ENA nucleic acid drugs that modify splicing in mRNA precursors

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.