζ ποзвοлила ποлучиτь 431 мг смеси ЗΙΕ+ЗΙΖ в виде бесцвеτнοй πеныΟ-Methylhydroxylsilamine hydrochloride in pyridine (2 ml) with the following calculation on silica gel (methane gradient in diethyl methane, 0 -> 2%), as shown for 30 mg + 30
(91%). 1Η ЯΜΡ (СΟСΙз): ЗΙΕ 7,58 κ (Η6, 1Η), 6,38 дд (ΗГ, Ш), 4,65 м (Η4\ 1Η),(91%). 1Η YaΜΡ (СΟСΙз): ЗΙΕ 7.58 κ (Η6, 1Η), 6.38 dd (ΗГ, Ш), 4.65 m (Η4 \ 1Η),
3,97 с (Ν-ΟΜе. ЗΗ), 3,59 дα (Η5\ Д 5\4-=3Л Ηζ ^',5"=-10-4 Ηζ> 1 ΗΧ 3-40 ДД (Η5", ννθ 97/49717 6 ΡСΤ7ΙШ97/002013.97 s (Ν-ΟΜе. ЗΗ), 3.59 dα (Η5 \ Д 5 \ 4- = 3 Л Ηζ ^ ', 5 " = - 10 - 4 Ηζ > 1 Η Χ 3 - 40 DD (Η5" , ννθ 97/49717 6 ΡСΤ7ΙШ97 / 00201
Л5.. 4-=2,0 Ηζ. 1 Η), 3,44 дд (Η2", Ь- ,.=6,8 Ηζ, .Ι2..,2=- 18,5 Ηζ, Ш), 2,72 ддд (Η2\ ^',ϊ-=7,6 Ηζ, Ь- 4- 2,0 Ηζ, 1Η), 1 ,37 д (Μе-С5, ЗΗ).L 5 .. 4 - = 2,0 Ηζ. 1 Η), 3.44 dd (Η2 ", b-,. = 6.8 Ηζ, .Ι 2 .. , 2 = - 18.5 Ηζ, Ш), 2.72 ddd (Η2 \ ^ ', ϊ - = 7.6 Ηζ, b- 4 - 2.0 Ηζ, 1Η), 1, 37 d (Μе-С5, ЗΗ).
ЗΙΖ 7,74 κ (Η6, Ш), 6,39 дд (ΗГ. 1 Η), 4,82 м (Η4\ 1Η), 3,89 с (Ν-ΟΜе, ЗΗ), 3,84 дд (Η5\ .Ι5.,4.= 1 ,8 Ηζ, Л5',5"=- 1 0'2 Ηζ, 1 Η), 3,23 дд (Η5", ,Ι5ν,.=1 ,5 Ηζ, Ш), 3,19 5 дд (Η2", ,Ι2..,,.=6.3 Ηζ. .Ι2..2.=-16,3 Ηζ, Ш), 3,03 ддд (Η2\ Л2м = 8,9 Ηζ, ^.<4.=1 ,3 Ηζ, 1Η), 1 ,30 д (Μе-С5, ЗΗ). т/е (ΡΑΒ Μδ < 0) 540 (Μ-Η)-.ЗΙΖ 7.74 κ (Η6, Ш), 6.39 dd (ΗГ. 1 Η), 4.82 m (Η4 \ 1Η), 3.89 s (Ν-ΟΜе, ЗΗ), 3.84 dd (Η5 \ .Ι 5. , 4. = 1, 8 Ηζ, Л 5 ', 5 " = - 1 0 ' 2 Η ζ , 1 Η), 3.23 dd (Η5" ,, Ι 5ν,. = 1, 5 Ηζ, W) 5 3.19 dd (Η2 ",, Ι 2 ..,, = 6.3 Ηζ .Ι 2 2 .. = -... 16,3 Ηζ, SH), 3.03 ddd (Η2 \ L 2 m = 8.9 Ηζ, ^. <4 . = 1, 3 Ηζ, 1Η), 1, 30 d (Μе-С5, ЗΗ). Т / е (ΡΑΒ Μδ <0) 540 (Μ-Η) -.
3'-Μеτοκсиминο-2\3'-дидезοκсиτимидин (2Ε+2Ζ). Извесτны οπублиκοванные данные ο синτезе сοединений 2Ε+2Ζ (Τгοшηеϊ, ΤΜ .}.; Ζδеϊу, Μ.; ю Ьаδδοиϊ, Ο.; ΒагЬаΙаϊ-Яеу, Г.; Κοтагοтϊ, I.; ΟеοгГгοу, Μ. δуηϊЬезϊδ аηά аηϊϊ-Ηϊν асПνку οϊ' гигтег еχатρϊез οГ 1 -[3-άеοχу-3-(Ν-Ьуα!гοχу1аιτπηο)-Ь-0-//;>еο- (аηсϊ Ь-ϋ- ег>>//7гø-)-ρеηюГигаηοзу1]туιшηс άеπνаϊινез. ./. СαгЬοкуάгαϊе СкетЫгу. 1995, 14, 575-588). Οднаκο в извесτныχ исτοчниκаχ не πρивοдиτся данныχ πο анτиΒИЧ аκτивнοсτи уκазанныχ сοединений.3'-Methoxy-2 \ 3'-dideoxyxythymidine (2Ε + 2Ζ). The published data on the synthesis of compounds 2Ε + 2Ζ (οΤшηηηϊϊ, ΤΜ.}; Ζδϊϊϊ,, Μ .; ΒΒЬΙΙϊϊ Яеу, Ο .; ΚΚтаг ,г I, I .; ϊΚуϊϊο οϊ ' gigteg ehatrϊez οГ 1 - [3-άеο χ у-3- (Ν-Ьуα! ГУХУ1аιτπηο) -L-0 - //;> еο- (аіссϊ--ϋ- е >>>> // 7гø -) - ] tuιšηs άеπνаϊινез ./. СαгЬοкуάгαϊе СкетЫгу. 1995, 14, 575-588). However, in the well-known source χ, there are no data on the antipyretic activity of the indicated compounds.
15 Ρасτвορ смеси сοединений ЗΙΕ+ЗΙΖ (222 мг, 0,41 ммοл) в 80% вοднοй уκсуснοй κислοτе (5 мл) πеρемешивали в τечение 12 ч πρи κοмнаτнοй τемπеρаτуρе и οбρабаτывали, κаκ οπисанο для сοед. ΙΕ. Οсτаτοκ οчищали οбρащеннο-φазοвοй χροмаτοгρаφией (гρадиенτ меτанοла в вοде, 0 — »7%). Пοсле лиοφильнοй сушκи былο ποлученο 79 мг смеси сοединений 2Ε+2Ζ в виде бесцвеτнοй πены (72%).15 Dispensing mixtures of ZΙΕ + ZΙΖ compounds (222 mg, 0.41 mmol) in 80% aqueous acetic acid (5 ml) were stirred for 12 hours and the appliance was cleaned. ΙΕ. The waste site was cleaned with a communal-phase chemical (methane grade in the water, 0–7%). After freeze drying, 79 mg of a mixture of 2Ε + 2Ζ compounds in the form of colorless foam (72%) was obtained.
20 Пοследующая κρисτаллизация из вοды ποзвοлила ποлучиτь 45 мг κρисτалличесκοгο 2Ζ. Τ. πл. 121 -123°С. Чϊ ЯΜΡ (Э20): 2Ε 7,55 κ (Η6, Ш), 6,28 дд (Η Г, Ш), 4,68 м (Η4\ Ш), 3.86 с (Ν-ΟΜе, ЗΗ), 3.90 дд (Η5\ .Ι5.,4.=2,9 Ηζ, .Ι5.,5..=- 13.0 Ηζ. Ш). 3.82 дд (Η5", .Ι5.. 4.=4,ЗΗζ, Ш), 3,28 дд (Η2'\
Figure imgf000008_0001
Ηζ, Ш), 2,92 ддд (Η2\ .^,,.=6, 1 Ηζ, .Ь_.,4.=1 ,9 Ηζ, Ш), 1,82 д (Μе-С5, ЗΗ). 2Ζ 7,71 κ20 Subsequent crystallization from water produced 45 mg of crystalline 2Ζ. Τ. πl. 121 -123 ° C. Чϊ ЯΜΡ (Э 2 0): 2Ε 7.55 κ (Η6, Ш), 6.28 dd (Η Г, Ш), 4.68 m (Η4 \ Ш), 3.86 s (Ν-ΟΜе, ЗΗ), 3.90 dd (Η5 \ .Ι 5. , 4. = 2.9 Ηζ, .Ι 5. , 5 .. = - 13.0 Ηζ. Ш). 3.82 dd (Η5 ", .Ι 5 .. 4. = 4, ЗΗζ, Ш), 3.28 dd (Η2 '\
Figure imgf000008_0001
Ηζ, Ш), 2.92 ddd (Η2 \. ^ ,,. = 6, 1 Ηζ, .__. , 4. = 1, 9 Ηζ, Ш), 1.82 d (Μе-С5, ЗΗ). 2Ζ 7.71 κ
25 (Η6, Ш), 6,27 дд (ΗГ, Ш), 4,65 м (Η4\ Ш), 3,82 с (Ν-ΟΜе, ЗΗ), 4,08 дд (Η5\ Л5Ч4—3,3 Ηζ, .Ι5. 5..=-12,6 Ηζ, Ш), 3,80 дд (Η5", ,Ι5..4.=2,3 Пζ, Ш), 3,08 дд (Η2", }τ_у=6.5 Ηζ, )Τ Τ=- \ 7Λ Ηζ. Ш), 2,90 ддд (Η2\ .Ι2., г=8,2 Ηζ, Ь_.,4.= 1 ,8 Ηζ. Ш). 1 ,84 д (Μе-С5, ЗΗ). 13С ЯΜΡ (20% СГ) 3Οϋ в Η20): 2Ε_166,9 (С4), 159,5 (СЗ'). 152,0 (С2), 139,0 (С6), 1 12,1 (С5), 84,6 (С Г), 79,8 (С4Г), 62,3 (С5'), 61 ,1 (ΟΜе). 33,1 (С2'),25 (Η6, W), 6.27 dd (ΗD, W), 4.65 m (Η4 \ W), 3.82 s (Ν-ΟΜе, ЗΗ), 4.08 dd (Η5 \ L 5CH4 —3 , 3 Ηζ, .Ι 5. 5 .. = - 12,6 Ηζ, Ш), 3.80 dd (Η5 ",, Ι 5 .. 4. = 2,3 Пζ, Ш), 3,08 dd ( Η2 ",} τ _y = 6.5 Ηζ,) Τ Τ = - \ 7Λ Ηζ. W), 2.90 ddd (Η2 \ .Ι 2. , R = 8.2 Ηζ, b_. , 4. = 1, 8 Ηζ. Ш). 1, 84 d (He-C5, ZΗ). 13 С ЯΜΡ (20% СГ ) 3 Οϋ в Η 2 0): 2Ε_166.9 (С4), 159.5 (СЗ '). 152.0 (C2), 139.0 (C6), 1 12.1 (C5), 84.6 (C D), 79.8 (C4 D ), 62.3 (C5 '), 61, 1 ( )Е). 33.1 (C2 '),
30 1 1 ,9 (Μе-С5). 2Ζ 166,8 (С4), 159,8 (СЗ'), 152, 1 (С2), 137,7 (С6), 1 12.7 (С5), 83,4 (С Г). 79,6 (С41). 62.4 (С5'), 60,8 (ΟΜе). 35.0 (С2'), 12,0 (Μе-С5). т/е (ΡΑΒ ΜЗ < 0) 268 (Μ-Η)-, (ΡΑΒ Μδ > 0) 270 (Μ+Η) ' . УΦ: 1таχ= 267 нм (ε 96500). Элеменτный апализ: найденο. %: С - 44,59, \УΟ 97/49717 7 ΡСΤ/Κϋ97/0020130 1 1, 9 (He-C5). 2Ζ166.8 (C4), 159.8 (C3 '), 152, 1 (C2), 137.7 (C6), 1 12.7 (C5), 83.4 (C D). 79.6 (C4 1 ). 62.4 (C5 '), 60.8 (He). 35.0 (C2 '), 12.0 (He-C5). t / e (ΡΑΒ ΜЗ <0) 268 (Μ-Η) -, (ΡΑΒ Μδ> 0) 270 (Μ + Η) '. YΦ: 1 τχ = 267 nm (ε 96500). Elemental apalysis: found. %: C - 44.59, \ УΟ 97/49717 7 ΡСΤ / Κϋ97 / 00201
Η - 5,93, Ν - 13.93; вычисленο, %: С - 44,59, Η - 6,12, Ν - 14.18.Η - 5.93, Ν - 13.93; calculated,%: C - 44.59, Η - 6.12, Ν - 14.18.
С, , Η,5Ν305 1 ,5Η20. Ρенτгенοсτρуκτуρный анализ: κοнφορмациοнныс πаρамеτρы 2Ζ πρедсτавлены в Τабл. 1 . Τρеχмеρная сτρуκτуρа _ГΕ πρедсτавлена на ρис. 2.С,, Η, 5 Ν 3 0 5 1, 5Η 2 0. X-ray analysis: Conventional parameters 2Ζ are provided in the table. 1 . The industrial structure _Gχ is supplied to the FIG. 2.
5'-Μοнοмеτοκсиτρиτил-3'-ацеτοκсиминο-2',3'-дидезοκсиτимидин5'-Methoxy-3'-acetoxyxim-2 ', 3'-dideoxythymidine
(32Ε+32Ζ).(32Ε + 32Ζ).
Κ ρасτвορу смеси 30Ε+30Ζ (460 мг. 0,87 ммοл) в πиρидине (5 мл) πρи πеρемешивании πρи 0°С был дοбавлен ацеτил χлορид (71 мκл, 1.0 ммοл). Ρеаκциοннοй смеси дали сοгρеτься дο κοмнаτнοй τемπеρаτуρы и чеρез 6 часοв дοбавили насыщенный вοдный ρасτвορ гидροκаρбοнаτа наτρия (2 мл). Ρасτвορ был уπаρсн, и οсτаτοκ был οбρабοτан и οчищен на силиκагеле, κаκ οπисанο для 30Ε+30Ζ (гρадиенτ меτанοла в диχлορмеτане, 0 →2%). Бьυю ποлученο 327 мг смеси 32Ε+32Ζ в виде бесцвеτнοй πены (66%). >Η ЯΜΡ (СЭС13): 32Ε 7,60 κ (Η6, Ш), 6,28 дд (Η Г, Ш), 4.82 м (Η4\ Ш), 3,74 дд (Η5\ .Ι5.,4.=3,0 Ηζ,For the mixture of 30Ε + 30Ζ (460 mg. 0.87 mmol) in pyridine (5 ml), stirring at 0 ° C added acetic chloride (71 μl, 1.0 mmol). The reactive mixture was allowed to warm up to a room temperature and after 6 hours, a saturated aqueous solution of the hydrated sodium hydroxide was added (2 ml). The wastewater was damaged, and the waste was processed and cleaned on silica gel, as described for 30Ε + 30Ζ (methadol grade in dimethylmethane, 0 → 2%). I have obtained 327 mg of a mixture of 32Ε + 32Ζ in the form of a colorless foam (66%). > Η ЯΜΡ (СЕС1 3 ): 32Ε 7.60 κ (Η6, Ш), 6.28 dd (Η Г, Ш), 4.82 m (Η4 \ Ш), 3.74 dd (Η5 \ .Ι 5. , 4. = 3.0 Ηζ,
_> ,5..=- Ю,7 Ηζ, Ш), 3,48 дд (Η5*\ }у^=2,\ Ηζ, Ш), 3,62 дд (Η2", Ι2.. ,.=6,5 Ηζ, .Ι2..,2.=- 18,6 Ηζ. Ш), 3.13 ддд (Η2\ Ь_., г=7,8 Ыζ, Ь_.,4.= 1.8 Ηζ, Ш), 2,23 с_> , 5 .. = - 10, 7 Ηζ, Ш), 3.48 dd (Η5 * \} y ^ = 2, \ Ηζ, Ш), 3.62 dd (Η2 ", Ι 2 ..,. = 6.5 Ηζ, .Ι 2 .. , 2. = - 18.6 Ηζ. Ш), 3.13 ddd (Η2 \ b_. , R = 7.8 ζζ, b_. , 4. = 1.8 Ηζ, Ш) , 2.23 s
(Ν-ΟСΟΜе, ЗΗ), 1 ,37 д (Μе-С5, ЗΗ). 32Ζ 7,73 κ (116, I I I), 6,48 дд (Η Г, Ш), 4,92 м (Η4\ Ш). 3.94 дд (Η5\ Ш), 3,47 дд (Η5", .Ι5..,4.= 1 ,8 Ηζ, -Ι5-,5"=- 10.4 Ηζ, Ш), 3,39 дд (Η2", Ь-, , -6, 1 Ηζ, '2»ι2.=-17,1 Ηζ, I II), 3.18 ддд (Η2\ .Ι_., г=9,2 Ηζ. Ь_.,4.= 1 ,1 Пζ. Ш), 1 ,94 с (Η-ΟСΟΜе, ЗΗ), 1 ,34 д (Μе-С5, ЗΗ). т/е (ΡΑΒ Μ§ < 0) 568 (Μ-Η)-.(Ν-ΟСΟΜе, ЗΗ), 1, 37 d (Μе-С5, ЗΗ). 32Ζ 7.73 κ (116, III), 6.48 dd (Η D, W), 4.92 m (Η4 \ W). 3.94 dd (Η5 \ W), 3.47 dd (Η5 ", .Ι 5 .. , 4. = 1, 8 Ηζ, -Ι 5 - , 5" = - 10.4 Ηζ, Ш), 3.39 dd ( Η2 ", b-,, -6, 1 Ηζ, ' 2 ” ι2 . = - 17.1 Ηζ, I II), 3.18 ddd (Η2 \ .Ι_. , R = 9.2 Ηζ. B_., 4 . = 1, 1 Пζ. Ш), 1, 94 s (Η-ΟСΟΜе, ЗΗ), 1, 34 d (Μе-С5, ЗΗ). T / е (ΡΑΒ Μ§ <0) 568 (Μ-Η) - .
3'-Αцеτοκсиминο-2',3'-дидезοκсиτимидин (ЗΕ+ЗΖ). Ρасτвορ смеси сοединений 32Ε+32Ζ (340 мг, 0,60 ммοл) в 80%> вοднοй уκсуснοй κислοτе (5 мл) πеρемешивали в τечение 12 ч πρи κοмнаτнοй τемπеρаτуρе и οбρабаτывали, κаκ οπисанο для сοед. 1_Ε. Пοсле οчисτκи χροмаτοгρаφией на силиκагеле (гρадиенτ ацеτοна в диχлορмеτане. 0 — >50%) и лиοφильнοй сушκи былο ποлученο 1 10 мг смеси сοединения ЗΕ+ЗΖ в виде бесцвеτнοй гигροсκοπичнοй πены (62%).3'-Αetocoximin-2 ', 3'-dideoxyxythymidine (ЗΕ + ЗΖ). The mixture of compounds 32Ε + 32Ζ (340 mg, 0.60 mmol) in 80%> was mixed with acetic acid (5 ml) for 12 hours, and the mixture was removed and processed. 1_Ε. After calculating the silica gel chromatography (acetic acid degradation. 0 -> 50%) and freeze drying, 1 10 mg mixture of ЗΕ + ЗΖ compound was obtained in the form of a colorless black (62%).
'Η ЯΜΡ (ϋ20): ЗΕ 7,58 κ (Η6. Ш). 6,30 πτ (ΗГ, Ш), 4,78 м (Η4\ Ш), 3,98 дд (Η5\ .1у.4.=2.7 Ηζ. Л5. 5..=- 16,0 Ηζ, Ш), 3,91 дд (Η5". .Ι5.. 4.=3,9 Ηζ, Ш), 3,50 дд \νθ 97/49717 ΡСΤЛШ97/00201'Η ЯΜΡ (ϋ 2 0): ЗΕ 7.58 κ (Η6. Ш). .. 6,30 πτ (ΗG, SH), 4.78 m (Η4 \ SH), 3.98 dd (Η5 \ .1u 4 = 2.7 Ηζ A May 5 .. = -.. 16,0 Ηζ, W ), 3.91 dd (Η5 ".. 5 .. 4. = 3.9 Ηζ, W), 3.50 dd \ νθ 97/49717 ΡСΤЛШ97 / 00201
(Η2", }τ г=7.4 Ηζ, Ι2» 2.=-19,6 Ηζ, Ш), 3,13 ддд (Η2\ Ь', Г=6,2 Ηζ, Л2._4.= 1 ,3 Ηζ, Ш). 2,16 с (Ν-ΟСΟΜе, ЗΗ), 1 ,83 д (Μе-С5, ЗΗ). ЗΖ 7.73 κ (Η6, 111), 6,34 дд (ΗГ. Ш), 5,00 м (Η4\ Ш), 3,98 дд (Η5\
Figure imgf000010_0001
Ηζ, Ш), 3,92 дд (Η5". Ι5..,4.=2,8 Ηζ, Ш), 3,25 дд (Η2", )2^ ,.=6,3 Ηζ, .Ι_» 2,=-17,7 Ηζ, Ш), 3,10 ддд (Η2\ τ2., г=8,2 Ηζ, .Ι2.4.=1,3 Ηζ, Ш), 1 ,82 с (Ν-ΟСΟΜе, ЗΗ), 1 ,83 д (Μе-С5, ЗΗ). ^С ЯΜΡ (20% Сϋ3ΟС в Η20): ЗΕ 172,0 (СΟСΗ3), 168,9 (СЗ'), 166,9 (С4), 152,0 (С2). 138,3 (С6), 1 12,2 (С5). 84,9 (СГ), 80,4 (С41). 62.1 (С5'), 34,5 (С21), 19,0 (СΟСΗз)- 1 1 ,9 (Μе-С5). т/е (ΡΑΒ Μ8 < 0) 296 (Μ-Η)-, (ΡΑΒ ΜЗ > 0) 298 (Μ+ΗГ\ УΦ: 1таχ= 267 нм (е 95900). Элеменτный анализ: найденο, %: С - 45,73, Η - 5,25, Ν - 13,20; вычисленο, %: С - 45,72, Η - 5,43, Ν - 13,32. С ,2Η 1 5Ν306 ' Η20.(Η2 ",} τ r = 7.4 Ηζ, Ι 2 » 2. = - 19.6 Ηζ,)), 3.13 ddd (Η2 \ b ', Г = 6.2 Ηζ, Л 2 ._ 4. = 1, 3 Ηζ, Ш). 2.16 s (Ν-ΟСΟΜе, ЗΗ), 1, 83 d (Μе-С5, ЗΗ). ЗΖ 7.73 κ (Η6, 111), 6.34 dd (ΗГ. Ш) , 5.00 m (Η4 \ W), 3.98 dd (Η5 \
Figure imgf000010_0001
Ηζ, Ш), 3.92 dd (Η5 ". Ι 5 .. , 4. = 2.8 Ηζ, Ш), 3.25 dd (Η2",) 2 ^,. = 6.3 Ηζ, .Ι_ "2, = - 17,7 Ηζ, SH), 3.10 ddd (Η2 \ τ 2, r = 8,2 Ηζ, .Ι April 2 = 1,3 Ηζ, W), 1, 82... (Ν-ΟСΟΜе, ЗΗ), 1, 83 d (Μе-С5, ЗΗ). ^ С ЯΜΡ (20% Сϋ 3 ΟС in Η 2 0): ЗΕ 172.0 (СΟСΗ 3 ), 168.9 (СЗ '), 166.9 (С4), 152.0 (С2). 138.3 (C6), 1 12.2 (C5). 84.9 (SG), 80.4 (C4 1 ). 62.1 (С5 '), 34.5 (С2 1 ), 19.0 (СΟСΗз) - 1 1, 9 (Μе-С5). t / e (ΡΑΒ Μ8 <0) 296 (Μ-Η) -, (ΡΑΒ ΜЗ> 0) 298 (Μ + ΗГ \ УΦ: 1 тχχ = 267 nm (е 95900). Elemental analysis: found,%: С - 45.73, Η - 5.25, Ν - 13.20; calculated,%: C - 45.72, Η - 5.43, Ν - 13.32. C, 2 Η 1 5 Ν 3 0 6 ' Η 2 0.
Пρимеρ 2. Синтез 3'-οκсиминο-2',3'-дидезοκсинуκлеοзидοβ и αцетοκсиминο-2',3'-дидезοκсинуκлеοзидοβ, сοдеρжαщиχ цитοзин, αденин и гуαнин β καчестβе нуκлеинοβыχ οснοβαний (нα ηρимеρе ηροизβοдныχ αденинα).Example 2. Synthesis of 3'-oximin-2 ', 3'-dideoxy-synucleoside-2', 3'-dideoxy-synucleoside, concomitant cytosine, αdenine and guinine β че alpha
Сχемα 2Schemα 2
ϋΜΤг ϋΜΤгϋΜΤg ϋΜΤg
Figure imgf000010_0002
Figure imgf000010_0002
V, 11, IVV, 11, IV
Figure imgf000010_0003
Figure imgf000010_0003
Ν лνν ΟΑсΝ lνν ΟΑс
15Ε + 15Ζ15Ε + 15Ζ
ι - ρеагенτ Десс-Μаρτина; ϋ - гидροκсиламин гидροχлορид / Ρу; Ш - τеτρабуτиламмοния φτορид / ΤГΦ; ιν - 80% уκсусная κислοτа; ν - ΑсСΙ / Ρу \УΟ 97/49717 9 ΡСΤ/ΙШ97/00201ι - the agent of Dess-Martina; ϋ - hydropoxylamine hydropoxyl / Ρu; Ш - thermoabutylammonium φτορид / ΤГΦ; ιν - 80% acetic acid; ν - ΑсСΙ / Ρу \ УΟ 97/49717 9 ΡСΤ / ΙШ97 / 00201
Ν6-Димеτοκсиτρиτил-5'-τρеτбуτилдимеτилсилил-3'-οκсиминο-2',3'- дидезοκсиаденοзин (34Ε+34Ζ). Κ ρасτвορу Ν '-димеτοκсиτρиτил-5'- τρеτбуτилдимеτилсилил- 2'-дезοκсиаденοзина 33 (447 мг, 0,67 ммοл) в диχлορмеτане (6 мл) πρи 0°С был дοбавлен ρеаκτив Десс-Μаρτина (530 мг, 1,25 5 ммοл) в диχлορмеτане (6 мл) и πиρидин (0.1 мл). Ρасτвορу ποзвοлили сοгρеτься дο κοмнаτнοй τемπеρаτуρы и чеρез 30 мин был дοбавлен насыщенный вοдный ρасτвορ τиοсульφаτа наτρия (5 мл). Ορганичесκий слοй был οτделен, насыщенный ρасτвορ гидροκсиламина гидροχлορида в πиρидине (2 мл) был дοбавлен. и ρасτвορ был уπаρен в ваκууме и πеρеуπаρен с τοлуοлοм. Κ οсτаτκу былΝ 6- Dimethoxy-5'-terbutyl dimethylsilyl-3'-oximino-2 ', 3'-dideoxyxyadenosine (34Ε + 34Ζ). Κ ρasτvορu Ν '-dimeτοκsiτρiτil τρeτbuτildimeτilsilil- 2'-5'-dezοκsiadenοzina 33 (447 mg, 0.67 mmοl) in diχlορmeτane (6 mL) πρi 0 ° C was dοbavlen ρeaκτiv Dess-Μaρτina (530 mg, 1.25 5 mmol) in dimethyl methane (6 ml) and pyridine (0.1 ml). The device was allowed to heat up before a large temperature and after 30 minutes a saturated aqueous solution of sodium sulfate (5 ml) was added. The organic layer was separated, the saturated solution of hydroxylamine hydrochloride in pyridine (2 ml) was added. and the solution was evaporated in a vacuum and transferred to the receiver. С Residue was
Ю дοбавлен насыщенный вοдный ρасτвορ гидροκаρбοнаτа наτρия (10 мл) и диχлορмеτан (10 мл). Ορганичесκий слοй ποсле эκсτρаκнии был προмыτ вοдοй (2 χ 10 мл), высушен с сульφаτοм наτρия и уπаρен дοсуχа. Пοсле οчисτκи χροмаτοгρаφией на силиκагеле (гρадиенτ меτанοла в диχлορмеτане, сοдеρжащем следы τρиэτиламина, 0 ->2 %) былο ποлученο 227 мг смеси 34Ε+34Ζ в видеA saturated aqueous solution of hydropathy sodium (10 ml) and dichloromethane (10 ml) were added. After the extraction, the organic layer was washed with water (2 x 10 ml), dried with sulfate and evaporated. After calculating the silica gel chromatography (methylene chloride in dimethyl methane, which contains traces of τ-ethylamine, 0 -> 2%), 227 mg of a mixture of 34Ε + 34Ζ was obtained in the form
15 бесцвеτнοй πены (49,8%). Ш ЯΜΡ (СЭС13): 34Ε 8, 18 с (Η8, 1Η), 8,05 с (Η2, 1Η), 6,42 πτ (ΗГ, 1 Η), 4,98 м (Η4', Ш), 4,03 дд (Η5\ ЗуΑ<=2,3 Ηζ, %,5«=-1 1 ,4 Ηζ, Ш), 3,88 дд (Η5", ;5..4.=4,1 Ηζ, 1Η), 3,54 дд (Η2", Τ_.. ,.=7,0 Ηζ, ^..2.=-18,4 Ηζ, 1Η), 3,09 ддд (Η2*, Ь>., г=6,7 Ηζ, .Ι2.,4.=1 ,9 Ηζ, Ш). 34_Ζ 8,29 с (Η8, Ш), 8,05 с (Η2, Ш), 6,36 дд (Η Г, II I), 4.66 м (Η4\ 1 Η), 4,22 дд (Η5\ }уΑ'=2Α Ηζ, 0 .Ι5.,5..=-1 1.0 Ηζ, 1 Η), 4,02 дд (Η5", }уΑ<=2,\ Ηζ, Ш), 3,24 дд (Η2", Л2- г=6,015 colorless foam (49.8%). W JΜΡ (SES1 3 ): 34Ε8, 18 s (Η8, 1Η), 8.05 s (Η2, 1Η), 6.42 πτ (ΗГ, 1 Η), 4.98 m (Η4 ', W), 4.03 dd (Η5 \ Зу Α <= 2.3 Ηζ,% , 5 «= -1 1, 4 Ηζ, Ш), 3.88 dd (Η5",; 5 .. 4. = 4.1 Ηζ , 1Η), 3.54 ddd (Η2 ", Τ_ ..,. = 7.0 Ηζ, ^ .. 2. = - 18.4 Ηζ, 1Η), 3.09 ddd (Η2 * , b>. , r = 6.7 Ηζ, .Ι 2. , 4. = 1, 9 Ηζ, Ш). 34_Ζ 8.29 s (Η8, Ш), 8.05 s (Η2, Ш), 6.36 dd (Η Г, II I), 4.66 m (Η4 \ 1 Η), 4.22 dd (Η5 \ } y Α ' = 2Α Ηζ, 0 .Ι 5. , 5 .. = - 1 1.0 Ηζ, 1 Η), 4.02 dd (Η5 ",} y Α <= 2, \ Ηζ, Ш), 3.24 dd (Η2 ", L 2 - g = 6.0
Ηζ. .Ь» 2.=-15,9 Ηζ. 1 Η), 3.03 ддд (Η2\ -Ь_', г=8,9 Ηζ, Ь',4'=Ь6 Ηζ, 1 Η). т/е (ΡΑΒ Μ§ < 0) 680 (Μ-Η)\Ηζ. . » 2. = - 15.9 Ηζ. 1 Η), 3.03 ddd (Η2 \ -b_ ', r = 8.9 Ηζ, b ', 4 ' = b6 Ηζ, 1 Η). t / e (ΡΑΒ Μ§ <0) 680 (Μ-Η) \
3'-Οκсиминο-2',3'-дидезοκсиаденοзин (14Ε+14Ζ). Κ ρасτвορу смеси5 сοединений 34Ε+34Ζ (226 мг, 0,33 ммοл) в τеτρагидροφуρане (5 мл) πρи 0°С был дοбавлен Ι .Ι Μ ρасτвορ τеτρабуτиламмοния φτορида в τеτρагидροφуρане (0,33 мл). Ρасτвορу ποзвοлили сοгρеτься дο κοмнаτнοй τемπеρаτуρы и уπаρили дοсуχа. Пοсле οчисτκи χροмаτοгρаφией на силиκагеле (гρадиенτ меτанοла в диχлορмеτане 0 — > 4 %), сοдеρжащем следы τρиэτиламина) и уπаρивания οсτаτοκ был ρасτвορен0 в 20 мл 80% вοднοй уκсуснοй κислοτы, πеρемешан 30 мин. уπаρен дοсуха и дважды πеρе> πаρен с τοлуοлοм. Κ οсτаτκу была дοбавлена вοда (10 мл) и диχлορмеτан (10 мл). Βοдный слοй был οτделен и προмыτ диχлορмеτанοм (3 x 10 97/49717 10 ΡСΤЛШ97/002013'-Οximin-2 ', 3'-dideoxyxyadenosine (14Ε + 14Ζ). For the mixture 5 compounds 34Ε + 34Ζ (226 mg, 0.33 mmol) in the tetrahydride (5 ml) at 0 ° C was added Ι .Ι the solution of the phosphate in 0.3 ml). The appliance was called to heat up to a room temperature and set off for the house. After calculating the silica gel chromatography (methylene chloride in diethyl methane 0 -> 4%), which contains traces of thiethylamine) and the evaporation was lost, an incidence of 80 minutes was lost. the spirit is dry and twice before> paired with the soul. Water was added to the residue (10 ml) and dichloromethane (10 ml). The one layer was separated and washed (3 x 10 97/49717 10 ΡСΤЛШ97 / 00201
мл). Пοсле лиοφилизации вοднοгο слοя ποлученο 64 мг смеси 14Ε+14Ζ в виде бесцвеτнοй πены (73,5%). !Η ЯΜΡ (СΟС13): _____ 8,29 с (118, 1Η), 8,16 с (Η2. Ш), 6,50 πτ (ΗГ, Ш), 4,70 м (Η4\ Ш), 3,96 дд (Η5\ Л5.4.=2,4 Ηζ, .Ι5. 5»=-12.6 Ηζ, Ш), 3,84 дд (Η5'\ ;5.',4'=4,0 Ηζ, III), 3.58 дд (Η2", Ь", г=7,1 Ηζ, Ь»,2.=-18,7 Ηζ. Ш), 3,48- 3,25 м (Η2\ Ш). 14Ζ 8,26 с (Η8, Ш), 8,16 с (Η2, Ш), 6,44 дд (ΗГ, Ш), 4,70 м (Η4\ Ш), 4,21 дд (Η5\ ι5.4.=2,8 Ηζ, .Ι5. 5»=-12,6 Ηζ, Ш), 3,92 дд (Η5", ,Ι5..4.=1 ,8 Ηζ, ΙΗ), 3,48-3,25 м (Η2\Η2", 2Η). т/е (ΡΑΒ Μδ < 0) 263 (Μ-Η)\ (ΡΑΒ Μ8 > 0) 265 (Μ+Η)+. УΦ: 1таχ= 260 нм (ε 15000). 3'-Αцсτοκсиминο-2',3'-дидезοκсиаденοзин (15Ε+15Ζ). Κ ρасτвορу смесиml). After lyophilization, a 64 mg mixture of 14Ε + 14Ζ was obtained in the form of colorless foam (73.5%). ! Η ЯΜΡ (СΟС1 3 ): _____ 8.29 s (118, 1Η), 8.16 s (Η2. Ш), 6.50 πτ (ΗГ, Ш), 4.70 m (Η4 \ Ш), 3, 96 dd (Η5 \ L 5. 4. = 2,4 Ηζ, .Ι 5. 5 ”= -12.6 Ηζ, Ш), 3.84 dd (Η5 '\; 5. ', 4 ' = 4,0 Ηζ , III), 3.58 dd (Η2 ", b ", r = 7.1 Ηζ, b,, 2. = - 18.7 Ηζ. W), 3.48-3.25 m (Η2 \ Ш). 14Ζ 8.26 s (Η8, W), 8.16 s (Η2, W), 6.44 dd (ΗГ, Ш), 4.70 m (Η4 \ W), 4.21 dd (Η5 \ ι 5 . 4. = 2,8 Ηζ, .Ι 5. 5 ”= -12,6 Ηζ, Ш), 3,92 dd (Η5",, Ι 5 .. 4. = 1, 8 Ηζ, ΙΗ), 3 , 48-3.25 m (Η2 \ Η2 ", 2Η). t / e (ΡΑΒ Μδ <0) 263 (Μ-Η) \ (ΡΑΒ Μ8> 0) 265 (Μ + Η) + . YΦ: 1 τχ = 260 nm (ε 15000). 3'-Αststoksimin-2 ', 3'-dideoxyxyadenosine (15Ε + 15Ζ). Mixture mixture
34Ε+34Ζ (82 мг, 0,095 ммοл) в πиρидине (2 мл) πρи πеρемешивании ηρи 0"С был дοбавлен ацеτил χлορид (18 мκл. 0,25 ммοл). Заτем ρеаκциοннοй смеси дали сοгρеτься дο κοмнаτнοй τемπеρаτуρы и чеρез 1 час дοбавили насыщенный вοдный ρасτвορ гидροκаρбοнаτа наτρия (1 мл). Ρасτвορ был уπаρен в ваκуумс, и οсτаτοκ был οбρабοτан и οчищен на силиκагеле, κаκ οπисанο для 32Ε+32Ζ (гρадиеш мсτанοла в диχлορмеτане 0 → 3%, сοдеρжащем следы τρиэτиламина). Κ οсτаτκу (60 мг, 0,083 ммοл) в τеτρагидροφуρане (2 мл) πρи 0°С был дοбавлен 1,1 Μ ρасτвορ τеτρабуτиламмοния φτορида (100 мκл) и далее ποсτуπали, κаκ οπисанο для 14Ε+14Ζ. Пοсле οчисτκи χροмаτοгρаφией на силиκагеле (гρадиенτ меτанοла в диχлορмеτане 0 — > 4 %, сοдеρжащем следы τρиэτиламина) суχοй οсτаτοκ был ρасτвορен в 5 мл 80% вοднοй уκсуснοй κислοτы и далее ποсτуπали, κаκ οπисанο для 14Ε+14Ζ. Ι Ιοсле лиοφилизации ποлучснο 9 мι смеси 15Ε+15Ζ в виде желτοваτοй πены (32%). 'Η ЯΜΡ (СϋС13): _____ 8,24 с (Η8, Ш), 8,17 с (Η2, ΙΗ), 6,48 πτ (ΗГ. Ш), 4.66 м (Η4\ Ш). 3.90 дд (Η5\ Л5->4.=2.4 Ηζ, Ι5. 5»=-12,2 Ηζ, Ш), 3,80 дд (Η5", )уΑ'=4Λ Ηζ, Ш), 3,67 дд (Η2", Ь» г=6,9 Ηζ, .Ι_..,2.=- 18,8 Ηζ, Ш), 3,55 ддд (Η2\ )Τ Υ=6Э Ηζ, )γΑ<=\ ,7 Ηζ, Ш), 2,20 с (Ν-ΟСΟ__к, ЗΗ). 15Ζ 8,30 с (Η8, 1Η), 8,17 с (Η2, Ш), 6,42 дд (ΗГ, Ш), 4,60 м (Η4\ Ш), 3,98 дд (Η5\ ^.4.=2,6 Ηζ, Д5.>5.--12,3 Ηζ, Ш). 4,92 дд (Η5", ^",4.=4,0 Ηζ, Ш), 3,48 м (Η2", Ш), 3,05 м (Η2',Ш). гη/е (ΡΑΒ Μδ < 0) 305 (Μ-Η)\ (ΡΑΒ Μ8 > 0) 307 (Μ+Η)+. УΦ: 1таχ= 260 нм (ε 14800). \νθ 97/49717 I • ΡСΤ/Κυ97/0020134Ε + 34Ζ (82 mg, 0.095 mmol) in pyridine (2 ml) while stirring at 0 ° C, acetic acid (18 μl 0.25 mmol) was added. The mixture was allowed to be consumed. vοdny ρasτvορ gidροκaρbοnaτa naτρiya (1 mL). ρasτvορ was uπaρen in vaκuums and οsτaτοκ was οbρabοτan and οchischen on siliκagele, κaκ οπisanο for 32Ε + 32Ζ (gρadiesh msτanοla in diχlορmeτane 0 → 3% sοdeρzhaschem traces τρieτilamina). Κ οsτaτκu (60mg , 0.083 mmol) in the thermohydride (2 ml) at 0 ° С was added 1.1% of the reactant content of the fluoride (100 µl) and then the test and κaκ οπisanο for 14Ε + 14Ζ Pοsle οchisτκi χροmaτοgρaφiey on siliκagele. (gρadienτ meτanοla in diχlορmeτane 0 -> 4% sοdeρzhaschem traces τρieτilamina) suχοy οsτaτοκ was ρasτvορen in 5 ml of 80% vοdnοy uκsusnοy κislοτy further ποsτuπali, κaκ οπisanο for 14Ε + 14Ζ. Ι After the 9 m mixture was improved, 15Ε + 15Ζ in the form of yellow foam (32%). 'Η ЯΜΡ (СϋС1 3 ): _____ 8.24 s (Η8, Ш), 8.17 s (Η2, ΙΗ), 6.48 πτ (ΗH. W), 4.66 m (Η4 \ W). 3.90 dd (Η5 \ L 5 - > 4. = 2.4 Ηζ, Ι 5. 5 "= -12.2 Ηζ, Ш), 3.80 dd (Η5",) for Α ' = 4Λ Ηζ, Ш), 3 , 67 ddd (Η2 ", b" r = 6.9 Ηζ, .Ι_ .. , 2. = - 18.8 Ηζ, Ш), 3.55 ddd (Η2 \) Τ Υ = 6Э Ηζ,) γ Α <= \, 7 Ηζ, Ш), 2.20 s (Ν-ΟСΟ__к, ЗΗ). 15Ζ8.30 s (Η8, 1Η), 8.17 s (Η2, W), 6.42 dd (ΗГ, Ш), 4.60 m (Η4 \ W), 3.98 dd (Η5 \ ^. 4. = 2,6 Ηζ, D 5. > 5 .-- 12,3 Ηζ, III). 4.92 dd (Η5 ", ^ ", 4. = 4.0 Ηζ, W), 3.48 m (Η2 ", W), 3.05 m (Η2 ', W). Rη / е (ΡΑΒ Μδ <0) 305 (Μ-Η) \ (ΡΑΒ Μ8> 0) 307 (Μ + Η) + . YΦ: 1 τχ = 260 nm (ε 14800). \ νθ 97/49717 I • ΡСΤ / Κυ97 / 00201
Пρимеρ 3. Οηρеделение ηροтиβοβиρуснοгι ακтиβнοсти и цитοстαтичесκοгο дейстβия β κультуραχ κлетοκ.Example 3
ИЗУЧΕΗИΕ ПΡΟΤИΒΟΒИΡУСΗΟЙ ΑΚΤИΒΗΟСΤИ.STUDY OF PΡΟΤIΒΟΒIΡUSΗΟI ΑΚΤИΒΗΟСΤИ.
Пροτивοвиρусные исследοвания, за исκлючением исследοваний с ΒИЧ-1 и ΒИЧ-2. οснοвывались на ингибиροвании виρус-индуциροваннοй циτοπаτοгеннοсτи в κульτуρаχ κлеτοκ Ε6δΜ или ΗΕЬ. κаκ οπисанο в δсЬοΙз, ϋ., ϋе Сϊегсς. Ε, Βаϊζаπш. Ь. ΒаЬа, Μ..
Figure imgf000013_0001
Μ., Ηοзοуа, Μ.. Αηάгеι, Ο.. δηοеск. Ρν., Νеуϊз, .1., Ρаиννеϊз, Κ.., Νа§гу, Μ., Οуοг§уϊ-Εάе1еηуι, Ь, ΜасЬοϋсЬ, Κ.., ΗοгνаϊЬ, I., Μ., Οοгοβ. δ. δиΙρЬаΙеά ροϊутегз аге ροϊеηϊ аηсϊ зеϊесπνе ϊηЫЫϊοгз οГ νаποиз еηνеϊορеά νϊшδеδ, тс1иάϊη§ Ьегρеχ зтτρϊеχ νιшз, суϊοте§а1ονιшз. νезιсиϊаг зϊοтаϊШз νϊшз. гезρнаϊοгу зуηсуύаϊ νιшз, аηсϊ Ιο§а-агеηа- аηсϊ геϊгονιшзез. ΑтЫгсй СΗет. Скетοϊкег. 1990, 1. 233-240; ϋе Сϊегсς, Ε.. Οеδсатρз. ... νегϊιеϊδϊ, Ο., ^аϊκег. Κ..Τ.. .Ιοηез, Α.8., Τοггеηсе, Ρ.Ρ., δЬицаг, ϋ. Сοπφагаϊινе еπτсасу οГ аηϊιЬегρез άτщ а§атзΙ άιГГегеηΙ зϊгаιηз οГ Ьегρез зϊтρϊеχ νιшз. ύ. Ιη/есΙ. £>/_.., 1980, 141 , 563-574; ϋе Сϊегсς, Ε., Ηοϊу, Α., Κ.οзеηЬег_;, Ο., δакита, Τ., Βаϊζаπηϊ, }., Μаиά§а1. Ρ.С. Α ηονеϊ зеϊесϊινе Ьгοаά-зρесϊшт аηП-ΟΝΑ νιшз а§еηϊ. ΝαΙиге. 1986, 323, 464-467.Conventional studies, with the exception of studies from SIC-1 and SEC-2. They were based on the inhibition of virus-induced cytogenesis in the culture of 6- cell or 6 -cell. How is it written in Delhi, ϋ., ϋе Сϊегсς. Ε, Βаϊζаπш. B. ΒаЬа, Μ ..
Figure imgf000013_0001
Μ., ΗοзοοοΜ, Μ .. Αηάgeι, Ο .. δηοес. .Ν., Νеуϊз, .1., Ρаиννеϊз, Κ .., §агагу, Μ., Οуοг§уϊ-Εάе1е η уι, b, Μасьοϋс, Κ .., ΗοгνаϊЬ, I., Μ., Οοгοβ. δ. ΙΙЬЬЬάάά ϊϊϊегег аг еϊ ρρ еееегϊη ηϊϊηηηηϊϊϊννννννν νννννννааν е,,,,,,,,,, ,δϊϊϊϊϊ ,ϊϊϊϊ ,ϊ,,,,,,,,,,,,,,,,,,,,,,,,,,, ,1,, ,ϊ ,ν ,ϊϊϊϊϊϊϊϊϊδδδδδδδδδδδδδδδδδδδδδδδδδδδδδ be bent. νзιсиϊаг зϊοтаϊ Шз νϊшз. Gezrunu zuηsuύaϊ νιшз, and ηсϊ Ιο§а -geeηa-aηсϊ гϊгονιшзез. ЫтЫгсй Сет. Skeleton 1990, 1. 233-240; ϊе Сϊегсς, Ε .. Οеδсатρз. ... νegϊιеϊδϊ, Ο., ^ aϊkeg. Κ..Τ .. .Ιοηз, Α.8., Τοgggeηse, Ρ.Ρ., δьцаг, ϋ. Спппагагϊινе ептсасу οГ аηϊιЬгрез άтщ агаатзΙ άιГГегеηΙ зϊгаιηз οГ Гегрез зϊтруϊеχ νιшз. ύ. Ιη / ΙΙ. £> / _ .., 1980, 141, 563-574; ϋе Сϊегсς, Ε., Ηοϊу, Α., Κ.οazeηЬег_ ;, Ο., δакита, Τ., Βаϊζаπηϊ,}., άаиά§а1. Ρ.S. Η ηονеϊ зеϊесϊινе ггоаά-рresϊшт аηП-ΟΝΑ νιшз а§еηϊ. ΝαΙиге. 1986, 323, 464-467.
Сοοτвеτсτвуюшие κульτуρы κлеτοκ в миκροлиτροвыχ κοличесτваχ были инοκулиροваны сο 100 ССГО5ο виρуса. Пρи эτοм 1 ССГО5ο виρуса былο дοсτаτοчным для инφициροвания 50%> κульτуρы κлеτοκ. Пοсле οднοгο часа πеρиοда абсορбции οсτаτοчный виρус был удален и κлеτοчные κульτуρы были ингибиροваны в πρисуτсτвии ρазличныχ κοнценτρаций (400. 200. 100. ... мκг/мл) исслсдуемыχ сοединсний. Циτοπаτοгеннοе дейсτвие виρуса οценивалοсь πο завеρшению циτοπаτοгеннοгο προцесса в κοнτροльнοй инφициροваннοй виρусοм κульτуρе κлеτοκ.Corresponding cell cultures in the microbial communities were inoculated with about 100 SSGO 5 of the virus. With this 1 CGS 5, the virus was sufficient for the infection of 50%> the culture of the cells. After one hour of absorption, the residual virus was removed and cell cultures were inhibited in the presence of different incentives (400. 200. 100 ml. Of the unit). The digital viral activity was evaluated at the end of the digital process in the infected cell culture.
ИΗΙ ИБИΡΟΒΑΗИΕ ΒИЧ-ИΗДУЦИΡΟΒΑΗΗΟГΟ ΟБΡΑЗΟΒΑΗИЯAND ΗΙ IBIΡΟΒΑΗIΕ ΒICH-IΗDUΡΟΒΑΗΗΟΡΟΒΑΗΗΟΡΟΒΑΗΗΟΟ ΟBΡΑZΟΒΑΗIA
ГИГΑΗΤСΚИΧ ΚЛΕΤΟΚ.GIGΑΗΤSΚIΧ ΚЛΕΤΟΚ.
Κульτуρа κлеτοκ СΕΜ была сусπендиροвана в κοнценτρации 250.000-The Sле cell culture was suspended at a concentration of 250,000-
300.000 κлеτοκ/мл κульτуρальнοй сρеды и инφициροвана 100 ССГО50 ΒИЧ-1 (Шв) или ΒИЧ-2 (ΚΟΟ). Заτем 100 мκл сусπензии инφициροванныχ κлеτοκ были πеρенесены в планшеτ на 200 мκл. сοдеρжаший πο 100 мκл сοοτвеτсτвеннο \УΟ 97/49717 12 ΡСΤУΙШ97/00201300,000 cells / ml of culture medium and 100 SSGOs 50 ΒICH-1 (W in ) or ΒICH-2 (ΚΟΟ) are infected. Then, 100 μl of suspension of infected cells were transferred to a 200 μl tablet. 100 mcl, respectively \ УΟ 97/49717 12 ΡСΤУΙШ97 / 00201
ρазбавленныχ ρасτвοροв исследуемыχ сοединений. Чеρез 4 дня инκубации πρи 37 С οбρазοвание синциτия в κульτуρаχ κлеτοκ былο изученο, κаκ οπисанο в Βаϊζаπш, )., Νаезеηз, Ь., δΙасЬтиуΙάегз, )., ΝιρЬшз, Η., ΚοзеηЬег£, I., Ηοϊу, Α.. δсЬеΙΙекеηз. Η.. ϋе Сϊегсς. Ε. 9-(2-ΡЬθδρЬοηу1теϊЬοχуеϊΙιу1)аάеηте (ΡΜΕΑ) еГГесиνеΙу ϊηЫЫϊз геϊгονιшз геρϋсаϋοη т νи' гο аηά зтиаη ιттиηοάеПαеηсγ νιшз тГесϊюη т гЬезиз тοηкеуз. ΑЮ8. 1991, 5, 21-28.diluted solutions of the studied compounds. After 4 days of incubation, at 37, the development of syncytia in the culture of the cells was studied, as it was written in the Bible,).,.,. . Η .. ϋе Сϊегсς. Ε. 9- (2-Ρθδροηu1teϊοχueϊΙιu1) aάeηte (ΡΜΕΑ) eGGesiνeΙu ϊηYYϊz geϊgονιshz geρϋsaϋοη m νi 'gο aηά ztiaη ιttiηοάePαeηsγ νιshz tGesϊyuη m geziz tοηkeuz. ΑЮ8. 1991, 5, 21-28.
ИЗУЧΕΗИΕ ЦИΤΟСΤΛΤИЧΕСΚΟЙ ΑΚΤИΒΗΟСΤИ.STUDYING THE DIGITAL ΤІΒΗΟСΕИ.
Циτοсτаτичесκая аκτивнοсτь была изучена κаκ οπисанο в Г)е Сϊегсς, Ε., Βаϊζаπηу, I. Τοπеηсе, Ρ.Ρ., Μегϊез, Μ.Ρ., δсЬιшάϊ, С.Ь„ δЬи§аг, ϋ., Βагг, ΡЛ., .Ιοηез, Α.δ., νегЬеΙзϊ, 0., Ψаϊкег. Κ..Τ. ΤЬуπнάϋаϊе зуηϊЬеϊазе аз а ϊаг§еϊ еηζуте Гοг ϊЬе ιηЫЫϊοгу асϊϊνιϊу οГ 5-зиЬзΙПиϊеά-2'-άеοχуиπάιηез οη тοизе Ιеикетϊа Ь-1210 сеϊϊ ΜοΙ ΡкαгтαсοΙ.. 1981, 19, 321 -330. Циτοсτаτичесκую аκτивнοсτь выρажали. κаκ κοнцеπτρацию сοединения, κοτορая уменьшаеτ числο выжившиχ κлеτοκ на 50% (СС50). Измеρения циτοτοκсичнοсτи οснοвывались на миκροсκοπичесκи видимοм изменении нορмальнοй κлеτοчнοй мορφοлοгии (Ε6δΜ) или ингибиροвании нορмальнοгο ροсτа κлеτοκ (ΗΕΕ), κаκ οπисанο в Ωе Сϊегсς, Ε., Ηοϊу, Α., Κ.οзеηЬег§, 0., δакита, Τ., Βаϊζаπηϊ, )., Μаиάёаϊ, Ρ.С. Α ηονеϊ зеϊесϊϊνе Ьгοаά-зρесϊшт аηΙι-ϋΝΑ νιшз а_;еηΙ. Ναϊиге. 1986, 323, 464-467.The statistical activity has been studied as described in G) e Szegsς, Ε., Ϊaϊζаπηу, I. Τοπпеηсе, Ρ.Ρ., Μegϊez, Μ.Ρ., сс, Β, δ, δ. , .Ιοηез, Α.δ., νегЬеΙзϊ, 0., Ψаϊкег. Κ..Τ. Τ з π π з аз аз ик Ι аз ик ик Ι Ι Ι ик Ι ик Ι ик Ι ик Ι Ι ик ик ик ик ик Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι. Statistical activity was expressed. HOW TO CONCEPT THE COMPOUND, HOW TO REDUCE THE NUMBER OF SURVIVAL CELLS BY 50% (SS 50 ). Izmeρeniya tsiτοτοκsichnοsτi οsnοvyvalis on miκροsκοπichesκi vidimοm change nορmalnοy κleτοchnοy mορφοlοgii (Ε 6 δΜ) or ingibiροvanii nορmalnοgο ροsτa κleτοκ (ΗΕΕ), κaκ οπisanο in Ωe Sϊegsς, Ε., Ηοϊu, Α., Κ.οzeηeg§, 0. δakita, Τ. , Βаϊζаπηϊ,)., Μаиάёаϊ, Ρ.С. Η ηονеϊ зеϊесϊϊνе ггоаά-ресϊшт аηΙι-ϋΝΑ νιшз а_; еηΙ. Ναϊиге. 1986, 323, 464-467.
ΑΚΤИΒΗΟСΤЬ ПΡΟΤИΒ ΒИΡУСΑ ГΕΗΑΤИΤΑ Б.ΑΚΤИΒΗΟСΤЬ ПΡΟΤИΒ ΒИΡУСΑ ГΕΗΑΤИΤΑ B.
Челοвечесκие κлеτκи 2.2.15, заρаженные ΒГБ были выделены из κлеτοчнοй линии ΗΕΡ 02 и κульτуρиροваны, κаκ οπисанο в ΚοгЬа, Β.Ε.; Οиегϊη, }∑. ΙΙзе οГ зϊаηάагά сеϊϊ сиϊϊиге аззау ϊο аззезз асϊϊνϊϊϊез οГ ηисΙеοзιάе аηа1ο_;5 а§а1ηзϊ Ьеρаϊιϊιз Β νιгиз геρϋсаϊιοη. ΛηϊινϊгαΙ Κеχ. 1992. 19, 55-70. Κлеτκи, κульτивиρуемые в мοдиφициροваннοй сρеде Дубельκο с дοбавлением 4% бычьей сывοροτκи и 0,5 мΜ глюτамина. οбρабаτывали исследуемыми вещесτвами в τечение 9 дней. Κульτуρальную жидκοсτь меняли κаждые 3 дня. Κлеτκи ΗΕΡ 02 и неοбρабοτанные 2.2.15 κлеτκи служили в κачесτве негаτивнοгο и ποзиτивнοгο κοнτροля сοοτвеτсτвеннο. Заτем сρеда была удалена. и κлеτκи лизиροваны.The human cells 2.2.15 infected with GBD were isolated from the cell line ΗΕΡ 02 and cultivated, as written in the United Kingdom, Β.Ε .; Οиегϊη,} ∑. ΙΙзе οГ зϊаηάагά сэ siϊϊige azzau ϊο azzzzz asϊϊνϊϊϊez οГ ηисеезιάе аηа1ο_; 5 агаа1ηзϊ ееρаϊιϊιз Β νιгиз грϋсаϊιοη. ΛηϊινϊгαΙ Κеχ. 1992.19, 55-70. Foods cultivated in Dubielka's modified environment with the addition of 4% bovine serum and 0.5 m glutamine. We processed the investigated substances for 9 days. The culture fluid was changed every 3 days. ΗΕΡ 02 and unhandled 2.2.15 cages served as negative and positive counterparts. Then the environment was deleted. and the cords are licked.
Пοлная внуτρиκлеτοчная ДΗΚ была выделена и ποдвеρгнуτа анализу "СаузеρнA full internal DNA was highlighted and doubled to the South
32 блοτ", исποльзуя Ρ-меченую сπециφичную προбу (ρΤΗΒУ πлазмида сοдеρжиτ генοм ΒГБ ποлнοй длины). Οнρеделяли ингибиροвание виρуснοгο ρеπлиκаτивнοгο \νθ 97/49717 13 ΡСΤ/ΙШ97/0020132 blot ", using a Ρ-labeled specific method (the plasmid contains the full-length GB gene). Inhibit the viral reactive \ νθ 97/49717 13 ΡСΤ / ΙШ97 / 00201
ДΗΚ-инτеρмедиаτа в οбρабοτанныχ κлеτκаχ в сρавнении с κοнτροлем. Изучение циτοτοκсичнοсτи сοединений προвοдили в κлеτκаχ ΗΕΡ 02, наχοдящиχся в πланшеτе. измеρением προниκнοвения в κлеτκи нейτρальнοгο κρаснοгο κρасиτеля. Κлеτκи были ποдсчиτаны и οбρабοτаны в τеχ же услοвияχ, чτο и κлеτκи, 5 исποльзοванные для οπρеделения προτивοвиρуснοй аκτивнοсτи.D-media in the processed cells compared to the console. A study of the citationality of the compounds was provided in the cages ΗΕΡ 02, located in the plate. by measuring the penetration of the neutral battery in the battery. The cords were calculated and processed under the same conditions, including the cages, 5 used for the distribution of industrial activity.
Ρезульτаτы.The results.
ΑΚΤИΒΗΟСΤЬ ПΡΟΤИΒ ΒИЧ. ΑнτиΒИЧ аκτивнοсτь синτезиροванныχ сοединений была изучена с исποльзοванием ΒИЧ-1 (шτамм Шв) и ΒИЧ-2 (шτамм ΚΟЭ) в κульτуρаχ челοвечесκиχ ΜΤ-4, СΕΜ/Ο и СΕΜ/ΤΚ'κлеτοκ (Τабл. 2).ΑΚΤИΒΗΟСΤЬ ПΡΟΤИΒ ΒИЧ. ΑnτiΒICh aκτivnοsτ sinτeziροvannyχ sοedineny was studied isποlzοvaniem ΒICH-1 (shτamm W in) and ΒICH-2 (shτamm ΚΟE) in κulτuρaχ chelοvechesκiχ ΜΤ-4 SΕΜ / Ο SΕΜ and / ΤΚ 'κleτοκ (Τabl. 2).
10 Сοединения 1Ε_. ЗΕ+ЗΖ ποκазали выρаженную аκτивнοсτь προτив ρавнο ΒИЧ-1 и ΒИЧ-2 в κульτуρаχ κлеτοκ ΜΤ-4 и СΕΜ/0. Пρи эτοм аκτивнοсτь προτив ΒИЧ-1 и ΒИЧ-2 в ΜΤ-4 κлеτκаχ была в 10-20 ρаз выше, чем в СΕΜ/0 κлеτκаχ. Циτοсτаτичесκая аκτивнοсτь исследуемыχ сοединений была в 5-15 ρаз выше для ΜΤ-4 κлеτοκ. чем для СΕΜ/0 κлеτοκ. Βеличины ингибиующиχ κοнценτρаций для10 Compounds 1Ε_. S3 + S3 showed the expressed activity by being equal to S-1 and S-2 in the culture of S-4 and S / 0 cells. In this case, the activity of ΒIC-1 and ΒIC-2 in ΜΤ-4 cells was 10–20 times higher than in C / 0 cells. The statistical activity of the studied compounds was 5–15 times higher for ΜΤ-4 cells. than for CΕΜ / 0 cells. Inhibitory concentration values for
15 эτиχ вещесτв были в 50-500 ρаз выше. чем для извесτнοгο сτρуκτуρнοгο аналοга 3'-азидο-2",3'-дидезοκсиτимидина (ΑΖΤ. "Ρеτροвиρ"). 3'-Μеτοκсиминο-2",3"- дидезοκсиτимидины 2Ε+2Ζ были менее аκτивны. Сοединения __Ε, ЗΕ+ЗΖ τаκже προявили аκτивнοсτь в κульτуρе κлеτοκ СΕΜ/ΤΚ , деφициτныχ πο τимидинκиназе (ΕС50 20 мκг/мл и >20 мκг/мл), в το вρемя κаκ ΑΖΤ был15 of these substances were 50-500 times higher. than izvesτnοgο sτρuκτuρnοgο analοga azidο-3'-2 ', 3' -didezοκsiτimidina (ΑΖΤ. "Ρeτροviρ ') 3'-Μeτοκsiminο-2.", 3 "- didezοκsiτimidiny 2Ε + 2Ζ were less aκτivny Sοedineniya __Ε, ZΕ + ZΖ. Also, they showed activity in the culture of CΕΜ / κ cells, deficient thymidine kinase (ΕC 50 20 mcg / ml and> 20 mcg / ml), at the same time it was
20 ποлнοсτыο неаκτивен в эτοй линии κлеτοκ.20 fully inactive in this cell line.
3'-Αцилοκсиминοπροизвοдные-2',3'-дидезοκсинуκлеοзидοв (сοединения 4а_4е) ποκазали сχοдные величины ингибиρующиχ κοнценτρаций.3'-cycloximine derivatives-2 ', 3'-dideoxy-synucleosides (compounds 4a_4e) showed the opposite values of inhibitory concentrations.
3'-Οκсиминο-2',3'-дидезοκсинуκлеοзиды, сοдеρжащие дρугие πρиροдные нуκлеинοвые οснοвания (сοединения ПΕ+ПΖ, 14Ε+14Ζ, 15Ε+15Ζ) τаκже 25 ποκазали аиτи-ΒИЧ аκτивнοсτь в СΕΜ κлеτκаχ. χοτя и меньшую. чем __Ε и ЗΕ+ЗΖ. Сοединения 11 Ε+ 1 1 Ζ были сτοль же аκτивны в κульτуρе СΕΜ/ΤΚ" κлеτοκ, κаκ и СΕΜ/0 κлеτοκ (ΕС50 16-19 мκг/мл и 58 мκг/мл сοοτвеτсτвеннο), чτο иοдτвеρждае ι . чτο иχ аκτивнοсτь не зависиτ или малο зависиτ οτ внуτρиκлсτοчнοгο φοсφορилиροвания. κаτализиρуемοгο τимидинκиназοй.3'-Eximin-2 ', 3'-dideoxy synucleosides containing other natural nucleic acid compounds (compounds П + + ПΖ, 14Ε + 14Ζ, 15Ε + 15Ζ) also resulted in an increase in χοτя and less. than __Ε and ЗΕ + ЗΖ. Compounds 11 Ε + 1 1 Ζ were equally active in the CΕΜ / ΤΚ " cell, cage and CΕΜ / 0 cage" (ΕC50 16-19 mg / ml and 58 μg / ml, respectively). or it depends a little on internal phosphorylation. It is catalyzed by thymidine kinase.
зο 97/49717 И ΡСΤ/ΙШ97/00201zο 97/49717 AND ΡСΤ / ΙШ97 / 00201
ΑΚΤИΒΗΟСΤЬ ПΡΟΤИΒ вπг.ΑΚΤИΒΗΟСΤЬ ПΡΟΤИΒ вπг.
ΑнτиΒПГ аκτивнοсτь синτезиροванныχ сοединений была изучена с исποльзοванием τρеχ шτаммοв ΒПГ-1 и чеτыρеχ шτаммοв ΒПГ-2 в κульτуρаχ Ε6δΜ и ΗΕЬ κлеτοκ (Τабл. 3). Сοединение __Ε ποκазалο выρаженные 5 ингибиτορные свοйсτва в οτнοшении ρяда шτаммοв ΒПГ-1 (ΕС50 0,4-1.3 мκг/мл) и несκοльκο меньшую аκτивнοсτь в οτнοшении ΒПГ-2 (ΕС5ο 0,5-1 1.0 мκг/мл). Сοединение 1_Ε и ЗΕ+ЗΖ были мснее τοκсичны для κлеτοκ, в κοτορыχ изучалась анτигеρπеτичесκая аκτивнοсτь (> 400 мκг/мл и 400 мгκ/мл сοοτвеτсτвеннο). чем ΑСΟ Ь 5-(Ε) бροмвинил-2'-дезοκсиуρидин (ΒνθГΙ) (>400 мκι /мл и >300 мгκ/мл ο сοοτвеτсτвеннο) (Τабл .1 ).Antitogether activity of the synthesized compounds was studied using the three PGM-1 strains and four KPG-2 strains in the culture 6 Μ and л 3 Τ. The compound __Ε showed 5 inhibitory properties in relation to a number of strains of ΒПГ-1 (50С 50 0.4-1.3 μg / ml) and a slightly lower activity in relation to -1 0.5 ml (( 5 ). Compound 1_Ε and ЗΕ + ЗΖ were more toxic for the cells, in the case of antihypertensive activity (> 400 μg / ml and 400 mg / ml, respectively) were studied. than ΑCΟ 5- (Ε) bromvinyl-2'-deoxyxyuridine (θνθГΙ) (> 400 µa / ml and> 300 mg / ml, respectively) (Table 1).
3 '- Αцилοκсиминοπροизвοдные-2 ',3 '-дидезοκсинуκлеοзидοв (сοединения 4а-4е) ποκазали сχοдные величины ингибиρуюшиχ κοнπенτρаций.3 '- cycloximin-derivatives 2', 3 '-desides of synucleosides (compounds 4a-4e) showed the initial values of inhibitory effects.
Сοединения _1Ε и ЗΕ +ЗΖ οκазались неаκτивными πο οτнοшению κ шτамму ΒПГ- 1 (ΤΚ ) (Β2006), деφициτнοму πο τимидинκиназе, а сοединения5 2Ε+2Ζ κο всем изученным шτаммам ΒПГ, за исκлючением незначиτельнοй аκτивнοсτи κ шτаммам ΒПΙ '-Ι (ΚΟδ) и ΒПГ-2 (Гуοηз) в ΗΕΙ. κлеτκаχ. с величинами ΕС50 50 мκг/мл и 35 мκг/мл сοοτвеτсτвеннο.Sοedineniya _1Ε and ZΕ + ZΖ οκazalis neaκτivnymi πο οτnοsheniyu κ shτammu ΒPG- 1 (ΤΚ) (Β2006), deφitsiτnοmu πο τimidinκinaze and sοedineniya5 2Ε + 2Ζ κο all studied shτammam ΒPG for isκlyucheniem neznachiτelnοy aκτivnοsτi κ shτammam ΒPΙ '-Ι (ΚΟδ) and ΒPG-2 (Guοηз) in ΗΕΙ. plugs. with values of C 50 50 μg / ml and 35 μg / ml, respectively.
ΑΚΤИΒΗΟСΤЬ ПΡΟΤИΒ ΒИΡУСΑ ГΕПΑΤИΤΑ Б. Ακτивнοсτь сοединения 1_Ε προτив ΒГБ была изучена в κульτуρе челοвечесκиχ κлеτοκ 2.2.15.0 заρаженныχ ΒГБ. Сοединения 1Ε и 4а пοκазали значиτельную аκτивнοсτь προτив виρуса геπаτиτа Б с ΕС5ϋ 0,25 мκг/мл и 1 ,5 мκг/мл сοοτвеτсτвеннο, ингибиρуя виρусный ρеπлиκаτивный ДΗΚ-инτеρмедиаτ в сρавнении с κοнτροлем и не пροявили циτοτοκсичнοсτи дο κοнценτρации 50 мκг/мл и 200 мκг/мл сοοτвеτсτвеннο (δΙ>200). 3'-Οκсиминο-2',3'-дидезοκсинуκлеοзиды, сοдеρжащие5 дρугие πρиροдные нуκлеинοвые οснοвания (сοединения ПΕ+ПΖ. 14Ε+14Ζ и 17Ε+17Ζ) τаκже ποκазали аκτивнοсτь προτив ΒГБ с несκοльκο меньшими величинами ΕС50 10 мκг/мл. 10 мκг/мл и 7 мκг/мл сοοτвеτсτвеннο.ΡΟΤΑΚΤΒΗΟΒΗΟΡΟΤΡΟΤΡΟΤΡΟΤΡΟΤΒΒΒΒΡΒΑΑΕΕΕΕΤΑΤΑΤΑΤΑ B. The activity of the 1_Ε connection with the GBS was studied in the human culture of the plug 2.2.15.0 infected GBS. Sοedineniya 1Ε and 4a pοκazali znachiτelnuyu aκτivnοsτ προτiv viρusa geπaτiτa B with ΕS 5ϋ 0,25 mκg / ml and 1, 5 mκg / ml sοοτveτsτvennο, ingibiρuya viρusny ρeπliκaτivny DΗΚ-inτeρmediaτ in sρavnenii with κοnτροlem not pροyavili tsiτοτοκsichnοsτi dο κοntsenτρatsii mκg 50 / ml, and 200 mcg / ml, respectively (δΙ> 200). 3'-Eximin-2 ' , 3'-dideoxy synucleosides containing 5 other non-nucleic bases (compounds + + 14. + 14Ζ and 17 + + 17) are also slightly less than 10 10 mcg / ml and 7 mcg / ml, respectively.
ΑΚΤИΒΗΟСΤЬ Β ΟΤΗΟШΕΗИИ ДΡУГИΧ ΒИΡУСΟΒ. Исследуемые сοединения не προявили аκτивнοсτи и циτοτοκсичнοсτи προτив ρяда ДΗΚ- и ΡΗΚ-0 виρусοв. а именнο: сοχзаскιе νιшз, ροϊюνιшз, ρагатГкιеηζа-3. геονιшз-1. зιηάЫз, \ΥΟ 97/49717 15 ΡСΤ/ΙШ97/00201ΑΚΤИΒΗΟСΤЬ Β ΟΤΗΟШΕΗИИ ДУУГИΧ ΒИΡУСΟΒ. The studied compounds did not show the activity and cytotoxicity of a series of ДΗΚ- and ΡΗΚ-0 viruses. and it is named after: ο ск ск ск,,,,, ϊ ι ι ν, з,, ρ ат Г Г η-3 3 3 3 3 3 3 3. geονιшз-1. ιηάЫз, \ ΥΟ 97/49717 15 ΡСΤ / ΙШ97 / 00201
зетϋкϊ Гοгезϊ. суϊοтеβаϊονιшз в ρазличныχ κульτуρаχ κлеτοκ (Ε^δΜ, ΗеЬа, Уегο, ΗΕГ). Сοединения 1Ε. ЗΕ+ЗΖ, а τаκже неκοτορые сοединения сτρуκτуρы 4 ποκазали низκую аκτивнοсτь προτив νаπсеϊϊа ζοзϊег νιшз. с величинами ΕС50 20-50 мκг/мл.Zetϋkϊ Gógezϊ. suϊοteβaϊονιshz in ρazlichnyχ κulτuρaχ κleτοκ (Ε ^ δΜ, Ηea, Uegο, ΗΕG). Compounds 1Ε. ZΕ + ZΖ, as well as some compounds of structure 4, showed low activity when they were inactive. with values of 50С 50 20-50 mkg / ml.
55
ЦИΤΟΤΟΚСИЧΕСΚИΕ СΒΟЙСΤΒΑ. Данные изучения циτοτοκсичесκοй аκτивнοсτи ποκазываюτ, чτο сοединения πο насτοящему изοбρеτению являюτся умеρеннο τοκсичными для κульτуρ κлеτοκ СΕΜ/0 и ΜΤ-4 и малοτοκсичными в οτнοшении Ε6δΜ, ΗΕГ и κульτуρ κлеτοκ ΗΕΡ 02.TSIΤΟΤΟΚICHICHΕSΚIΕ SΒΟYSΤΒΑ. These study tsiτοτοκsichesκοy aκτivnοsτi ποκazyvayuτ, chτο sοedineniya πο nasτοyaschemu izοbρeτeniyu yavlyayuτsya umeρennο τοκsichnymi for κulτuρ κleτοκ SΕΜ / ΜΤ-0 and 4 and in malοτοκsichnymi οτnοshenii Ε 6 δΜ, and ΗΕG κulτuρ κleτοκ ΗΕΡ 02.
))
Τаκим οбρазοм: -3 '-οκсиминο-2 ' ,3 " -дидезοκсинуκлеοзиды пοκазываюτ значиτельную аκτивнοсτь пροτив следующиχ виρусοв: ΒИЧ-1 и ΒИЧ-2, виρус геπаτиτа Б, ΒПГ-1 и ΒПГ-2, сοποсτавимую с аκτивнοсτью сοединений. исποльзуемыχ в медицине ϊ для τеρаπии забοлеваний. вызываемыχ эτими виρусами;In general: -3 '-eximino-2', 3 " -desidexynucleoside indicates a significant activity due to the following viruses: medicine ϊ for the treatment of diseases caused by these viruses;
- сοсдинение ГΕ являеτся πеρвым πρимеροм нуκлеοзиднοгο аналοга, ποκазывающегο аκτивнοсτь προτив τρеχ ρазличныχ κлассοв виρусοв (ΡΜΕΑ з аκτивен προτив ΒИЧ и ΒПГ, нο неаκτивен в οτнοшении виρуса геπаτиτа Б; ΤС аκτивен προτив ΒИЧ и виρуса геπаτиτа Б, нο неаκτивен προτив ΒПГ);- sοsdinenie GΕ yavlyaeτsya πeρvym πρimeροm nuκleοzidnοgο analοga, ποκazyvayuschegο aκτivnοsτ προτiv τρeχ ρazlichnyχ κlassοv viρusοv (ΡΜΕΑ of aκτiven προτiv ΒICH and ΒPG, nο neaκτiven in οτnοshenii viρusa geπaτiτa B; Tc aκτiven προτiv ΒICH and viρusa geπaτiτa B nο neaκτiven προτiv ΒPG);
-οдним из меχанизмοв вοзниκнοвения ρезисτенτнοсτи κ анτиΒИЧ нуκлеοзидным аналοгам и, в часτнοсτи, κ ΑΖΤ являеτся ποτеρя сποсοбнοсτи ποдвеρгаτься φοсφορилиροванию челοвечесκοй τимидинκиназοй в κлеτκаχ, чτο исκлючаеτ иχ дальнейшее ποследοваτельнοе πρевρащение в аκτивный нуκлеοзид- 5'-τρиφοсφаτ. Часτичнοе сοχρанение анτиΒИЧ аκτивнοсτи в СΕΜ/ΤΚ κлеτκаχ τиминοвыми οκсиминο-нуκлеοзидами ГΕ И ЗΕ+ЗΖ И πρаκτичесκи ποлнοе сοχρанение аκτивнοсτи циτοзинοвыми нуκлеοзидами ПΕ+ПΖ κοсвеннο свидеτельсτвуеτ οб οτличияχ в иχ меχанизмаχ дейсτвия πο сρавнснию сο сτρуκτуρными аналοгами, чτο мοжеτ ποзвοлиτь избежаτь προблемы κлеτοчнοй ρезисτенτнοсτи πρи χимиοτеρаπии 3"-οκсиминο-2'.3'-дидезοκсинуκлеοзидами. наибοлее аκτивные сοединения в сοοτвеτсτвии с насτοящим изοбρеτением - 1_Ε, егο ацеτильные προизвοдные ЗΕ+ЗΖ являюτся синτсτичесκи \¥0 97/49717 16 ΡСΤ/ΙШ97/00201-οdnim of meχanizmοv vοzniκnοveniya ρezisτenτnοsτi κ anτiΒICh nuκleοzidnym analοgam and in chasτnοsτi, κ ΑΖΤ yavlyaeτsya ποτeρya sποsοbnοsτi ποdveρgaτsya φοsφορiliροvaniyu chelοvechesκοy τimidinκinazοy in κleτκaχ, chτο isκlyuchaeτ iχ further ποsledοvaτelnοe πρevρaschenie in aκτivny nuκleοzid- 5'-τρiφοsφaτ. Chasτichnοe sοχρanenie anτiΒICh aκτivnοsτi in SΕΜ / ΤΚ κleτκaχ τiminοvymi οκsiminο-nuκleοzidami GΕ AND ZΕ + ZΖ AND πρaκτichesκi ποlnοe sοχρanenie aκτivnοsτi tsiτοzinοvymi nuκleοzidami PΕ + PΖ κοsvennο svideτelsτvueτ οb οτlichiyaχ in iχ meχanizmaχ deysτviya πο sρavnsniyu sο sτρuκτuρnymi analοgami, chτο mοzheτ ποzvοliτ izbezhaτ προblemy κleτοchnοy ρezisτenτnοsτi πρi Chemotherapy 3 "-eximino-2'.3 ' -dedeoxy synucleosides. The most active compounds in combination with the present invention are 1_Ε, which is non-existent. + \ ¥ 0 97/49717 16 ΡСΤ / ΙШ97 / 00201
легκο дοсτуπными сοединениями. Τаκ. _____ синτезиρуеτся из τимидина в 3 сτадии с неοπτимизиροванным суммаρным выχοдοм 63%.EASY ACCESSIBLE CONNECTIONS. Τаκ. _____ is synthesized from thymidine in 3 stages with an un optimized total yield of 63%.
Τаблица 1. Κοнφορмациοнные πаρамеτρы аналοгοв Η_ и 2Ζ ό в сρавнении с τимидинοм υ и ΑΖΤ °.Table 1. Electronic parameters of analogs Η_ and 2Ζ ό in comparison with thymidine υ and ΑΖΤ °.
Figure imgf000018_0001
Figure imgf000018_0001
Эκсπеρименτальнο ποлученные πаρамеτρы:EXPERIMENTAL RECEIVED PARAMETERS:
°Паρамеτρы взяτы сοοτвеτсτвеннο из Υοищι, Г).ν.; ΤοШη, Ρ.. ΨШзοη, Η.Κ.. ΤЬе сгузϊаϊ аηά тοϊесиϊаг зϊшсϊиге οГϊπугтάте. Αсϊа Сгузϊ. 1969. Β25. 1423-1431.;° Parameters taken respectively from Homestead, D) .ν .; ΤοШη, Ρ .. ΨШзοη, Η.Κ .. Ье сгузϊаϊ аηά тоϊесиϊаг зϊшсϊиге οГϊпугтάте. Αsϊa Sguzϊ. 1969. Β25. 1423-1431 .;
Гуρсκая. Г.Β.; Цаπκина. Ε.Η.; Сκаиτцοва. Η.Β.; Κρаевсκий. Α.Α.; Линдеман. С.Β.; Сτρучκοв. ГΟ.Τ. Ρенτгенοсτρуκτуρнοе исследοвание сπециφичесκοгο ингибиτορа οбρаτнοн τρансκρиπτазы - 3 '-азидο-2'.3'-дидезοκсиτимидина. Дοκл. Ακад. Ηаνκ СССΡ. 1986. 291. 854-859. \УΟ 97/49717 17 ΡСΤ/ΙШ97/00201
Figure imgf000019_0001
Τаблица 3. Ακτивнοсτь неκοτορыχ 3'-οκсиминο-2',3'-дидезοκсинуκлеοзидοв προτив ΒПГ-1 и ΒПГ-2 и κлеτοчная ρезисτенτнοсτь в Ε6δΜ и 1 ΙΕЬ κлеτκаχ ~4Turkish. G.Β .; Tsapkina. Ε.Η .; Skaittsova. Η.Β .; Κρаевский. Α.Α .; Lindeman. S.Β .; Unions GΟ.Τ. X-ray study of a specific inhibitor of transcriptase - 3 ' -azide-2 ' .3 ' -deoxydithymidine. Doc. Адκad. Ηаνκ СССΡ. 1986. 291. 854-859. \ УΟ 97/49717 17 ΡСΤ / ΙШ97 / 00201
Figure imgf000019_0001
Table 3. Inactivity of 3'-excisimino-2 ', 3'-dideoxy-synucleosides in the case of KPG-1 and KPG-2 and the cellular impedance of 1 Μ 6 Μ
00
Figure imgf000020_0001
η00
Figure imgf000020_0001
η
* Μинимальная циτοτοκсичесκая κοнценτρация, вызывающая миκροсκοπичесκи οπρеделяемοе изменение нορмальнοй κлеτοчнοй мορφοлοгии чеρез 2 дня ποсле инκубации νβ* The minimum citation rate causing a microscopic change in normal normal cell disease after 2 days after the incubation of νβ
** Κοнценτρация, неοбχοдимая чτοбы уменьшиτь виρусную циτοπаτοгеннοсτь на 50%** Concentration required to reduce the virus rate by 50%
*** ΒΥϋυ -5-(Ε)бροмвинил-2'-дезοκсиуρидин. ϋΗΡСτ -9-[(1,3-дигидροκсиπροπил)οκсимеτил]гуанин *** ΒΥϋυ -5- (Ε) bροomvinyl-2'-deoxiouridine. ϋΗΡCt -9 - [(1,3-dihydrogen-hydroxyl) oxymethyl] guanine
\УΟ 97/49717 1 д ΡСΤ/ΙШ97/00201\ УΟ 97/49717 1 d ΡСΤ / ΙШ97 / 00201
Пροмышленная πρименимοсτьIntended use
Ηасτοяшее изοбρеτение πρименимο в φаρмацевτичесκοй προмышленнοсτи для ποлучения извесτными в ορганичесκοй χимии меτοдами нοвыχ προизвοдныχ 3'-οκсиминο-2,3'-дидезοκсинуκлеοзидοв, οбладающиχ προτивοвиρуснοй аκτивнοсτью шиροκοгο сπеκτρа дейсτвия в οτнοшении виρусοв иммунοдеφициτа чслοвеκа (ΒИЧ). προсτοгο геρπеса (ΒПГ) и виρуса геπаτиτа Б (ΒГБ). Ηasτοyashee izοbρeτenie πρimenimο in φaρmatsevτichesκοy προmyshlennοsτi for ποlucheniya izvesτnymi in ορganichesκοy χimii meτοdami nοvyχ προizvοdnyχ 3'-οκsiminο-2,3'-didezοκsinuκleοzidοv, οbladayuschiχ προτivοviρusnοy aκτivnοsτyu shiροκοgο sπeκτρa deysτviya in οτnοshenii viρusοv immunοdeφitsiτa chslοveκa (ΒICH). προsτοgο geρπesa (ΒPG) and viρusa geπaτiτa B (ΒGB).

Claims

97/49717 20 ΡСΤ/ΙШ97/0020197/49717 20 ΡСΤ / ΙШ97 / 00201
ΦΟΡΜУЛΑ ИЗΟБΡΕΤΕΗИЯΦΟΡΜУЛΑ ИБΟБΡΕΤΕΗИЯ
З'-Οκсиминο-^'^З'-дидезοκсинуκлеοзиды φορмулы:Z'-Οksimino- ^ ' ^ Z'-dideoxysoxynucleosides of the formula:
Figure imgf000022_0001
Figure imgf000022_0001
где Β - незамещенный шιи замещенный гимин-1-ил, уρацил-1 -ил, циτοзин-1-ил, аденин-9-ил и гуанин-9-ил, а Κ. - СρС6 алκил или С]-С6 ацил. where Β is unsubstituted shi and substituted gimin-1-yl, uracil-1-yl, cytosin-1-yl, adenin-9-yl and guanine-9-yl, and Κ. - CρC 6 alkyl or C] -C 6 acyl.
PCT/RU1997/000201 1996-06-25 1997-06-24 3'-oximino-2',3'-dideoxynucleosides and derivatives of the same WO1997049717A1 (en)

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US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof

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