Substituted 2′-thio-bicyclic nucleosides and oligomeric compounds prepared therefrom
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A01N-043/04
A61K-031/70
C12N-015/113
C07H-019/10
C07H-019/207
C07H-019/06
C07H-019/16
C07H-019/20
출원번호
US-0049450
(2013-10-09)
등록번호
US-9029335
(2015-05-12)
발명자
/ 주소
Prakash, Thazha P.
Swayze, Eric E.
출원인 / 주소
Isis Pharmaceuticals, Inc.
대리인 / 주소
Casimir Jones, S.C.
인용정보
피인용 횟수 :
0인용 특허 :
137
초록▼
Provided herein are novel bicyclic nucleosides, oligomeric compounds that include such bicyclic nucleosides and methods of using the oligomeric compounds. More particularly, the novel bicyclic nucleosides comprise a furanose ring system having a bridge comprising a 4′-methylene group attached to a 2
Provided herein are novel bicyclic nucleosides, oligomeric compounds that include such bicyclic nucleosides and methods of using the oligomeric compounds. More particularly, the novel bicyclic nucleosides comprise a furanose ring system having a bridge comprising a 4′-methylene group attached to a 2′-sulfoxide or sulfone group and optionally including one or more substituent groups attached to the 4′-methylene and or the 5′-position. In certain embodiments, the oligomeric compounds provided herein are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.
대표청구항▼
1. A bicyclic nucleoside having Formula Ia: wherein: Bx is a heterocyclic base moiety;one of T1 and T2 is H or a hydroxyl protecting group and the other of T1 and T2 is H, a hydroxyl protecting group or a reactive phosphorus group;Q1 and Q2 are each independently, H, C1-C6 alkyl, substituted C1-C6
1. A bicyclic nucleoside having Formula Ia: wherein: Bx is a heterocyclic base moiety;one of T1 and T2 is H or a hydroxyl protecting group and the other of T1 and T2 is H, a hydroxyl protecting group or a reactive phosphorus group;Q1 and Q2 are each independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;G1 and G2 are each independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;each substituted group is, independently, mono or poly substituted with substituent groups independently selected from halogen, OJ1, SJ1, NJ1J2, N3, CN, C(═O)OJ1, C(═O)NJ1J2, C(═O)J1, O—C(═O)NJ1J2, N(H)C(═O)NJ1J2 and N(H)C(═S)NJ1J2;each J1 and J2 is, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 aminoalkyl or a protecting group; andn is 1 or 2. 2. The bicyclic nucleoside of claim 1 wherein Bx is an optionally protected pyrimidine, substituted pyrimidine, purine or substituted purine. 3. The bicyclic nucleoside of claim 2 wherein Bx is uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methylcytosine, 4-N-benzoyl-5-methylcytosine, adenine, 6-N-benzoyladenine, guanine or 2-N-isobutyrylguanine. 4. The bicyclic nucleoside of claim 1 wherein at least one of Q1, Q2, G1 and G2 is CH3 and the remaining of Q1, Q2, G1 and G2 are each H. 5. The bicyclic nucleoside of claim 1 wherein Q1, Q2, G1 and G2 are each H. 6. The bicyclic nucleoside of claim 1 wherein T1 is 4,4′-dimethoxytrityl and T2 is diisopropylcyanoethoxy phosphoramidite. 7. The bicyclic nucleoside of claim 1 wherein n is 1 and the configuration at the sulfur atom is R. 8. The bicyclic nucleoside of claim 1 wherein n is 1 and the configuration at the sulfur atom is S. 9. The bicyclic nucleoside of claim 1 wherein n is 2. 10. The bicyclic nucleoside of claim 1 wherein Q1, Q2, G1 and G2 are each H, T1 is 4,4′-dimethoxytrityl and T2 is diisopropylcyanoethoxy phosphoramidite. 11. An oligomeric compound comprising at least one bicyclic nucleoside of Formula IIa: wherein independently for each bicyclic nucleoside of Formula IIa: Bx is a heterocyclic base moiety;one of T3 and T4 is an internucleoside linking group attaching the bicyclic nucleoside to the remainder of one of the 5′ or 3′ end of the oligomeric compound and the other of T3 and T4 is hydroxyl, a protected hydroxyl, a 5′ or 3′ terminal group or an internucleoside linking group attaching the bicyclic nucleoside to the remainder of the other of the 5′ or 3′ end of the oligomeric compound;Q1 and Q2 are each independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;G1 and G2 are each independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;each substituted group is, independently, mono or poly substituted with substituent groups independently selected from halogen, OJ1, SJ1, NJ1J2, N3, CN, C(═O)OJ1, C(═O)NJ1J2, C(═O)J1, O—C(═O)NJ1J2, N(H)C(═O)NJ1J2 and N(H)C(═S)NJ1J2;each J1 and J2 is, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 aminoalkyl or a protecting group;n is 1 or 2; andwherein said oligomeric compound comprises from 8 to 40 monomeric subunits linked by internucleoside linking groups and wherein at least some of the heterocyclic base moieties are capable of hybridizing to a nucleic acid molecule. 12. The oligomeric compound of claim 11 wherein each Bx is, independently, uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methylcytosine, 4-N-benzoyl-5-methylcytosine, adenine, 6-N-benzoyladenine, guanine or 2-N-isobutyrylguanine. 13. The oligomeric compound of claim 11 comprising at least one 5′ or 3′-conjugate group. 14. The oligomeric compound of claim 11 wherein at least one of Q1, Q2, G1 and G2 is CH3 and the remaining of Q1, Q2, G1 and G2 are each H for each bicyclic nucleoside of Formula IIa. 15. The oligomeric compound of claim 11 wherein Q1, Q2, G1 and G2 are each H for each is bicyclic nucleoside of Formula IIa. 16. The oligomeric compound of claim 11 wherein n is 1 and the configuration at the sulfur atom is R for each bicyclic nucleoside of Formula IIa. 17. The oligomeric compound of claim 11 wherein n is 1 and the configuration at the sulfur atom is S for each bicyclic nucleoside of Formula IIa. 18. The oligomeric compound of claim 11 wherein n is 2 for each bicyclic nucleoside of Formula IIa. 19. The oligomeric compound of claim 11 comprising from about 8 to about 20 linked monomer subunits. 20. The oligomeric compound of claim 11 comprising a gapped oligomeric compound comprising a first region consisting of from 2 to 5 modified nucleosides, a second region consisting of from 2 to 5 modified nucleosides and a gap region located between the first and second regions, wherein at least one of the modified nucleosides of the first and second region is a bicyclic nucleoside having Formula IIa and wherein each monomer subunit in the gap region is independently, a nucleoside or a modified nucleoside that is different from each bicyclic nucleoside of Formula IIa and each of the modified nucleosides in the first and second regions. 21. The oligomeric compound of claim 20 wherein the gap region comprises from about 8 to about 14 contiguous β-D-2′-deoxyribonucleosides. 22. The oligomeric compound of claim 20 wherein essentially each modified nucleoside of the first and second region is a bicyclic nucleoside having Formula IIa. 23. The oligomeric compound of claim 20 wherein each of the modified nucleosides that is other than a bicyclic nucleoside having Formula II is, independently, a substituted nucleoside having one or more sugar substituent groups, an optionally substituted 4′-S nucleoside or an optionally substituted bicyclic nucleoside. 24. The oligomeric compound of claim 11 wherein each internucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group. 25. The oligomeric compound of claim 11 wherein essentially each internucleoside linking group is a phosphorothioate internucleoside linking group. 26. A method of inhibiting gene expression comprising contacting a cell with an oligomeric compound of claim 11 wherein said oligomeric compound is complementary to a target RNA.
연구과제 타임라인
LOADING...
LOADING...
LOADING...
LOADING...
LOADING...
이 특허에 인용된 특허 (137)
Tkachuk Zenovy (Kiev SUX) Kvasyuk Eugeny (Kiev SUX) Matsuka Gennady (Kiev SUX) Mikhailopulo Igor (Kiev SUX), (2′-5′) oligoadenylate analogues useful as inhibitors of host-v5.-graft response.
Huynh Dinh Tam (Croissy/Seine FRX) Gouyette Catherine (Vanves FRX) Igolen Jean (Le Mesnil St. Denis FRX), 2,N6-disubstituted and 2,N6-trisubstituted adenosine-3′-phosphoramidites.
Suhadolnik Robert J. (Roslyn PA) Pfleiderer Wolfgang (Constance DEX), 2′,5′-phosphorothioate oligoadenylates and their covalent conjugates with polylysine.
Cook Philip D. (Carlsbad CA) Delecki Daniel J. (Radnor PA) Guinosso Charles (Vista CA), Acyclic nucleoside analogs and oligonucleotide sequences containing them.
Summerton James E. (Corvallis OR) Weller Dwight D. (Corvallis OR) Stirchak Eugene P. (Corvallis OR), Alpha-morpholino ribonucleoside derivatives and polymers thereof.
Sanghvi Yogesh S. (Carlsbad CA) Cook Phillip D. (Carlsbad CA), Backbone modified oligonucleotide analogs and preparation thereof through reductive coupling.
Cook Phillip D. (Carlsbad CA) Sanghvi Yogesh S. (San Marcos CA) Vasseur Jean J. (San Marcos CA) Debart Francoise (Montpellier FRX), Backbone modified oligonucleotide analogues.
Sanghvi Yogesh S. (San Marcos CA) Cook Phillip D. (Vista CA), Backbone-modified oligonucleotide analogs and preparation thereof through radical coupling.
Spielvogel Bernard F. (Raleigh NC) Sood Anup (Durham NC) Hall Iris H. (Chapel Hill NC) Ramsay Shaw Barbara (Durham NC), Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same.
Altmann Karl-Heinz (Basel CHX) Imwinkelried Rene (Brig-Glis CHX) Eschenmoser Albert (Kusnacht CHX), Carbocyclic nucleosides containing bicyclic rings, oligonucleotides therefrom, process for their preparation, their use.
Altmann Karl-Heinz (Basel CHX) Imwinkelried Rene (Brig-Glis CHX) Eschenmoser Albert (Kusnacht CHX), Carbocyclic nucleosides containing bicyclic rings, oligonucleotides therefrom, process for their preparation, their use.
Ohtsuka Eiko (Sappro JPX) Inoue Hideo (Sappro JPX) Morisawa Hirokazu (Kawasaki JPX) Shibahara Susumu (Kawasaki JPX) Mukai Sachiko (Kawasaki JPX) Nishihara Tohru (Kurashiki JPX), Compounds for the cleavage at a specific position of RNA, oligomers employed for the formation of said compounds, and st.
Baxter Anthony D. (Northwich GB2) Baylis Eric K. (Stockport GB2) Collingwood Stephen P. (Westhoughton GB2) Taylor Roger J. (Stretford GB2) De Mesmaeker Alain (Kanerkinden CHX) Schmit Chantal (Basel C, Dinucleoside phosphinates and their pharmaceutical compositions.
Froehler Brian (Belmont CA) Matteucci Mark (Burlingame CA), Enhanced triple-helix and double-helix formation with oligomers containing modified purines.
Froehler Brian (Belmont CA) Wagner Rick (Belmont CA) Matteucci Mark (Burlingame CA) Jones Robert J. (Millbrae CA) Gutierrez Arnold J. (Sandy Lane CA) Pudlo Jeff (Burlingame CA), Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines.
Rogers Thomas E. (Manchester MO) Gray Steven H. (Ellisville MO) Devadas Balekudru (Chesterfield MO) Adams Steven P. (St. Charles MO), Improved probes using nucleosides containing 3-dezauracil analogs.
Cohen Jack S. (Bethesda MD) Neckers Len (Bethesda MD) Stein Cy (Gaithersburg MD) Loke She L. (Wheaton MD) Shinozuka Kazuo (Kazo JPX), Inhibitors for replication of retroviruses and for the expression of oncogene products.
Cohen Jack S. (Bethesda MD) Neckers Len (Bethesda MD) Stein Cy (Gaithersburg MD) Loke She L. (Wheaton MD) Shinozuka Kazuo (Kazo JPX), Inhibitors for replication of retroviruses and for the expression of oncogene products.
Cohen Jack S. (Bethesda MD) Neckers Len (Bethesda MD) Stein Cy (Gaithersburg MD) Loke Shee L. (Wheaton MD) Shinozuka Kazuo (Kazo JPX), Inhibitors for replication of retroviruses and for the expression of oncogene products.
Benner Steven A. (Hadlaubstrasse 151 CH-8006 Zurich CHX), Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Walder Joseph A. (Iowa City IA) Walder Roxanne Y. (Iowa City IA) Eder Paul S. (Iowa City IA) Dagle John M. (Iowa City IA), Methods for blocking the expression of specifically targeted genes.
Froehler Brian ; Wagner Rick ; Matteucci Mark ; Jones Robert J. ; Gutierrez Arnold J. ; Pudlo Jeff, Methods of using oligomers containing modified pyrimidines.
Matteucci Mark (Burlingame CA) Jones Robert J. (Daly City CA) Munger John (San Francisco CA), Modified internucleoside linkages having one nitrogen and two carbon atoms.
Ts\o Paul O. P. (2117 Folkstone Rd. Lutherville MD 21093) Miller Paul S. (225 Hopkins Rd. Baltimore MD 21212), Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof.
Cook Philip D. (Carlsbad CA) Sanghvi Yogesh S. (San Marcos CA), Nuclease resistant, pyrimidine modified oligonucleotides that detect and modulate gene expression.
Swaminathan Sundaramoorthi ; Matteucci Mark ; Jones Robert J. ; Pudlo Jeff ; Munger John, Nuclease stable and binding competent oligomers and methods for their use.
Walder Joseph A. (Iowa City IA) Walder Roxanne Y. (Iowa City IA), Nucleic acid hybridization and amplification method for detection of specific sequences in which a complementary labeled.
Buhr Chris (Daly City CA) Matteucci Mark (Burlingame CA) Bischofberger Norbert W. (San Carlos CA) Froehler Brian (Belmont CA), Nucleoside 5′-methylene phosphonates.
Froehler Brian C. (Belmont CA) Buhr Chris A. (Daly City CA), Nucleoside hydrogen phosphonodithioate diesters and activated phosphonodithioate analogues.
Baxter Anthony D. (Northwich GB2) Baylis Eric K. (Stockport GB2) Collingwood Stephen P. (Westhoughton GB2) Taylor Roger J. (Stretford GB2) Mesmaeker Alain (Kanerkinden CHX) Schmit Chantal (Basel CHX), Nucleoside phosphinate compounds and compositions.
Meyer ; Jr. Rich B. (Woodinville WA) Adams A. David (Snohomish WA) Petrie Charles R. (Woodinville WA), Oligo (aa
상세보기
Letsinger Robert L. (Wilmette IL) Gryaznov Sergei M. (San Mateo CA), Oligodeoxyribonucleotides including 3′-aminonucleoside-phosphoramidate linkages and terminal 3′-amino groups.
Bischofberger Norbert (San Carlos CA) Kent Ken (Mountain View CA) Wagner Rick (Burlingame CA) Buhr Chris (Daly City CA) Lin Kuei-Ying (Fremont CA), Oligonucleotide analogs capable of passive cell membrane permeation.
Weis Alexander Ludvik (Berwyn PA) Hausheer Frederick Herman (San Antonio TX) Chaturvedula Prasad Venkata Chala (Exton PA) Delecki Daniel Joseph (Radnor PA) Cavanaugh ; Jr. Paul Francis (West Chester , Oligonucleotide analogues containing phosphate diester linkage substitutes, compositions thereof, and precursor dinucleo.
Smith Lloyd M. (South Pasadena CA) Fung Steven (Palo Alto CA) Kaiser ; Jr. Robert J. (Glendale CA), Oligonucleotides possessing a primary amino group in the terminal nucleotide.
Lebleu Bernard (Montpellier FRX) Bayard Bernard (Castelnau Le Lez FRX), Oligonucleotides with modified phosphate and modified carbohydrate moieties at the respective chain termini.
Imbach Jean-Louis (Montpellier FRX) Gosselin Gilles J. M. (Montpellier FRX), Oligonucleotides, a process for preparing the same and their application as mediators of the action of interferon.
Spielvogel Bernard F. (Raleigh NC) Sood Anup (Durham NC) Hall Iris H. (Chapel Hill NC) Shaw Barbara R. (Durham NC), Oligoribonucleoside and oligodeoxyribonucleoside boranophosphates.
Misiura Konrad (Lodz PLX) Gait Michael (Cambridge GB3), Phosphoramidite derivatives, their preparation and the use thereof in the incorporation of reporter groups on synthetic.
Allerson, Charles; Bhat, Balkrishen; Swayze, Eric E.; Prakash, Thazha P., Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation.
Maddry Joseph A. (Birmingham AL) Reynolds Robert C. (Birmingham AL) Secrist John A. (Birmingham AL) Montgomery John A. (Birmingham AL) Crooks Peter A. (Lexington KY), Polynucleotide analogs containing sulfonate and sulfonamide internucleoside linkages.
Caruthers Marvin H. (Boulder CO) Marshall William S. (Boulder CO) Brill Wolfgang (Freiburg DEX) Nielsen John (Horsholm DKX), Polynucleotide phosphorodithioate.
Urdea Michael S. (Alamo CA) Horn Thomas (Berkeley CA), Polynucleotide reagents containing modified deoxyribose moieties, and associated methods of synthesis and use.
Spielvogel Bernard F. (Raleigh NC) Sood Anup (Durham NC) Hall Iris H. (Chapel Hill NC) Ramsay Shaw Barbara (Durham NC), Process for preparing oligoribonucleoside and oligodeoxyribonucleoside boranophosphates.
Hawkins Mary E. (Potomac MD) Pfleiderer Wolfgang (Konstanz MD DEX) Davis Michael D. (Rockville MD) Balis Frank (Bethesda MD), Pteridine nucleotide analogs as fluorescent DNA probes.
Van Ness Jeffrey (Bothell WA) Petrie Charles R. (Woodinville WA) Tabone John C. (Bothell WA) Vermeulen Nicolaas M. J. (Woodinville WA), Solid supports for nucleic acid hybridization assays.
Cook Phillip Dan (Carlsbad CA) Manoharan Muthiah (Carlsbad CA) Ramasamy Kanda S. (Laguna Hills CA), Substituted purines and oligonucleotide cross-linking.
Summerton James E. (Corvallis OR) Weller Dwight D. (Corvallis OR), Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages.
※ AI-Helper는 부적절한 답변을 할 수 있습니다.