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US 7,053,207 B2Granted
L-ribo-LNA analogues
AssigneeExiqon A/S
InventorJesper Wengel
Life of this patent
Estimating the term…
Abstract
Provided are L-ribo bicyclic nucleotide compounds as well as syntheses of such compounds. The nucleoside compounds of the invention are useful in forming oligonucleotides that can produce nucleobase specific duplexes with complementary single stranded and double stranded nucleic acids.
Claims29
An oligomer comprising at least one unit comprising an L-ribo-LNA composition of the general formula Ia:
- wherein
- X is selected from the group consisting of:
- —O—;
- —S—;
- —N(RN*)—;
- and —C(R6R6*)—;
- B is selected from the group consisting of:
- hydrogen;
- hydroxy;
- nucleobases, C1-4-alkoxy;
- C1-4-alkyl;
- C1-4-acyloxy;
- and substituted forms thereof;
- P designates a linkage to a succeeding monomer, oligomer, or a 5′-terminal group, said linkage or 5′-terminal group optionally including the substituent R5 or the substituent R5*;
- P* designates a linkage to a preceding monomer, oligomer, or a 3′-terminal group;
- R2* and R4* together represent a biradical consisting of 1–4 groups selected from the group consisting of:
- —C(RaRb)—;
- —C(Ra)═C(Ra)—;
- —C(Ra)═N—;
- —O—;
- —Si(Ra)2—;
- —S—;
- —SO2—;
- —N(Ra)—;
- and >C═Z;
- wherein Z is selected from —O—, —S—, and —N(Ra)—;
- and
- Ra and Rb each is independently selected from the group consisting of:
- hydrogen;
- hydroxy;
- nitro;
- azido;
- sulphanyl;
- sulphono;
- halogen;
- amino;
- carbamido;
- carbamoyl;
- carboxy;
- formyl;
- aryl;
- C1-2-alkyl;
- C2-12-alkenyl;
- C2-12-alkynyl;
- C1-12-alkoxy;
- C2-12-alkenyloxy;
- C1-12-alkoxycarbonyl;
- C1-12-alkylcarbonyl;
- aryloxy-carbonyl;
- aryloxy;
- arylcarbonyl;
- heteroaryl;
- heteroaryloxy-carbonyl;
- heteroaryloxy;
- heteroarylcarbonyl;
- mono- di(C1-6-alkyl)amino;
- di(C1-6-alkyl) amino;
- mono-(C1-6-alkyl)-amino-carbonyl;
- di(C1-6-alkyl)-amino-carbonyl;
- amino-C1-6-alkyl-aminocarbonyl;
- mono-(C1-6-alkyl)amino-C1-6-alkyl-aminocarbonyl;
- di(C1-6-alkyl)amino-C1-6-alkyl-aminocarbonyl;
- C1-6-alkyl-carbonylamino;
- C1-6-alkanoyloxy;
- sulphono;
- C1-6alkylsulphonyloxy;
- C1-6-alkylthio;
- substituted forms thereof, and a DNA intercalator, a photochemically active group, a thermochemically active group, a chelating group, a reporter group, and a ligand;
- or where Ra and Rb together designate methylene olefin (═CH2) or a substituted form thereof;
- and further wherein:
- each of the substituents R1*, R2, R3*, R5, R5*, R6, and R6* is independently selected from the group consisting of:
- hydrogen;
- hydroxy;
- nitro;
- azido;
- sulphanyl;
- sulphono;
- halogen;
- amino;
- carbamido;
- carbamoyl;
- carboxy;
- formyl;
- aryl;
- C1-12-alkyl;
- C2-12-alkenyl;
- C2-12-alkynyl;
- C1-12-alkoxy;
- C2-12-alkenyloxy;
- C1-12-alkoxycarbonyl;
- C1-12-alkylcarbonyl;
- aryloxy-carbonyl;
- aryloxy;
- arylcarbonyl;
- heteroaryl;
- heteroaryloxy-carbonyl;
- heteroaryloxy;
- heteroarylcarbonyl;
- mono-(C1-6-alkyl)amino;
- di(C1-6-alkyl)amino;
- carbamoyl;
- mono-(C1-6-alkyl)-amino-carbonyl;
- di(C1-6-alkyl)-ammo-carbonyl;
- amino-C1-6-alkyl-aminocarbonyl;
- mono-(C1-6-alkyl)amino-C1-6-alkyl-aminocarbonyl;
- di(C1-6-alkyl)amino-C1-6-alkyl-aminocarbonyl;
- C1-6-alkyl-carbonylamino;
- carbamido;
- C1-6-alkanoyloxy;
- C1-6-alkylsulphonyloxy;
- C1-6-alkylthio;
- and substituted forms thereof;
- or
- wherein two geminal substituents together designate oxo, thioxo, imino or optionally substituted methylene, or together form a spiro biradical consisting of a 1–5 carbon atom alkylene chain which is optionally interrupted and/or terminated by one or more heteroatoms selected from —O—, —S—, and —(NRN)— where RN is selected from the group consisting of hydrogen;
- C1-4-aIkyl;
- a basic addition salt of C1-4-alkyl;
- an acid addition salt of C1-4-alkyl;
- and substituted forms thereof;
- and/or two adjacent non-geminal substituents are bonded together by a double bond, and RN*, when present is selected from hydrogen and C1-4-alkyl;
- wherein the L-ribo-LNA composition has an (alpha) configuration.
117 more elements
A composition having the following formula IIa:
- wherein B comprises a nucleobase, DNA intercalator, a photochemically active group, a thermochemically active group, a chelating group, a reporter group, or a ligand;
- X is selected from —O—, —S—, —N(RN)—, and —C(R6R6*)—;
- each of Q and Q* is independently selected from the group consisting of:
- hydrogen;
- azido;
- halogen;
- cyano;
- nitro;
- hydroxy;
- carboxy;
- carboxymethyl;
- sulphono;
- sulphonomethyl;
- hydroxymethyl;
- monophosphate;
- diphosphate;
- triphosphate;
- mercapto;
- amino;
- aminomethyl;
- Prot-O—;
- Prot-O—CH2—;
- Act-O—;
- Act-O—CH2—;
- Prot-S—;
- Act-S—;
- Prot-N(RH)—;
- Act-N(RH)—;
- Prot-N(RH)—CH2—;
- Act-N(RH)—CH2—;
- mono-(C1-6-alkyl)amino;
- di(C1-6-alkyl)amino;
- C1-6-alkylthio;
- C1-6-alkoxy, C1-6-alkyl, C2-6-alkenyl, C2-6-alkenyloxy, C2-6-alkynyl, C2-6-alkynyloxy, and substituted forms thereof;
- wherein Prot is a protection group for —OH, —SH, and —NH(RH), respectively, Act is an activation group for —OH, —SH, and —NH(RH), respectively, and RH is selected from hydrogen and C1-6-alkyl;
- and
- R2* and R4* together designate a biradical selected from —O—, —(CR*R*)r+s—, —(CR*R*)r—O—(CR*R*)s—, —(CR*R*)r—S—(CR*R*)s, —(CR*R*)r—N(R*)—(CR*R*)s—, —O—(CR*R*)r+s—O—, —S—(CR*R*)r+s—O—, —O—(CR*R*r+s—S—, —N(R*)—(CR*R*)r+s—O—, —O—(CR*Rr+s—N(R*)—, —S—(CR*R*)r+s—S—, —N(R*) —(CR—R*)r+s—N(R*), —N(R)—(CR*R*)r+s—S—, and —S—(CR*R*)r+s—N(R*)—;
- wherein each R* is independently selected from hydrogen, halogen, azido, cyano, nitro, hydroxy, mercapto, amino, mono-(C1-6-alkyl)amino;
- di(C1-6-alkyl)amino;
- C1-6-alkoxy, C1-6-alkyl, and substituted forms thereof;
- and/or two adjacent (non-geminal) R* may together designate a double bond, and each of r and s is 0–3 with the proviso that the sum r+s is 1–4;
- each of substituents R1*, R2, R3*, R4, R5*, R6, and R6* is independently selected from the group consisting of:
- hydrogen;
- hydroxy;
- halogen;
- nitro;
- azido;
- sulphanyl;
- sulphono;
- carboxy;
- carbamoyl;
- carbamido;
- amino;
- formyl;
- aryl;
- aryloxy;
- arylcarbonyl;
- heteroaryl;
- heteroaryloxy-carbonyl;
- heteroaryl-oxy;
- heteroarylcarbonyl;
- C1-12-alkyl;
- C2-12-alkenyl;
- C2-12-alkynyl;
- C1-12-alkoxy;
- C2-12-alkenyloxy;
- C1-12-alkoxycarbonyl;
- C1-12-alkylcarbonyl;
- aryl-oxy-carbonyl, mono-(C1-6-alkyl)amino;
- di-(C1-6-alkyl)amino;
- mono-(C1-6-alkyl)-amino-carbonyl;
- di-(C1-6-alkyl)-amino-carbonyl;
- 1-6-alkyl-aminocarbonyl;
- mono-(C1-6-alkyl)amino-C1-6-alkyl-aminocarbonyl;
- di-(C1-6-alkyl)amino-C1-6-alkyl-aminocarbonyl;
- C1-6-alkyl-carbonylamino;
- C1-6-alkanoyloxy;
- C1-6-alkylsulphonyloxy;
- C1-6-alkylthio;
- and substituted forms thereof;
- or
- wherein two geminal substituents together designate oxo, thioxo, imino, or optionally substituted methylene, or together form a spiro biradical consisting of a 1–5 carbon alkylene chain which is optionally interrupted and/or terminated by one or more heteroatoms selected from —O—, —S—, and —(NRN)—
- wherein RN is selected from the group consisting of hydrogen;
- C1-4-alkyl;
- a basic addition salt of C1-4-alkyl;
- an acid addition salt of C1-4-alkyl;
- and substituted forms thereof;
- and/or two adjacent non-geminal substituents are bonded together by a double bond;
- and further,
- wherein any chemical group which is reactive under the conditions prevailing in oligonucleotide synthesis, is optionally functional group protected, and RN*, when present is selected from hydrogen and C,1-4-alkyl;
- wherein the composition has an α(alpha) configuration.
88 more elements
Dependencies are inferred from the claim text.