CARBOHYDRATE CONJUGATES AS DELIVERY AGENTS FOR OLIGONUCLEOTIDES

• US 20120136042A1
• Filed: 12/14/2011
• Published: 05/31/2012
• Est. Priority Date: 12/04/2007
• Status: Active Grant

• Current Assignee: Alnylam Pharmaceuticals Incorporated
• Original Assignee: Alnylam Pharmaceuticals Incorporated
• Inventors: MANOHARAN, Muthiah, RAJEEV, Kallanthottathil G., JAYAPRAKASH, Narayanannair K., MAIER, Martin
• Granted Patent: US 8,450,467 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7004 Monosaccharides having only carbon, hydrogen and oxygen atoms
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/16 containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/28 Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
• CPC Class Codes: A61K 47/543 Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: A61K 47/56 the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• CPC Class Codes: Y02P 20/55 : Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention provides iRNA agents comprising at least one subunit of the formula (I):

• • wherein:
  • A and B are each independently for each occurrence O, N(R^N) or S;
  • X and Y are each independently for each occurrence H, OH, a hydroxyl protecting group, a phosphate group, a phosphodiester group, an activated phosphate group, an activated phosphite group, a phosphoramidite, a solid support, —P(Z′)(Z″)O-nucleoside, —P(Z′)(Z″)O-oligonucleotide, a lipid, a PEG, a steroid, a lipophile, a polymer, —P(Z′)(Z″)O-Linker-OP(Z′″)(Z″″)O-oligonucleotide, a nucleotide, an oligonucleotide, —P(Z′)(Z″)-formula (I), —P(Z′)(Z″)— or -Linker-R;
  • R is L^G, -Linker-L^G, or has the structure shown below:

• • L^G is independently for each occurrence a carbohydrate, e.g., monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide, polysaccharide;
  • R^N is independently for each occurrence H, methyl, ethyl, propyl, isopropyl, butyl, or benzyl; and
  • Z′, Z″, Z′″ and Z″″ are each independently for each occurrence O or S.

Claims

1. An iRNA agent comprising a compound having the structure shown in formula (I)

3. The iRNA agent of claim 1, wherein said iRNA agent is double stranded.

4. The iRNA agent of claim 3, wherein said compound is at the 3′

-end of one of the strands.

5. The iRNA agent of claim 4, wherein said compound is at the 3′

-end of the sense strand.

6. The iRNA agent of claim 1, wherein the iRNA agent further comprises at least one structure of formula (VI)

7. The iRNA agent of claim 6, wherein R^L is a lipophile.

8. The iRNA agent of claim 6, wherein R^L is cholesterol.

9. The iRNA agent of claim 6, wherein R^L is

18. A method of modulating the expression of a target gene in a cell, comprising providing to said cell an iRNA agent of claim 1.

19. The method of claim 18, wherein the target gene is selected from the group consisting of Factor VII, Eg5, PCSK9, TPX2, apoB, SAA, TTR, RSV, PDGF beta gene, Erb-B gene, Src gene, CRK gene, GRB2 gene, RAS gene, MEKK gene, JNK gene, RAF gene, Erk1/2 gene, PCNA(p21) gene, MYB gene, JUN gene, FOS gene, BCL-2 gene, Cyclin D gene, VEGF gene, EGFR gene, Cyclin A gene, Cyclin E gene, WNT-1 gene, beta-catenin gene, c-MET gene, PKC gene, NFKB gene, STAT3 gene, survivin gene, Her2/Neu gene, topoisomerase I gene, topoisomerase II alpha gene, mutations in the p73 gene, mutations in the p21(WAF1/CIP1) gene, mutations in the p27(KIP1) gene, mutations in the PPM1D gene, mutations in the RAS gene, mutations in the caveolin I gene, mutations in the MIB I gene, mutations in the MTAI gene, mutations in the M68 gene, mutations in tumor suppressor genes, and mutations in the p53 tumor suppressor gene.

20. A pharmaceutical composition comprising an iRNA agent of claim 1 alone or in combination with a pharmaceutically acceptable carrier or excipient.

2. An iRNA agent comprising a compound having the structure shown in formula (I′

);

10. The iRNA agent of claim 2, wherein R is one of formula (II), formula (III), formula (IV) or formula (V).

11. The iRNA agent of claim 10, wherein R having the structure of formula (V):

12. The iRNA agent of claim 11, wherein R is

13. The iRNA agent of claim 11, wherein R is

14. The iRNA agent of claim 2, wherein said compound has the structure

15. The iRNA agent of claim 2, wherein said compound has the structure

16. The iRNA agent of claim 2, wherein said compound has the structure