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Nucleotide precursors, nucleotide analogs and oligomeric compounds containing the same

A technology of compounds and meanings applied in the field of nucleotide precursors and analogs of siRNA

Pending Publication Date: 2020-12-18
SANOFI SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Other major challenges in RNAi technology are targeted delivery and cellular uptake of siRNA

Method used

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  • Nucleotide precursors, nucleotide analogs and oligomeric compounds containing the same
  • Nucleotide precursors, nucleotide analogs and oligomeric compounds containing the same
  • Nucleotide precursors, nucleotide analogs and oligomeric compounds containing the same

Examples

Experimental program
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Effect test

preparation example Construction

[0209] 教导上述含磷的核苷间键的制备的代表性美国专利包括美国专利3,687,808;4,469,863;4,476,301;5,023,243;5,177,196;5,188,897;5,264,423;5,276,019;5,278,302;5,286,717;5,321,131;5,399,676;5,405,939;5,453,496;5,455,233;5,466,677 ;5,476,925;5,519,126;5,536,821;5,541,306;5,550,111;5,563,253;5,571,799;5,587,361;5,194,599;5,565,555;5,527,899;5,721,218;5,672,697和5,625,050,其中每个通过引用并入本文。

[0210] In one embodiment, the non-phosphodiester backbone linkage is selected from phosphorothioate, phosphorodithioate, alkyl-phosphonate and phosphoramidate backbone linking groups.

[0211] In one embodiment, phosphorus-containing internucleoside linking groups encompass phosphodiesters, phosphotriesters, and phosphorothioates.

[0212] In some embodiments, oligonucleotides of the invention comprise one or more internucleoside linking groups that do not comprise a phosphorus atom. Such oligonucleotides include, but are not limited to, consisting of short chain alkyl or cycloalkyl internucleoside linking groups, mixed heteroatom...

Embodiment

[0700] Abbreviations used:

[0701] -AcOH: acetic acid

[0702] -FA: formic acid

[0703] -ACN: Acetonitrile

[0704] -DCM: dichloromethane

[0705] -DMA: Dimethylacetamide

[0706] -DCE: Dichloroethane

[0707] -DMF: Dimethylformamide

[0708] -DMSO: Dimethyl Sulfoxide

[0709] -EtOAc: ethyl acetate

[0710] -EtOH: ethanol

[0711] -Et 2 O: Ether

[0712] -iPrOH: Isopropanol

[0713] -THF: Tetrahydrofuran

[0714] -MeOH: Methanol

[0715] -NMP: N-methyl-2-pyrrolidone

[0716] -PE: petroleum ether

[0717] -Pyr: pyridine

[0718] -iPr: isopropyl

[0719] -cHex: cyclohexyl

[0720] -MTB: methyl-tert-butyl

[0721] -DIPEA: Diisopropylethylamine

[0722] -DMAP: 4-(Dimethylamino)-pyridine

[0723] -HBTU: (2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-hexafluorophosphate)

[0724] -TBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate

[0725] -DDTT: 3-((N,N-Dimethyl-aminomethylene)amino)-3H-1,2,4-dithiazole-5-thione

[0726] -NEt ...

Embodiment A1

[0823] Synthetic scheme 1

[0824]

[0825] 1a: Acetic acid [(2S,3S,4R,5R)-4-acetoxy-3-benzyloxy-2-(benzyloxymethyl)-5-(5-methyl-2,4- Dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methyl ester

[0826] Under an argon atmosphere, 42.5 g (87.4 mmol) of starting material G3 and 22.3 g (174.7 mmol) of thymidine were dissolved in 500 ml of dry ACN. After addition of 106.6 g (128.2 ml, 524.1 mmol) of BSA, the solution was stirred at 80° C. for 1 hour. After cooling the solution to 50°C, 31.8 g (25.9 ml, 141.5 mmol) TMSOTf were added and heating was continued at 80°C for 1 hour. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc and washed with saturated NaHCO 3 solution, H 2 O and saturated NaCl solution. Using MgSO 4 After drying, the organic layer was evaporated and the crude product was purified by silica gel chromatography (10 to 100% ethyl acetate in n-heptane) to give the desired thymidine derivative 1a as a colorless foam (40.9 g, 84.7%).

[0827...

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Abstract

The present disclosure relates to novel nucleotide precursors and nucleotide analogs that can be incorporated into oligonucleotides, including double-stranded oligonucleotides such as siRNAs. Oligonucleotides containing these analogs have superior biological activity, for example, increased in vitro stability and improved in vivo potency especially duration of action. The improved oligonucleotidesare useful for silencing (e.g., reducing or eradicating) the expression of a target gene. In particular embodiments, this invention encompasses specific nucleotide analogs to be included in double-stranded RNAs (dsRNAs), and especially in siRNAs, that can hybridize to messenger RNAs (mRNAs) of interest, so as to reduce or block the expression of target genes of interest. The present compounds have general formula (I), wherein each of Ra, Rb, Rc and Rd is independently, H or a (C1-C6) alkyl group and B is a heterocyclic nucleobase.

Description

technical field [0001] The present disclosure relates to the field of targeted gene silencing with small interfering RNA (siRNA), and more particularly to nucleotide precursors and analogs for siRNA. Background technique [0002] The concept of using synthetic oligonucleotides to control the expression of specific genes dates back to the late 1970s, when the use of short synthetic oligonucleotides for targeted gene silencing was first demonstrated (Stephenson et al., 1978, Proc NatlAcad Sci. USA, 75:285-288). Following Stephenson's discovery, the RNA interference pathway used to regulate gene expression and the role of siRNA in this process were elucidated, greatly expanding scientists' understanding of post-transcriptional gene expression control in eukaryotic cells. [0003] Synthetic oligonucleotides include single-stranded oligonucleotides, such as antisense oligonucleotides ("ASOs"), antimiR and antagomiR, and double-stranded oligonucleotides, such as siRNA. Both ASO ...

Claims

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Application Information

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IPC IPC(8): C07H15/26C07H21/02C07H21/00C07D413/04C07F9/6533C07F9/655C07F9/6558C07F9/6561C07D405/04C07D473/18C07D473/34C07F7/18A61P35/00
CPCC07D405/04C07F9/6533C07F9/6552C07F9/65583C07F9/65586C07F9/65616C07H15/26C07H21/00C07H21/02A61P35/00C07D413/04
Inventor A·霍夫迈斯特K·杰恩-霍夫曼
Owner SANOFI SA
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