EP1625138A2 - Monomeres proteges - Google Patents

Monomeres proteges

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Publication number
EP1625138A2
EP1625138A2 EP04759940A EP04759940A EP1625138A2 EP 1625138 A2 EP1625138 A2 EP 1625138A2 EP 04759940 A EP04759940 A EP 04759940A EP 04759940 A EP04759940 A EP 04759940A EP 1625138 A2 EP1625138 A2 EP 1625138A2
Authority
EP
European Patent Office
Prior art keywords
monomer
alkyl
hydrogen
ligand
ofthe
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04759940A
Other languages
German (de)
English (en)
Other versions
EP1625138A4 (fr
Inventor
Muthiah Manoharan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alnylam Pharmaceuticals Inc
Original Assignee
Alnylam Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2004/007070 external-priority patent/WO2004080406A2/fr
Priority claimed from PCT/US2004/010586 external-priority patent/WO2004090108A2/fr
Priority claimed from PCT/US2004/011255 external-priority patent/WO2004091515A2/fr
Application filed by Alnylam Pharmaceuticals Inc filed Critical Alnylam Pharmaceuticals Inc
Publication of EP1625138A2 publication Critical patent/EP1625138A2/fr
Publication of EP1625138A4 publication Critical patent/EP1625138A4/fr
Withdrawn legal-status Critical Current

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Definitions

  • FG a and FG a can be "deprotected,” or restored to their original chemical form.
  • One example where the protecting group strategy has been utilized to provide functional group reaction selectivity is in the synthesis of oligoribonucleotides from individual ribonucleotide monomer units.
  • the ribonucleoside monomers There are several chemically similar sites on the ribonucleoside monomers, e.g. the 2'-, 3'- and 5'- hydroxyl (OH) groups.
  • the monomer subunits must be attached in a site-specific manner during RNA synthesis.
  • R when taken together with R forms a double bond between the carbon and nitrogen atoms to which they are attached, or R 8 when taken together with R 11 forms a double bond between the carbon and nitrogen atoms to which they are attached;
  • R is hydrogen, or when taken together with R forms a double bond between the carbon atoms to which they are attached;
  • R 28 is C1-C10 alkyl
  • R 29 is a liquid or solid phase support reagent
  • Q' is N or CR 45 ;
  • R c is C ⁇ -C 6 alkyl
  • X 2 can be -OC[OCH 2 CH 2 OC(O)CH 3 ] 2 ;
  • R 27 can be CH 3 ;
  • R 28 can be (CH 3 ) 2 CH-;
  • X5' and X5" can be trimethylsiloxy;
  • X5'" can be cyclododecyloxy; and
  • B can be:
  • X 2 can be -OC[OCH 2 CH 2 OC(O)CH 3 ] 2 ;
  • R 27 can be CH 3 ;
  • R 28 can be (CH 3 ) 2 CH-;
  • X5' and X5" can be trimethylsiloxy;
  • X5'" can be cyclododecyloxy; and
  • B can be:
  • R 3 is hydrogen, halo, C ⁇ -C 4 alkyl, d-C 4 thioalkoxy, NH 2 , NHR , or NR R c ; R 4 when taken together with R 4 forms oxo, or R 4 when taken together with R 5 forms a double bond between the carbon and nitrogen atoms to which they are attached;
  • R 10 is hydrogen or is absent
  • R 20 is:
  • R is hydrogen, or when taken together with R forms a double bond between the carbon atoms to which they are attached; R 22 is hydrogen;
  • R d is hydrogen, hydroxy, protected hydroxy, or OOH
  • R e is hydrogen, a nitrogen protecting group, or COOR g
  • R is hydrogen, or d-C 6 alkyl
  • R g is d-C 10 alkyl
  • R h is hydrogen, or
  • Preferred X5', X5", and X5"' include siloxy and alkoxy or cycloalkoxy.
  • the second functionalized hydroxyl group can have the formula:
  • halo or halogen refers to any radical of fluorine, chlorine, bromine or iodine.
  • cycloalkenyl as employed herein includes partially unsaturated, nonaromatic, cyclic, bicyclic, tricyclic,or polycyclic hydrocarbon groups having 5 to 12 carbons, preferably 5 to 8 carbons, wherein any ring atom can be substituted.
  • the cycloalkenyl groups herein described may also contain fused rings. Fused rings are rings that share a common carbon- carbon bond or a common carbon atom (e.g., spiro-fused rings).
  • Examples of cycloalkenyl moieties include, but are not limited to cyclohexenyl, cyclohexadienyl, or norbornenyl.
  • RNA Modification Database maintained by Pamela F. Crain, Jef Rozenski and James A. McCloskey; Departments of Medicinal Chemistry and Biochemistry, University of Utah, Salt Lake City, UT 84112, USA (RNAmods@lib.med.utah.edu )
  • the 5'-O-silyl group can be removed via exposure to fluoride ions, which can include any source of fluoride ion, e.g., those salts containing fluoride ion paired with inorganic counterions e.g., cesium fluoride and potassium fluoride or those salts containing fluoride ion paired with an organic counterion, e.g., a tefraalkylammonium fluoride.
  • a crown ether catalyst can be utilized in combination with the inorganic fluoride in the deprotection reaction.
  • iRNA agents ofthe invention are particularly useful when targeted to the liver.
  • An iRNA agent can be targeted to the liver by incorporation of a monomore derivitzed with a ligand which targets to the liver.
  • a liver-targeting agent can be a lipophilic moiety.
  • Preferred lipophilic moieties include lipid, cholesterols, oleyl, retinyl, or cholesteryl residues (see Table 1).
  • Candidate agents can be evaluated for suitability as described below.
  • the 2' modifications can be used in combination with one or more phosphate linker modifications (e.g., phosphorothioate).
  • phosphate linker modifications e.g., phosphorothioate
  • chimeric oligonucleotides are those that contain two or more different modifications.
  • Examples include the mophilino, cyclobutyl, pyrrolidine and peptide nucleic acid (PNA) nucleoside surrogates.
  • a preferred surrogate is a PNA surrogate.
  • EDTA lipophilic carriers
  • lipophilic carriers e.g., cholesterol, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, l,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid,O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine)and peptide conjugates (e.g., antennapedia peptide, Tat peptide), alkylating agents, phosphate, amino, mercapto, PEG (e.g., PEG-40K), MPEG, [MPEG] 2 , polya
  • Terminal modifications can be added for a number of reasons, including as discussed elsewhere herein to modulate activity or to modulate resistance to degradation.
  • Terminal modifications useful for modulating activity include modification ofthe 5' end with phosphate or phosphate analogs.
  • iRNA agents, especially antisense strands are 5' phosphorylated or include a phosphoryl analog at the 5' prime terminus.
  • 5 '-phosphate modifications include those which are compatible with RISC mediated gene silencing.
  • X 1 , X 2 , X 3 , and X 4 are each, independently, O or S.
  • An iRNA agent can include monomers which have been modifed so as to inhibit degradation, e.g., by nucleases, e.g., endonucleases or exonucleases, found in the body of a subject. These monomers are referred to herein as NRMs, or nuclease resistance promoting monomers or modifications.
  • a modification can include the alteration, e.g., replacement, of one or both ofthe non- linking (X and Y) phosphate oxygens and/or of one or more ofthe linking (W and Z) phosphate oxygens.
  • Formula X depicts a phosphate moiety linking two sugar/sugar surrogate-base moieties, SB t and SB 2 .
  • the population of stereogenic phosphorus atoms may have the Rp configuration and may be substantially free of stereogenic phosphorus atoms having the Sp configuration.
  • the phrase "substantially free of stereogenic phosphorus atoms having the R P configuration" means that moieties containing stereogenic phosphorus atoms having the R P configuration cannot be detected by conventional methods known in the art (chiral HPLC, 1H NMR analysis using chiral shift reagents, etc.).
  • R a is:
  • Preferred carriers have the general formula (R-3) provided below.
  • stracture preferred backbone attachment points can be chosen from R 1 or R 2 ; R 3 or R 4 ; or R 9 and R 10 if Y is CR 9 R 10 (two positions are chosen to give two backbone attachment points, e.g., R 1 and R 4 , or R 4 and R 9 .
  • Preferred tethering attachment points include R 7 ; R 5 or R 6 when X is CH 2 .
  • the carriers are described below as an entity, which can be inco ⁇ orated into a strand.
  • OFG 2 is preferably attached directly to one ofthe carbons in the six-membered ring (-OFG 2 in E).
  • -(CH ⁇ n OFG 1 and OFG 2 may be disposed in a geminal manner on the ring, i.e., both groups may be attached to the same carbon, e.g., at C-2, C-3, or C-4.
  • a targeting group can be a thyrotropin, melanotropin, lectin, glycoprotein, surfactant protein A, Mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetyl- galactosamine, N-acetyl-gulucosamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, multivalent galactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, biotin, or an RGD peptide or RGD peptide mimetic.
  • Ligands can be proteins, e.g., glycoproteins, or peptides, e.g., molecules having a specific affinity for a co-ligand, or antibodies e.g., an antibody, that binds to a specified cell type such as a cancer cell, endothelial cell, or bone cell.
  • Ligands may also include hormones and hormone receptors. They can also include non-peptidic species, such as lipids, lectins, carbohydrates, vitamins, cofactors, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl- gulucosamine multivalent mannose, or multivalent fucose.
  • the ligand can be, for example, a lipopolysaccharide, an activator of p38 MAP kinase, or an activator of NF- ⁇ B.
  • An RGD peptide moiety can be used to target a tumor cell, such as an endothelial tumor cell or a breast cancer tumor cell (Zitzmann et al, Cancer Res., 62:5139-43, 2002).
  • An RGD peptide can facilitate targeting of an iRNA agent to tumors of a variety of other tissues, including the lung, kidney, spleen, or liver (Aoki et al, Cancer Gene Therapy 8:783-787, 2001).
  • the RGD peptide will facilitate targeting of an iRNA agent to the kidney.
  • the RGD peptide can be linear or cyclic, and can be modified, e.g., glycosylated or methylated to facilitate targeting to specific tissues.
  • a glycosylated RGD peptide can deliver an iRNA agent to a tumor cell expressing o B 3 (Haubner et al, Jour. Nucl. Med., 42:326-336, 2001).
  • a targeting peptide tethered to an RRMS can be an amphipathic a- helical peptide.
  • exemplary amphipathic ⁇ -helical peptides include, but are not limited to, cecropins, lycotoxins, paradaxins, buforin, CPF, bombinin-like peptide (BLP), cathelicidins, ceratotoxins, S. clava peptides, hagfish intestinal antimicrobial peptides (HFIAPs), magainines, brevinins-2, dermaseptins, melittins, pleurocidin, H 2 A peptides, Xenopus peptides, esculentinis-
  • helix stabilization residues g., leu, ala, or lys
  • a minimum number helix destabilization residues e.g., proline, or cyclic monomeric units.
  • the capping residue will be considered (for example Gly is
  • the first (or second) monomer forms a canonical Watson-Crick pairing with the base in the complemetary position on the target, or forms a non canonical Watson-Crick pairing having a higher free energy of dissociation and a higher Tm than seen in the paring in the iRNA agent.
  • the classical Watson-Crick parings are as follows: A-T, G-C, and A-U.
  • Non-canonical Watson-Crick pairings are known in the art and can include, U-U, G-G, G-Atrans, G-Acj S , and GU.
  • first and second iRNA agent sequences can also be joined, e.g., by additional bases to form a hai ⁇ in, or by other non-base linkers.
  • the target sequence for the second strand has a monomer which will form a canonical Watson-Crick pairing with the monomer selected for the selected position in the second strand.
  • the monomer at the selected site in the first sequence includes U (or a modified base which pairs with A), and the monomer in at the selected position in the second sequence is chosen from a monomer which will not pair or which will form a non-canonical pairing, e.g., U or G.
  • the iRNA agent can be selected to target a broad spectrum of genes, including any ofthe genes described herein.
  • the iRNA agent has an architecture (architecture refers to one or more of overall length, length of a duplex region, the presence, number, location, or length of overhangs, sing strand versus double strand form) described herein.
  • the duplex region ofthe iRNA agent will have, mismatches, in addition to the selected or constrained site or sites. Preferably it will have no more than 1, 2, 3, 4, or 5 bases, which do not form canonical Watson-Crick pairs or which do not hybridize. Overhangs are discussed in detail elsewhere herein but are preferably about 2 nucleotides in length. The overhangs can be complementary to the gene sequences being targeted or can be other sequence. TT is a preferred overhang sequence.
  • the first and second iRNA agent sequences can also be joined, e.g., by additional bases to form a hai ⁇ in, or by other non-base linkers.
  • the monomer at the selected site in the anti-sense stand includes an A (or a modified base which pairs with T), the corresponding monomer in the target is a T, and the sense strand is chosen from a base which will not pair or which will form a noncanonical pair, e.g., G;
  • the monomer at the selected site in the anti-sense stand includes a U (or a modified base which pairs with A), the corresponding monomer in the target is an A, and the sense strand is chosen from a monomer wliich will not pair or which will form a non-canonical pairing, e.g., U or G;
  • the monomer at the selected site in the anti-sense stand includes a C (or a modified base which pairs with G), the corresponding monomer in the target is a G, and the sense strand is chosen a monomer which will not pair or which will form a non-canonical pairing, e.g., G, A C J S , A t r
  • both strands can be modified to optimize the same property, e.g., to increase resistance to nucleolytic degradation, but different modifications are chosen for the sense and the antisense strands, e.g., because the modifications affect other properties as well. E.g., since some changes can affect RISC activity these modifications are chosen for the sense strand.

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Abstract

La présente invention a trait à des monomères protégés pour la synthèse d'agents d'ARNi.
EP04759940A 2003-04-17 2004-04-16 Monomeres proteges Withdrawn EP1625138A4 (fr)

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US46377203P 2003-04-17 2003-04-17
US46566503P 2003-04-25 2003-04-25
US46580203P 2003-04-25 2003-04-25
US46961203P 2003-05-09 2003-05-09
US49398603P 2003-08-08 2003-08-08
US49459703P 2003-08-11 2003-08-11
US50634103P 2003-09-26 2003-09-26
US51024603P 2003-10-09 2003-10-09
US51031803P 2003-10-10 2003-10-10
US51845303P 2003-11-07 2003-11-07
PCT/US2004/007070 WO2004080406A2 (fr) 2003-03-07 2004-03-08 Compositions therapeutiques
PCT/US2004/010586 WO2004090108A2 (fr) 2003-04-03 2004-04-05 Conjugues d'arni
PCT/US2004/011255 WO2004091515A2 (fr) 2003-04-09 2004-04-09 Conjugues arni
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