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ENA nucleic acid drugs that modify splicing in mRNA precursors

机译:修饰mRNA前体中剪接的ENA核酸药物

摘要

A compound capable of inducing the exon 46 jump of the dystrophin gene, which is (a) an oligonucleotide consisting of the nucleotide sequence shown in any one of SEQ ID NO: 21, 22, 19, 20 and 18, where at least one of the sugars constituting the oligonucleotide is modified, and where said sugar is Dribofuranose and at least one modification of said sugar is 2'-O, 4'-C-alkyleneation of D-ribofuranose, or (b) a compound represented by the general formula (V '), (VI') and (VII ') or a pharmacologically acceptable salt thereof, wherein said general formulas are defined as follows: BT'5-BM'5-BB'5 ( V ') where BT'5 is a group represented by any one of the following (5a') to (5g '): (5a') HO-, (5b ') HO-Bt-, (5c') HO-Bt -Bt-, (5d ') HO-Bt-Bt-Bt-, (5e') HO-Bt-Bt-Bt-Bt-, (5f ') HO-Bc-Bt-Bt-Bt-Bt-, or (5g ') HO-Bg-Bc-Bt-Bt-Bt-Bt- BM'5 is a group represented by the following formula (5'): -Bc-Bt-Bt-Bt-Bt-Ba-Bg-Bt -Bt-Bg-Bc-Bt-Bg-Bc- (5 ') BB'5 is a group represented by any one of the following (52a ') to (52i'): (52a ') - CH2CH2OH, (52b') - Bt-CH2CH2OH, (52c ') - Bt-Bc-CH2CH2OH, (52d') - Bt-Bc-Bt-CH2CH2OH, (52e ') - Bt-Bc-Bt-Bt-CH2CH2OH, (52f') - Bt-Bc-Bt-Bt-Bt-CH2CH2OH, (52g ') - Bt-Bc-Bt -Bt-Bt-Bt-CH2CH2OH, (52h ') - Bt-Bc-Bt-Bt-Bt-Bt-Bc-CH2CH2OH, or (52i') - Bt-Bc-Bt-Bt-Bt-Bt-Bc- Bc-CH2CH2OH where Bg is a group represented by the following formula (G1) or (G2); Ba is a group represented by the following formula (A1) or (A2); Bc is a group represented by the following formula (C1) or (C2); and Bt is a group represented by the following formula (U1) or (T2): ** Formula ** where X is individually and independently a group represented by the following formula (XI) or (X2): Y is individually and independently a hydrogen atom, a hydroxyl group or an alkoxy group with 1-6 carbon atoms; and Z is individually and independently a single bond or an alkylene group with 1-5 carbon atoms; with the proviso that at least one of the nucleosides constituting the compound represented by the formula (V ') has a 2'-O, 4'-C-alkylene group. BT'6-BM'6-BB'6 (VI ') where BT'6 is a group represented by any one of the following (6a') to (6r '): (6a') HO-, (6b ') HO-Bc-, (6c ') HO-Bt-Bc-, (6d') HO-Bc-Bt-Bc-, (6e ') HO-Bg-Bc-Bt-Bc-, (6f') HO- Bt-Bg-Bc-Bt-Bc-, (6g ') HO-Bc-Bt-Bg-Bc-Bt-Bc-, (6h') HO-Bg-Bc-Bt-Bg-Bc-Bt-Bc- , (6j ') HO-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, (6k') HO-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, ( 6l ') HO-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, (6m') HO-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc- Bt-Bc-, (6n ') HO-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, (6o') HO-Bt-Bt-Ba-Bg- Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, (6p ') HO-Bt-Bt-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt -Bc-, (6q ') HO-Bt-Bt-Bt-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, or (6r') HO-Bc- Bt-Bt-Bt-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc- BM'6 is a group represented by the following formula (6 '): -Bt-Bt -Bt-Bt-Bc-Bc- (6 ') BB'6 is a group represented by any one of the following (62a') to (62m '): (62a') - CH2CH2OH, (62b ') - Ba- CH2CH2OH, (62c ') - Ba-Bg-CH2CH2OH, (62d') - Ba-Bg-Bg-CH2CH2OH, (62e ') - Ba-Bg-Bg-Bt-CH2CH2OH, (62f') - Ba-Bg- Bg-Bt-Bt-CH2 CH2OH, (62g ') - Ba-Bg-Bg-Bt-Bt-Bc-CH2CH2OH, (62h') - Ba-Bg-Bg-Bt-Bt-Bc-Ba-CH2CH2OH, (62i ') - Ba-Bg -Bg-Bt-Bt-Bc-Ba-Ba-CH2CH2OH, (62j ') - Ba-Bg-Bg-Bt-Bt-Bc-Ba-Ba-Bg-CH2CH2OH, (62k') - Ba-Bg-Bg -Bt-Bt-Bc-Ba-Ba-Bg-Bt-CH2CH2OH, (621 ') - Ba-Bg-Bg-Bt-Bt-Bc-Ba-Ba-Bg-Bt-Bg-CH2CH2OH, or (62m' ) -Ba-Bg-Bg-Bt-Bt-Bc-Ba-Ba-Bg-Bt-Bg-Bg-CH2CH2OH where Bg, Ba, Bt and Bc are as defined above; with the proviso that at least one of the nucleosides constituting the compound represented by the formula (VI ') has a 2'-O, 4'-C-alkylene group; BT'7-BM'7-BB'7 (VII ') where BT'7 is a group represented by any one of the following (7a') to (7f '): (7a') HO-, (7b ') HO-Bt-, (7c ') HO-Ba-Bt-, (7d') HO-Bt-Ba-Bt-, (7e ') HO-Bt-5 Bt-Ba-Bt-, or (7f') HO-Bg-Bt-Bt-Ba-Bt- BM'7 is a group represented by the following formula (7 '): -Bc-Bt-Bg-Bc-Bt-Bt-Bc-Bc-Bt- Bc-Bc -Ba-Ba-Bc-Bc- (7 ') where Bg, Ba, Bt and Bc are as defined above; BB'7 is a group represented by the following (72a '): (72a') - CH2CH2OH with the proviso that at least one of the nucleosides constituting the compound represented by formula (VII ') has a group 2'- Or, 4'-C-alkylene.
机译:一种能够诱导抗肌萎缩蛋白基因外显子46跳跃的化合物,该化合物是(a)由SEQ ID NO:21、22、19、20和18中任一个所示的核苷酸序列组成的寡核苷酸,其中至少一个为构成寡核苷酸的糖被修饰,并且其中所述糖是三呋喃呋喃糖并且所述糖的至少一个修饰是D-呋喃呋喃糖的2'-O,4'-C-亚烷基化,或(b)通式表示的化合物(V'),(VI')和(VII')或其药理学上可接受的盐,其中所述通式定义如下:BT'5-BM'5-BB'5(V')其中BT'5为由以下(5a')至(5g')中的任何一个表示的基团:(5a')HO-,(5b')HO-Bt-,(5c')HO-Bt -Bt-,(5d') HO-Bt-Bt-Bt-,(5e')HO-Bt-Bt-Bt-Bt-Bt-,(5f')HO-Bc-Bt-Bt-Bt-Bt-Bt-,或(5g')HO-Bg- Bc-Bt-Bt-Bt-Bt-BM'5是下式(5')表示的基团:-Bc-Bt-Bt-Bt-Bt-Bt-Ba-Bg-Bt -Bt-Bg-Bc-Bt -Bg-Bc-(5')BB'5是由以下任何一个(5 2a')至(52i'):(52a')-CH2CH2OH,(52b')-Bt-CH2CH2OH,(52c')-Bt-Bc-CH2CH2OH,(52d')-Bt-Bc-Bt-CH2CH2OH,( 52e')-Bt-Bc-Bt-Bt-CH2CH2OH,(52f')-Bt-Bc-Bt-Bt-Bt-Bt-CH2CH2OH,(52g')-Bt-Bc-Bt -Bt-Bt-Bt-CH2CH2OH, (52h')-Bt-Bc-Bt-Bt-Bt-Bt-Bc-CH2CH2OH,或(52i')-Bt-Bc-Bt-Bt-Bt-Bt-Bt-Bc- Bc-CH2CH2OH由下式(G1)或(G2)表示; Ba是由下式(A1)或(A2)表示的基团。 Bc是下式(C1)或(C2)表示的基团。并且Bt是由下式(U1)或(T2)表示的基团:**式**其中X分别独立地是由下式(XI)或(X2)表示的基团:Y分别且独立地是氢原子,羟基或具有1-6个碳原子的烷氧基; Z分别独立地为单键或碳数1〜5的亚烷基。条件是构成式(V')表示的化合物的至少一个核苷具有2'-O,4'-C-亚烷基。 BT'6-BM'6-BB'6(VI'),其中BT'6是由以下(6a')至(6r')中的任何一个表示的基团:(6a')HO-,(6b') HO-Bc-,(6c')HO-Bt-Bc-,(6d')HO-Bc-Bt-Bc-,(6e')HO-Bg-Bc-Bt-Bc-,(6f')HO- Bt-Bg-Bc-Bt-Bc-,(6g')HO-Bc-Bt-Bg-Bc-Bt-Bc-,(6h')HO-Bg-Bc-Bt-Bg-Bc-Bt-Bc- ,(6j')HO-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-,(6k')HO-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-,( 6l')HO-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-,(6m')HO-Ba-Bg-Bt-Bt-Bt-Bg-Bc-Bt-Bg-Bc- Bt-Bc-(6n')HO-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-,(6o')HO-Bt-Bt-Bt-Ba-Bg- Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-,(6p')HO-Bt-Bt-Bt-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt -Bc-,(6q')HO-Bt-Bt-Bt-Bt-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-或(6r')HO-Bc- Bt-Bt-Bt-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-BM'BM'6是下式(6')表示的基团:-Bt-Bt -Bt-Bt-Bc-Bc-(6')BB'6是由以下(62a')至(62m')中的任何一个表示的基团:(62a')-CH2CH2OH,(62b')-Ba- CH 2 CH 2 OH,(62c′)-Ba-Bg-CH 2 CH 2 OH,(62d′)-Ba-Bg-Bg-CH 2 CH 2 OH,(62e′)-Ba-Bg-Bg-Bt-Bt-CH 2 CH 2OH,(62f')-Ba-Bg- Bg-Bt-Bt-CH2 CH2OH,(62g')-Ba-Bg-Bg-Bt-Bt-Bc-CH2CH2OH,(62h')-Ba-Bg-Bg- Bt-Bt-Bc-Ba-CH2CH2OH,(62i')-Ba-Bg -Bg-Bt-Bt-Bt-Bc-Ba-Ba-Ba-CH2CH2OH,(62j')-Ba-Bg-Bg-Bg-Bt-Bt-Bc- Ba-Ba-Bg-CH2CH2OH,(62k')-Ba-Bg-Bg-Bt-Bt-Bc-Ba-Ba-Bg-Bt-CH2CH2OH,(621')-Ba-Bg-Bg-Bt-Bt- Bc-Ba-Ba-Bg-Bt-Bg-CH2CH2OH或(62m')-Ba-Bg-Bg-Bt-Bt-Bt-Bc-Ba-Ba-Bg-Bt-Bg-Bg-Bg-CH2CH2OH,其中Bg,Ba, Bt和Bc如上定义;前提是构成式(VI')表示的化合物的至少一个核苷具有2'-O,4'-C-亚烷基。 BT'7-BM'7-BB'7(VII'),其中BT'7是由以下(7a')至(7f')中的任何一个表示的基团:(7a')HO-,(7b') HO-Bt-,(7c')HO-Ba-Bt-,(7d')HO-Bt-Ba-Bt-,(7e')HO-Bt-5 Bt-Ba-Bt-或(7f') HO-Bg-Bt-Bt-Ba-Bt-BM'7是下式(7')表示的基团:-Bc-Bt-Bg-Bc-Bt-Bt-Bc-Bc-Bt-Bc-Bc -Ba-Ba-Bc-Bc-(7′),其中Bg,Ba,Bt和Bc如上所定义; BB'7是由以下(72a')表示的基团:(72a')-CH 2 CH 2 OH,条件是构成式(VII')表示的化合物的至少一个核苷具有基团2'-或4 '-C-亚烷基。

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