RU2020137170A - ANTISENSE OLIGONUCLEOTIDES OF MATRIX METALLOPROTEINASE-1 - Google Patents

Claims (61)

1. A peptide nucleic acid derivative represented by formula I, or a pharmaceutically acceptable salt thereof:

where n is an integer from 10 to 21; the compound of formula I has at least a 10-mer complementary overlap with the 16-mer pre-mRNA sequence [(5'→3') CAUAUAUGGUGAGUAU] in human MMP-1 pre-mRNA; a compound of formula I is fully complementary to human pre-MMP-1 mRNA or partially complementary to human pre-mRNA MMP-1 with one or two mismatches; S ₁ , S ₂ , ..., S _n-1 , S _n , T ₁ , T ₂ , ..., T _n-1 and T _n independently denote a hydrogen atom, a deuterium atom, a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group; X and Y independently represent a hydrogen atom, a deuterium atom, a formyl group [H-C(=O)-], an aminocarbonyl group [NH ₂ -C(=O)-], an aminothiocarbonyl group [NH ₂ -C(=S)-], substituted или незамещенную алкилгруппу, замещенную или незамещенную арилгруппу, замещенную или незамещенную алкилоксигруппу, замещенную или незамещенную арилоксигруппу, замещенную или незамещенную алкилацилгруппу, замещенную или незамещенную арилацилгруцпу, замещенную или незамещенную алкилоксикарбонйлгруппу, замещенную или незамещенную арилоксикарбонилгруппу, замещенную или незамещенную алкиламинокарбонилгруппу, замещенную или незамещенную ариламинокарбонилгруппу, замещенную or an unsubstituted alkylaminothiocarbonyl group, a substituted or unsubstituted arylaminothiocarbonyl group, a substituted or unsubstituted alkyloxythiocarbonyl group, a substituted or unsubstituted aryloxythiocarbonyl group, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group, a substituted or unsubstituted alkylphosphonyl group or a substituted or unsubstituted arylphosphonyl group; Z is a hydrogen atom, a deuterium atom, a hydroxy group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted amino group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group; _{B 1} , _{B 2} , . and at least four of _{B 1} , B ₂ , . 2. A derivative of a peptide nucleic acid according to claim 1 or its pharmaceutical salt, where n is an integer from 10 to 21; the compound of formula I has at least a 10-mer complementary overlap with the 16-mer pre-mRNA sequence [(5'→3') CAUAUAUGGUGAGUAU] in human MMP-1 pre-mRNA; a compound of formula I is fully complementary to human pre-MMP-1 mRNA or partially complementary to human pre-mRNA MMP-1 with one or two mismatches; S ₁ , S ₂ , ..., S _n-1 , S _n , T ₁ , T ₂ , ..., T _n-1 and T _n independently denote a hydrogen atom, a deuterium atom; X and Y independently represent a hydrogen atom, a deuterium atom, a formyl group [H-C(=O)-], an aminocarbonyl group [NH ₂ -C(=O)-], an aminothiocarbonyl group [NH ₂ -C(=S)-], substituted or an unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkylacyl group, a substituted or unsubstituted arylacyl group, a substituted or unsubstituted alkyloxycarbonyl group, a substituted or unsubstituted aryloxycarbonyl group, a substituted or unsubstituted alkylaminocarbonyl group, a substituted or unsubstituted alkylaminocarbonyl group, a substituted or unsubstituted alkylaminocarbonyl group, or an unsubstituted alkylaminothiocarbonyl group, a substituted or unsubstituted arylaminothiocarbonyl group, a substituted or unsubstituted alkyloxythiocarbonyl group, a substituted or unsubstituted aryloxythiocarbonyl group, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group, a substituted or unsubstituted alkylphosphonyl group or a substituted or unsubstituted arylphosphonyl group; Z is a hydrogen atom, a hydroxy group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aryloxy group, or a substituted or unsubstituted amino group; B ₁ , B ₂ , ..., B _n-1 and are independently selected from naturally occurring nucleobases including adenine, thymine, guanine, cytosine, and uracil, and non-naturally occurring nucleobases; at least four of B ₁ , B ₂ , ..., B _n-1 and are independently selected from non-naturally occurring nucleic bases represented by formula II, formula III or formula IV:

where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently selected from a hydrogen atom and a substituted or unsubstituted alkyl group; L ₁ , L ₂ and L ₃ are a covalent linker represented by formula V, covalently connecting the basic amino group with the remainder of the nucleic base:

where Q ₁ and Q _m represent a substituted or unsubstituted methylene group (-CH ₂ -) and Q _m directly binds the basic amino group; Q ₂ , Q ₃ , ... and Q _m-1 are independently selected from substituted or unsubstituted methylene group, oxygen atom (-O-), sulfur atom (-S-) and substituted or unsubstituted amino group [-N(H)- or -N (deputy)-]; and m is an integer from 1 to 15. 3. A derivative of a peptide nucleic acid according to claim 2 or a pharmaceutical salt thereof, where n is an integer from 11 to 16; the compound of formula I has at least a 10-mer complementary overlap with the 16-mer pre-mRNA sequence [(5'→3') CAUAUAUGGUGAGUAU] in human MMP-1 pre-mRNA; the compound of formula I is fully complementary to human pre-mRNA MMP-1; S ₁ , S ₂ , ..., S _n-1 , S _n , T ₁ , T ₂ , T _n-1 and T _n represent a hydrogen atom; X and Y independently represent a hydrogen atom, a substituted or unsubstituted alkylacyl group, or a substituted or unsubstituted alkyloxycarbonyl group; Z is a substituted or unsubstituted amino group; B ₁ , B ₂ , ..., B _n-1 and are independently selected from naturally occurring nucleobases including adenine, thymine, guanine, cytosine and uracil and non-natural nucleobases; at least five of B ₁ , B ₂ , ..., B _n-1 and are independently selected from non-naturally occurring nucleic bases represented by formula II, formula III or formula IV; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are a hydrogen atom; Q ₁ and Q _m represent a methylene group and Q _m directly binds the basic amino group; Q ₂ , Q ₃ , ... and Q _m-1 are independently selected from a methylene group and an oxygen atom; and m is an integer from 1 to 9. 4. A derivative of a peptide nucleic acid according to claim 3 or a pharmaceutical salt thereof, where n is an integer from 11 to 16; the compound of formula I has at least a 10-mer complementary overlap with the 16-mer pre-mRNA sequence [(5'→3') CAUAUAUGGUGAGUAU] in human MMP-1 pre-mRNA; the compound of formula I is fully complementary to human pre-mRNA MMP-1; S ₁ , S ₂ , ..., S _n-1 , S _n , T ₁ , T ₂ , ..., T _n-1 and T _n represent a hydrogen atom; X is a hydrogen atom; Y is a substituted or unsubstituted alkyloxycarbonyl group; Z is a substituted or unsubstituted amino group; B ₁ , B ₂ , ..., B _n-1 and are independently selected from naturally occurring nucleobases including adenine, thymine, guanine, cytosine, and uracil, and non-naturally occurring nucleobases; at least five of _{B 1} , B ₂ , . R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are hydrogen atoms; L ₁ denotes -(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -, -CH ₂ -O-(CH ₂ ) ₂ -, -CH ₂ -O-(CH ₂ ) ₃ -, -CH ₂ -O -(CH ₂ ) ₄ - or -CH ₂ -O-(CH ₂ ) ₅ - with the right end directly associated with the basic amino group; and L2 and L3 are independently selected from -(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -O-(CH ₂ ) ₂ -, -(CH ₂ ) ₂ -O-(CH ₂ ) ₃ -, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄ -, -(CH ₂ ) ₅ -, -(CH ₂ ) ₆ -, -(CH ₂ ) ₇ - and -(CH ₂ ) ₈ - with the right end is directly associated with the basic amino group. 5. A peptide nucleic acid derivative according to claim 4, which is a peptide nucleic acid derivative of the following, or a pharmaceutically acceptable salt thereof: (N→C) Fethoc-TA(6)C-TCA(6)-CC(1O2)A(6)-TA(6)TA(6)T-NH ₂ , where A, T and C are peptide nucleic acid monomers with natural nucleic base adenine, thymine and cytosine, respectively; C(pOq) and A(p) are non-naturally occurring peptide nucleic acid monomers represented by formula VI and formula VII, respectively;

where p and q are integers and p is 1 or 6 and q is 2; and "Fethoc-" is an abbreviation for "[2-(9-fluorenyl)ethyl-1-oxy]carbonyl group". 6. A method of treating diseases or conditions associated with human MMP-1 gene transcription, comprising administering to a patient a peptide nucleic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 7. A method for treating skin aging, comprising administering to a patient the peptide nucleic acid derivative of claim 1 or a pharmaceutically acceptable salt thereof. 8. Pharmaceutical composition for the treatment of diseases or conditions associated with the transcription of the human MMP-1 gene, comprising a peptide nucleic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 9. Cosmetic composition for the treatment of diseases or conditions associated with transcription of the human MMP-1 gene, comprising a peptide nucleic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition for the treatment of skin aging, comprising a peptide nucleic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 11. A cosmetic composition for the treatment of skin aging, comprising a peptide nucleic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof.