RU2009114154A - POLYMERIC DRUGS WITH DIRECTED DELIVERY CONTAINING POLYFUNCTIONAL LINKERS - Google Patents

POLYMERIC DRUGS WITH DIRECTED DELIVERY CONTAINING POLYFUNCTIONAL LINKERS Download PDF

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RU2009114154A
RU2009114154A RU2009114154/15A RU2009114154A RU2009114154A RU 2009114154 A RU2009114154 A RU 2009114154A RU 2009114154/15 A RU2009114154/15 A RU 2009114154/15A RU 2009114154 A RU2009114154 A RU 2009114154A RU 2009114154 A RU2009114154 A RU 2009114154A
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substituted
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compound
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Хун ЧЖАО (US)
Хун Чжао
Мария Белен РУБИО (US)
Мария Белен РУБИО
Прасанна РЕДДИ (US)
Прасанна РЕДДИ
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Энзон Фармасьютикалз, Инк. (Us)
Энзон Фармасьютикалз, Инк.
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Abstract

1. Соединение формулы (I) !! где R1 обозначает практически не антигенный водорастворимый полимер; ! A обозначает кэппирующую группу или ! ! каждый D1 независимо выбран из группы, состоящей из мишень-специфичных фрагментов, функциональных и уходящих групп; ! каждый D2 независимо выбран из группы, состоящей из биологически активных фрагментов, функциональных и уходящих групп; ! каждый L1 обозначает независимо выбранный стабильный линкер или высвобождаемый линкер; ! L2 обозначает полифункциональный линкер; ! каждый L3 обозначает независимо выбранный стабильный линкер или высвобождаемый линкер; и ! (a) и (b) независимо обозначают нуль или положительное целое число. ! 2. Соединение по п.1, где L2 выбран из группы, включающей ! ! ! где R2 и R'2 независимо выбраны из группы, включающей водород, C1-6 алкил, C2-6 алкенил, C2-6 алкинил, C3-19 разветвленный алкил, C3-8 циклоалкил, C1-6 замещенный алкил, C2-6 замещенный алкенил, C2-6 замещенный алкинил, C3-8 замещенный циклоалкил, арил, замещенный арил, гетероарил, замещенный гетероарил, C1-6 гетероалкил, замещенный C1-6 гетероалкил, C1-6 алкокси, арилокси, C1-6 гетероалкокси, гетероарилокси, C2-6 алканоил, арилкарбонил, C2-6 алкоксикарбонил, арилоксикарбонил, C2-6 алканоилокси, арилкарбонилокси, C2-6 замещенный алканоил, замещенный арилкарбонил, C2-6 замещенный алканоилокси, замещенный арилоксикарбонил, C2-6 замещенный алканоилокси и замещенный арилкарбонилокси; ! (c1), (c2), (c3), (c4), (c5), (c6), (c'6), (c"6), (c7) и (c8) независимо обозначают нуль или положительное целое число; и ! (d1), (d2), (d3), (d4), (d5) и (d7) независимо обозначают нуль или положительное целое число. ! 3. Соединение по п.2, где L2 выбран из группы, включающей ! ! 4. Соединение по п.2, выбр 1. The compound of formula (I) !! where R1 is a substantially non-antigenic water-soluble polymer; ! A denotes a capping group or! ! each D1 is independently selected from the group consisting of target-specific fragments, functional and leaving groups; ! each D2 is independently selected from the group consisting of biologically active fragments, functional and leaving groups; ! each L1 is an independently selected stable linker or a releasable linker; ! L2 is a multifunctional linker; ! each L3 is an independently selected stable linker or a releasable linker; and! (a) and (b) independently represent zero or a positive integer. ! 2. The compound according to claim 1, where L2 is selected from the group comprising! ! ! where R2 and R'2 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-19 branched alkyl, C3-8 cycloalkyl, C1-6 substituted alkyl, C2-6 substituted alkenyl, C2-6 substituted alkynyl, C3-8 substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C1-6 heteroalkyl, substituted C1-6 heteroalkyl, C1-6 alkoxy, aryloxy, C1-6 heteroalkoxy, heteroaryloxy, C2 -6 alkanoyl, arylcarbonyl, C2-6 alkoxycarbonyl, aryloxycarbonyl, C2-6 alkanoyloxy, arylcarbonyloxy, C2-6 substituted alkanoyl, substituted arylcarbonyl, C2-6 substituted lkanoiloksi substituted aryloxycarbonyl, C2-6 substituted alkanoyloxy and substituted arylcarbonyloxy; ! (c1), (c2), (c3), (c4), (c5), (c6), (c'6), (c "6), (c7) and (c8) independently denote zero or a positive integer ; and! (d1), (d2), (d3), (d4), (d5) and (d7) independently denote zero or a positive integer.! 3. The compound according to claim 2, where L2 is selected from the group including !! 4. Connection according to claim 2, select

Claims (30)

1. Соединение формулы (I)1. The compound of formula (I)
Figure 00000001
Figure 00000001
 где R1 обозначает практически не антигенный водорастворимый полимер;where R 1 denotes a practically non-antigenic water-soluble polymer; A обозначает кэппирующую группу илиA denotes a capping group or
Figure 00000002
Figure 00000002
 каждый D1 независимо выбран из группы, состоящей из мишень-специфичных фрагментов, функциональных и уходящих групп;each D 1 is independently selected from the group consisting of target-specific fragments, functional and leaving groups; каждый D2 независимо выбран из группы, состоящей из биологически активных фрагментов, функциональных и уходящих групп;each D 2 is independently selected from the group consisting of biologically active fragments, functional and leaving groups; каждый L1 обозначает независимо выбранный стабильный линкер или высвобождаемый линкер;each L 1 is an independently selected stable linker or a releasable linker; L2 обозначает полифункциональный линкер;L 2 denotes a multifunctional linker; каждый L3 обозначает независимо выбранный стабильный линкер или высвобождаемый линкер; иeach L 3 is an independently selected stable linker or releasable linker; and (a) и (b) независимо обозначают нуль или положительное целое число.(a) and (b) independently represent zero or a positive integer. 2. Соединение по п.1, где L2 выбран из группы, включающей2. The compound according to claim 1, where L 2 selected from the group including
Figure 00000003
Figure 00000003
Figure 00000004
Figure 00000004
 где R2 и R'2 независимо выбраны из группы, включающей водород, C1-6 алкил, C2-6 алкенил, C2-6 алкинил, C3-19 разветвленный алкил, C3-8 циклоалкил, C1-6 замещенный алкил, C2-6 замещенный алкенил, C2-6 замещенный алкинил, C3-8 замещенный циклоалкил, арил, замещенный арил, гетероарил, замещенный гетероарил, C1-6 гетероалкил, замещенный C1-6 гетероалкил, C1-6 алкокси, арилокси, C1-6 гетероалкокси, гетероарилокси, C2-6 алканоил, арилкарбонил, C2-6 алкоксикарбонил, арилоксикарбонил, C2-6 алканоилокси, арилкарбонилокси, C2-6 замещенный алканоил, замещенный арилкарбонил, C2-6 замещенный алканоилокси, замещенный арилоксикарбонил, C2-6 замещенный алканоилокси и замещенный арилкарбонилокси;where R 2 and R ′ 2 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-19 branched alkyl, C 3-8 cycloalkyl, C 1-6 substituted alkyl, C 2-6 substituted alkenyl, C 2-6 substituted alkynyl, C 3-8 substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 1-6 heteroalkyl, substituted C 1-6 heteroalkyl, C 1- 6 alkoxy, aryloxy, C 1-6 heteroalkoxy, heteroaryloxy, C 2-6 alkanoyl, arylcarbonyl, C 2-6 alkoxycarbonyl, aryloxycarbonyl, C 2-6 alkanoyloxy, arylcarbonyloxy, C 2-6 substituted alkanoyl, substituted arylcarbonyl, C 2- 6 s substituted alkanoyloxy, substituted aryloxycarbonyl, C 2-6 substituted alkanoyloxy and substituted arylcarbonyloxy; (c1), (c2), (c3), (c4), (c5), (c6), (c'6), (c"6), (c7) и (c8) независимо обозначают нуль или положительное целое число; и(c1), (c2), (c3), (c4), (c5), (c6), (c'6), (c "6), (c7) and (c8) independently denote zero or a positive integer ; and (d1), (d2), (d3), (d4), (d5) и (d7) независимо обозначают нуль или положительное целое число.(d1), (d2), (d3), (d4), (d5) and (d7) independently denote zero or a positive integer. 3. Соединение по п.2, где L2 выбран из группы, включающей3. The compound according to claim 2, where L 2 selected from the group including
Figure 00000005
Figure 00000005
 4. Соединение по п.2, выбранное из группы, включающей4. The compound according to claim 2, selected from the group including
Figure 00000006
Figure 00000006
Figure 00000006
Figure 00000006
 5. Соединение по п.4, выбранное из группы, включающей5. The compound according to claim 4, selected from the group including
Figure 00000007
Figure 00000007
Figure 00000008
Figure 00000008
Figure 00000008
Figure 00000008
Figure 00000009
Figure 00000009
 6. Соединение по п.1, где биологически активный фрагмент выбран из группы, включающей -NH2-содержащие фрагменты, -OH-содержащие фрагменты и -SH-содержащие фрагменты.6. The compound according to claim 1, where the biologically active fragment is selected from the group consisting of -NH 2 -containing fragments, -OH-containing fragments and -SH-containing fragments. 7. Соединение по п.1, где биологически активный фрагмент выбран из группы, включающей фармацевтически активные соединения, ферменты, белки, олигонуклеотиды, антитела, моноклональные антитела, одноцепочечные антитела и пептиды.7. The compound according to claim 1, where the biologically active fragment is selected from the group comprising pharmaceutically active compounds, enzymes, proteins, oligonucleotides, antibodies, monoclonal antibodies, single chain antibodies and peptides. 8. Соединение по п.7, где фармацевтически активные соединения выбраны из группы, включающей ингибиторы ДНК-топоизомеразы, лекарственные средства, ингибирующие микротрубочки, средства, разрушающие ДНК, антиметаболиты, аналоги нуклеозидов и противораковые лекарственные средства.8. The compound of claim 7, wherein the pharmaceutically active compounds are selected from the group consisting of DNA topoisomerase inhibitors, microtubule inhibitory drugs, DNA disrupters, antimetabolites, nucleoside analogs, and anti-cancer drugs. 9. Соединение по п.1, где биологически активный фрагмент представляет собой олигонуклеотид.9. The compound according to claim 1, where the biologically active fragment is an oligonucleotide. 10. Соединение по п.9, где олигонуклеотид выбран из группы, включающей антисмысловые олигонуклеотиды, закрытые нуклеиновые кислоты (LNA), короткие интерферирующие РНК (siРНК), микроРНК (миРНК), аптамеры, пептидные нуклеиновые кислоты (PNA) и фосфородиамидатморфолиновые олигонуклеотиды (PMO).10. The compound of claim 9, wherein the oligonucleotide is selected from the group consisting of antisense oligonucleotides, closed nucleic acids (LNAs), short interfering RNAs (siRNAs), microRNAs (siRNAs), aptamers, peptide nucleic acids (PNAs), and phosphorodiamidate morpholine oligonucleotides ) 11. Соединение по п.9, где олигонуклеотид выбран из группы, включающей антисмысловые олигонуклеотиды bcl-2, антисмысловые олигонуклеотиды HIF-1a и антисмысловые олигонуклеотиды Survivin.11. The compound of claim 9, wherein the oligonucleotide is selected from the group consisting of bcl-2 antisense oligonucleotides, HIF-1a antisense oligonucleotides, and Survivin antisense oligonucleotides. 12. Соединение по п.1, где мишень-специфичное средство выбрано из группы, включающей моноклональные антитела, одноцепочечные антитела, пептиды клеточной адгезии, пептиды, способные проникать в клетку, лиганды рецепторов, мишень-специфичные молекулы углеводов или лектины и олигонуклеотиды.12. The compound according to claim 1, where the target-specific agent is selected from the group consisting of monoclonal antibodies, single chain antibodies, cell adhesion peptides, cell penetrating peptides, receptor ligands, target specific carbohydrate or lectin molecules and oligonucleotides. 13. Соединение по п.1, где мишень-специфичное средство выбрано из группы, включающей пептид RGD, селектин, TAT, пенетратин, (Arg)9 и фолевую кислоту.13. The compound according to claim 1, where the target-specific agent is selected from the group comprising the peptide RGD, selectin, TAT, penetratin, (Arg) 9 and folic acid. 14. Соединение по п.1, где высвобождаемый линкер выбран из группы, включающей линкеры с отщеплением по бензилу, линкеры с фиксацией триалкила, линкеры на основе бицина, чувствительные к кислотам линкеры, расщепляемые в лизосомах пептиды, а также пептиды, расщепляемые катепсином B.14. The compound according to claim 1, where the releasable linker is selected from the group consisting of benzyl-cleaved linkers, trialkyl-fixed linkers, bicin-based linkers, acid-sensitive linkers, peptides cleaved in lysosomes, and cathepsin B-cleaved peptides. 15. Соединение по п.1, где высвобождаемые линкеры независимо выбраны из группы, включающей15. The compound according to claim 1, where the released linkers are independently selected from the group including
Figure 00000010
Figure 00000010
Figure 00000011
Figure 00000011
Figure 00000012
Figure 00000012
Figure 00000012
Figure 00000012
 -Val-Cit-,-Val-Cit-, -Gly-Phe-Leu-Gly-,-Gly-Phe-Leu-Gly-, -Ala-Leu-Ala-Leu-, -Ala-Leu-Ala-Leu-, -Phe-Lys-,-Phe-Lys-,
Figure 00000013
Figure 00000013
 -Val-Cit-C(=O)-CH2OCH2-C(=O)-,-Val-Cit-C (= O) -CH 2 OCH 2 -C (= O) -, -Val-Cit-C(=O)-CH2SCH2-C(=O)- и -Val-Cit-C (= O) -CH 2 SCH 2 -C (= O) - and -NHCH(CH3)-C(=O)-NH(CH2)6-C(CH3)2-C(=O)-,-NHCH (CH 3 ) -C (= O) -NH (CH 2 ) 6 -C (CH 3 ) 2 -C (= O) -, где Y11-19 независимо обозначают O, S или NR48;where Y 11-19 independently represent O, S or NR 48 ; R31-48, R50, R100 и A51 независимо выбраны из группы, включающей водород, C1-6 алкилы, C3-12 разветвленные алкилы, C3-8 циклоалкилы, C1-6 замещенные алкилы, C3-8 замещенные циклоалкилы, арилы, замещенные арилы, аралкилы, C1-6 гетероалкилы, замещенные C1-6 гетероалкилы, C1-6 алкокси, C1-6 алкилоксикарбонил, фенокси и C1-6 гетероалкокси;R 31-48 , R 50 , R 100 and A 51 are independently selected from the group consisting of hydrogen, C 1-6 alkyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 3- 8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, C 1-6 alkyloxycarbonyl, phenoxy and C 1-6 heteroalkoxy; Ar обозначает арильный или гетероарильный фрагмент;Ar is an aryl or heteroaryl moiety; L11-15 независимо обозначают бифункциональные спейсеры;L 11-15 independently indicate bifunctional spacers; Z и Z' независимо выбраны из группы, включающей фрагменты, активно транспортируемые в клетку-мишень, гидрофобные фрагменты, бифункциональные связующие фрагменты и их сочетания;Z and Z 'are independently selected from the group consisting of fragments actively transported to the target cell, hydrophobic fragments, bifunctional binding fragments, and combinations thereof; (c11), (h11), (k11), (l11), (m1l) и (n11) независимо обозначают положительные целые числа;(c11), (h11), (k11), (l11), (m1l) and (n11) independently denote positive integers; (a11), (e11), (g11), (j11), (o11) и (q1l) независимо обозначают нуль или положительное целое число; и(a11), (e11), (g11), (j11), (o11) and (q1l) independently denote zero or a positive integer; and (b11), (x1l), (x'11), (f11), (i11) и (p11) независимо обозначают нуль или единицу.(b11), (x1l), (x'11), (f11), (i11) and (p11) independently denote zero or one. 16. Соединение по п.1, где стабильные линкеры независимо выбраны из группы, включающей16. The compound according to claim 1, where stable linkers are independently selected from the group including
Figure 00000014
Figure 00000014
 17. Соединение по п.1, где L1 и L3 независимо выбраны из группы, включающей аминокислоту, производное аминокислоты и пептид.17. The compound according to claim 1, where L 1 and L 3 are independently selected from the group consisting of an amino acid, an amino acid derivative, and a peptide. 18. Соединение по п.1, где R1 включает линейный, разветвленный на конце или многолучевой полиалкиленоксид.18. The compound according to claim 1, where R 1 includes a linear, branched at the end or multipath polyalkylene oxide. 19. Соединение по п.18, где полиалкиленоксид выбран из группы, включающей полиэтиленгликоль и полипропиленгликоль.19. The compound of claim 18, wherein the polyalkylene oxide is selected from the group consisting of polyethylene glycol and polypropylene glycol. 20. Соединение по п.18, где полиалкиленоксид выбран из группы, включающей20. The compound of claim 18, wherein the polyalkylene oxide is selected from the group consisting of -Y21-(CH2CH2O)n-CH2CH2Y21-,-Y 21 - (CH 2 CH 2 O) n -CH 2 CH 2 Y 21 -, -Y21-(CH2CH2O)n-CH2C(=Y22)-Y21-,-Y 21 - (CH 2 CH 2 O) n -CH 2 C (= Y 22 ) -Y 21 -, -Y21-C(=Y22)-(CH2)a2-Y23-(CH2CH2O)n-CH2CH2-Y23-(CH2)a2-C(=Y22)-Y21- и-Y 21 -C (= Y 22 ) - (CH 2 ) a2 -Y 23 - (CH 2 CH 2 O) n -CH 2 CH 2 -Y 23 - (CH 2 ) a2 -C (= Y 22 ) - Y 21 - and -Y21-(CR51R52)a2-Y23-(CH2)b2-O-(CH2CH2O)n-(CH2)b2-Y23-(CR51R52)a2-Y21-,-Y 21 - (CR 51 R 52 ) a2 -Y 23 - (CH 2 ) b2 -O- (CH 2 CH 2 O) n - (CH 2 ) b2 -Y 23 - (CR 51 R 52 ) a2 -Y 21 -, где Y21 и Y23 независимо обозначают O, S, SO, SO2, NR53 или связь;where Y 21 and Y 23 independently represent O, S, SO, SO 2 , NR 53 or a bond; Y22 обозначает O, S или NR53;Y 22 is O, S or NR 53 ; R51-53 независимо выбраны из группы, описанной для R2;R 51-53 are independently selected from the group described for R 2 ; (a2) и (b2) независимо обозначают нуль или положительное целое число; и(a2) and (b2) independently represent zero or a positive integer; and (n) обозначает целое число от приблизительно 10 до приблизительно 2300.(n) is an integer from about 10 to about 2300. 21. Соединение по п.18, где полиалкиленоксид представляет собой полиэтиленгликоль формулы -О-(CH2CH2O)n-,21. The compound of claim 18, wherein the polyalkylene oxide is a polyethylene glycol of the formula —O— (CH 2 CH 2 O) n -, где (n) обозначает целое число от приблизительно 10 до приблизительно 2300.where (n) is an integer from about 10 to about 2300. 22. Соединение по п.1, где R1 имеет среднюю молекулярную массу от приблизительно 2000 до приблизительно 100000 дальтон.22. The compound according to claim 1, where R 1 has an average molecular weight of from about 2000 to about 100,000 daltons. 23. Соединение по п.1, где R1 имеет среднюю молекулярную массу от приблизительно 5000 до приблизительно 60000 дальтон.23. The compound according to claim 1, where R 1 has an average molecular weight of from about 5000 to about 60,000 daltons. 24. Соединение по п.1, где R1 имеет среднюю молекулярную массу от приблизительно 5000 до приблизительно 25000 дальтон или от приблизительно 20000 до приблизительно 45000 дальтон.24. The compound according to claim 1, where R 1 has an average molecular weight of from about 5,000 to about 25,000 daltons or from about 20,000 to about 45,000 daltons. 25. Соединение по п.1, выбранное из группы, включающей25. The compound according to claim 1, selected from the group including
Figure 00000015
Figure 00000015
Figure 00000016
Figure 00000016
Figure 00000017
Figure 00000017
Figure 00000018
Figure 00000018
Figure 00000019
Figure 00000019
 где mPEG имеет формулу CH3-O(CH2CH2O)n-;where mPEG has the formula CH 3 —O (CH 2 CH 2 O) n -; PEG имеет формулу -О(CH2CH2O)n-;PEG has the formula —O (CH 2 CH 2 O) n -; (n) обозначает положительное целое число от приблизительно 10 до приблизительно 2300;(n) denotes a positive integer from about 10 to about 2300; R51 и R52 независимо выбраны из группы, включающей водород, C1-6 алкилы, C3-12 разветвленные алкилы, C3-8 циклоалкилы, C1-6 замещенные алкилы, C3-8 замещенные циклоалкилы, арилы, замещенные арилы, аралкилы, C1-6 гетероалкилы, замещенные C1-6 гетероалкилы, C1-6 алкокси, C1-6 алкилоксикарбонил, арилоксикарбонил, фенокси и C1-6 гетероалкокси;R 51 and R 52 are independently selected from the group consisting of hydrogen, C 1-6 alkyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 3-8 substituted cycloalkyls, aryls, substituted aryls , aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, C 1-6 alkyloxycarbonyl, aryloxycarbonyl, phenoxy and C 1-6 heteroalkoxy; D1 обозначает мишень-специфичный фрагмент, функциональную группу или уходящую группу; иD 1 denotes a target-specific fragment, a functional group or a leaving group; and D2 обозначает биологически активный фрагмент, функциональную группу или уходящую группу.D 2 denotes a biologically active fragment, a functional group or a leaving group. 26. Соединение по п.1, выбранное из группы, включающей26. The compound according to claim 1, selected from the group including
Figure 00000020
Figure 00000020
Figure 00000021
Figure 00000021
Figure 00000022
Figure 00000022
Figure 00000024
Figure 00000024
Figure 00000025
Figure 00000025
Figure 00000026
Figure 00000026
Figure 00000027
Figure 00000027
Figure 00000028
Figure 00000028
Figure 00000029
Figure 00000029
Figure 00000030
Figure 00000030
Figure 00000031
Figure 00000031
Figure 00000032
Figure 00000032
Figure 00000033
Figure 00000033
Figure 00000034
Figure 00000034
Figure 00000035
Figure 00000035
 где S-SCA представляет собой одноцепочечное антитело;where S-SCA is a single chain antibody; RGD представляет собойRGD is a
Figure 00000036
Figure 00000036
 LNA представляет собой закрытую нуклеиновую кислоту;LNA is a closed nucleic acid; фолевая кислота имеет следующую структуруfolic acid has the following structure
Figure 00000037
Figure 00000037
 mPEG имеет формулу CH3-O(CH2CH2O)n-;mPEG has the formula CH 3 —O (CH 2 CH 2 O) n -; PEG имеет формулу -О(CH2CH2O)n-; иPEG has the formula —O (CH 2 CH 2 O) n -; and (n) обозначает положительное целое число от приблизительно 10 до приблизительно 2300.(n) denotes a positive integer from about 10 to about 2300. 27. Способ получения полимерного конъюгата, содержащего полифункциональный линкер, включающий27. A method of obtaining a polymer conjugate containing a multifunctional linker, including взаимодействие соединения формулы (IIIa):the interaction of the compounds of formula (IIIa):
Figure 00000038
Figure 00000038
 с соединением формулы (IIIb), содержащим биологически активный фрагмент:with a compound of formula (IIIb) containing a biologically active fragment: M3-(L3)b-D22 M 3 - (L 3 ) b -D 22 в условиях, обеспечивающих получение соединения формулы (IIIc):under conditions ensuring the preparation of a compound of formula (IIIc):
Figure 00000039
Figure 00000039
 где R1 обозначает практически не антигенный водорастворимый полимер;where R 1 denotes a practically non-antigenic water-soluble polymer; A21 обозначает кэппирующую группу илиA 21 denotes a capping group or
Figure 00000040
Figure 00000040
 A22 обозначает кэппирующую группу илиA 22 denotes a capping group or
Figure 00000041
Figure 00000041
 M1 обозначает функциональную группу;M 1 denotes a functional group; D22 обозначает биологически активный фрагмент;D 22 denotes a biologically active fragment; M2 обозначает OH или уходящую группу;M 2 is OH or a leaving group; M3 обозначает OH, NH2 или SH;M 3 is OH, NH 2 or SH; L1 обозначает стабильный линкер или высвобождаемый линкер;L 1 is a stable linker or a releasable linker; L2 обозначает полифункциональный линкер;L 2 denotes a multifunctional linker; L3 обозначает стабильный линкер или высвобождаемый линкер; иL 3 is a stable linker or a releasable linker; and (a) и (b) независимо обозначают нуль или положительное целое число.(a) and (b) independently represent zero or a positive integer. 28. Способ по п.27, дополнительно включающий28. The method according to item 27, further comprising взаимодействие соединения формулы (IIIc):the interaction of the compounds of formula (IIIc):
Figure 00000042
Figure 00000042
 с соединением формулы (IIId), содержащим нуклеофильный фрагмент:with a compound of formula (IIId) containing a nucleophilic fragment:
Figure 00000043
Figure 00000043
 в условиях, обеспечивающих получение соединения формулы (IIIe):under conditions ensuring the preparation of a compound of formula (IIIe):
Figure 00000044
Figure 00000044
 где A23 обозначает кэппирующую группу илиwhere A 23 denotes a capping group or
Figure 00000045
Figure 00000045
 M1 обозначает функциональную группу;M 1 denotes a functional group; D21 обозначает мишень-специфичный фрагмент;D 21 denotes a target-specific fragment; M4 обозначает OH, NH2 или SH; аM 4 is OH, NH 2 or SH; but все остальные переменные имеют значения, указанные в п.27.all other variables have the values specified in clause 27. 29. Способ лечения млекопитающего, включающий введение эффективного количества соединения формулы (I) пациенту, нуждающемуся в таком введении.29. A method of treating a mammal, comprising administering an effective amount of a compound of formula (I) to a patient in need of such administration. 30. Способ введения полинуклеотидов в клетки млекопитающего, включающий доставку эффективного количества соединения формулы (I) в клетку, нуждающуюся в такой обработке. 30. A method of introducing polynucleotides into mammalian cells, comprising delivering an effective amount of a compound of formula (I) to a cell in need of such treatment.
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