Oligonucleotide composition and method of use thereof

Abstract

This invention provides a designed APOC3 oligonucleotide, a composition, and a method for producing it. [Solution] The oligonucleotide composition provided improves single-stranded RNA interference and / or RNase H-mediated knockdown. This disclosure includes the recognition that structural elements of oligonucleotides can significantly influence the properties and activities of oligonucleotides (e.g., RNA interference (RNAi) activity, stability, delivery, etc.), such structural elements include the base sequence, chemical modifications (e.g., sugar modifications, base modifications, and / or modifications of internucleotide bonds) or their patterns, complexation with additional chemical moieties, and / or stereochemistry [e.g., stereochemistry of the skeletal chiral center (chiral internucleotide bond)] and / or their patterns. In one embodiment, this disclosure provides a method for treating a disease using the oligonucleotide composition provided.

Claims

[Claim 1] Compounds having formula O1: Y １ -L １ -(Z １０ ) ｚａ O1 or a pharmaceutically acceptable salt of the compound, wherein Y １ This is an oligonucleotide that targets APOC3, za is 1, 2, or 3. L １ is a compound of formula L11, L12, L13, L43, L44, L45, L46, L47, L48, L49, L50, L51, L52, L53 or L54, and Y １ and Z １０ The bonding position with is shown, 【Chemistry 1】 【change】 【change】 【change】 【change】 In the formula, each T １ is independently absent or is alkylene, alkenylene, or alkynylene, where one or more —CH ２ — groups of the alkylene, alkenylene, or alkynylene may each independently be replaced with a heteroatom group independently selected from —O—, —S—, and —N(R ４９ ), where the heteroatom groups are separated by at least two carbon atoms. Each Q １ These are either independent, non-existent, or -C(O)-, -C(O)-NR ４９ -, -NR ４９ -C(O)-, -OC(O)-NR ４９ -, -NR ４９ -C(O)-O-, -CH ２ -, -NR ４９ C(O)NR ４９ -, divalent heteroaryl group, or -O-, -S-, -S-S-, -S(O)-, -S(O) ２ -, and -NR ４９ - A heteroatom group selected from (where at least two carbon atoms are the heteroatom groups -O-, -S-, -S-S-, -S(O)-, -S(O)) ２ - and -NR ４９ - is separated from any other heteroatomic group), or has the following structure: 【Chemistry 2】 Here, R ５３ is -O or -NH-, R ５４ is -O or -S, Each R ４９ These are independently -H, -(C １ -C ２０ ) alkyl, or -(C ３ -C ６ ) is a cycloalkyl group, where 1 to 6 -CH groups of the alkyl or cycloalkyl group separated by at least two carbon atoms. ２ - The group is -O-, -S-, or -N(R) ４９ａ ) may be replaced with -CH, and the alkyl -CH ３ is -N(R ４９ａ ) ２ , -OR ４９ａ , and -S(R ４９ａ ) may be replaced by a heteroatomic group selected from, where the heteroatomic group is separated by at least two carbon atoms, where the alkyl and cycloalkyl may be substituted with a halo atom, and each R ４９ａ These are independently -H, -(C １ -C ６ ) alkyl, or -(C ３ -C ６ ) It is a cycloalkyl, R ５３ is -O or -NH, R ５４ is -O or -S, Each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, and if n is greater than 0, each (T １ -Q １ -T １ -Q １ Each T of ) １ and each Q １ They are selected independently, Each Z １０ Independently, L is a compound of formula Z12, Z13, Z14, Z15, Z16, Z17, Z18, Z19, Z20, or Z21, or a geometric isomer or positional isomer thereof. １ The bonding position with is shown, 【Transformation 3】 Here, each R ４６ is independently, -CN, -CH ２ -CN, -C≡CH, -CH ２ -N ３ 、-CH ２ -NH ２ 、-CH ２ -N(R ５２ )-S(O) ２ -R ５１ 、-CH ２ -CO ２ H, -CO ２ H, -CH ２ -OH, -CH ２ -SH, -CH=CH-R ５１ 、-CH ２ -R ５１ 、-CH ２ -S-R ５１ 、-CH ２ -N(R ５２ )-R ５１ 、-CH ２ -N(R ５２ )-C(O)-R ５１ 、-CH ２ -N(R ５２ )-C(O)-O-R ５１ 、-CH ２ -N(R ５２ )-C(O)-N(R ５２ )-R ５１ 、-CH ２ -O-R ５１ 、-CH ２ -O-C(O)-R ５１ 、-CH ２ -O-C(O)-N(R ５２ )-R ５１ 、-CH ２ -O-C(O)-O-R ５１ 、-CH ` ２ -S(O)-R ５１ 、-CH ２ -S(O) ２ -R ５１ 、-CH ２ -S(O) ２ -N(R ５２ )-R ５１ 、-C(O)-NH ２ 、-C(O)-O-R ５１ 、-C(O)-N(R ５２ )-R ５１ , or aryl or heteroaryl, where the aryl or heteroaryl is R ５１ It is arbitrarily replaced with, Each R ４７ These are independently -OH and -N ３ , -N(R ４８ ) ２ , -N(R ４８ )-C(O)-R ４８ , -N(R ４８ )-C(O)-N(R ４８ ) ２ , -N(R ４８ )-C(O)-OR ４８ , -N(R ４８ )-S(O) ２ -R ４８ , tetrazole, or triazole, where the tetrazole and triazole are R ４８ It is arbitrarily replaced with, Each R ４８ These are independently -H, -(C １ -C ５ ) alkyl, halosubstituted (C １ -C ５ ) Alkyl, halo-substituted (C ３ -C ６ ) Cycloalkyl, -(C １ -C ５ ) Alkenil, - (C １ -C ５ ) Alkinyl, halo substitution - (C １ -C ５ ) Alkenyl, halo substitution - (C １ -C ５ ) Alkinyl, or -(C ３ -C ６ ) is a cycloalkyl, where the alkyl or cycloalkyl -CH ２ - The groups are -O-, -S-, and -N(R) ５２ Each of the heteroatom groups selected from the above may be independently replaced, and the alkyl group -CH ３ is -N(R ５２ ) ２ , -OR ５２ , and -S(R ５２ Each of these may be independently replaced by a heteroatomic group selected from the above, where the heteroatomic group is separated by at least two carbon atoms. Each R ５１ These are independently -H, -(C ３ -C ２０ ) Cycloalkyl, -(C １ -C ６０ ) Alkenil, - (C １ -C ６０ ) Alkinyl, or -(C １ -C ６０ ) is alkyl, where 1 to 6 -CH of the cycloalkyl group ２ - Group or 1 to 20 -CH groups of the alkyl group ２ - The groups are -O-, -S-, and -N(R) ４９ ) - may be independently replaced by heteroatoms independently selected from the alkyl group, where the heteroatoms are separated by at least two carbon atoms and the alkyl group -CH ３ is -N(R ４９ ) ２ , -OR ４９ , and -S(R ４９ Each of the heteroatoms selected from the above may be independently replaced, where the heteroatom is separated by at least two carbon atoms, and where the alkyl, alkenyl, alkynyl, and cycloalkyl groups may be substituted with halo atoms. Each R ５２ These are independently -H, -(C １ -C ２０ ) alkyl, -(C １ -C ２０ ) Alkenil, - (C １ -C ２０ ) Alkinyl, or -(C ３ -C ６ ) is a cycloalkyl group, where 1 to 6 -CH groups of the alkyl or cycloalkyl group separated by at least two carbon atoms. ２ - The group is -O-, -S-, or -N(R) ４９ ) - may be independently replaced by heteroatoms independently selected from the alkyl -CH ３ is -N(R ４９ ) ２ , -OR ４９ , and -S(R ４９ Each of the heteroatoms selected from the above may be independently replaced, where the heteroatom group is separated by at least two carbon atoms, and where the alkyl, alkenyl, alkynyl, and cycloalkyl groups may be substituted with halo atoms. The aforementioned compound or the aforementioned pharmaceutically acceptable salt.

Images