Phosphate and thiophosphate protecting groups
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-019/04
C07H-001/00
출원번호
US-0268797
(1999-03-16)
발명자
/ 주소
Guzaev Andrei P.
Manoharan Muthiah
출원인 / 주소
Isis Pharmaceuticals, Inc.
대리인 / 주소
Woodcock Washburn Kurtz Mackiewicz & Norris LLP
인용정보
피인용 횟수 :
36인용 특허 :
17
초록▼
Novel phosphorus protecting groups, intermediates thereof, and synthetic processes for making the same are disclosed. Oligomeric compounds are prepared through the protection of one or more internucleosidic phosphorus functionalities, preferably followed by oxidation and cleavage of the protecting g
Novel phosphorus protecting groups, intermediates thereof, and synthetic processes for making the same are disclosed. Oligomeric compounds are prepared through the protection of one or more internucleosidic phosphorus functionalities, preferably followed by oxidation and cleavage of the protecting groups to provide oligonucleotides.
대표청구항▼
[ What is claimed is:] [1.] A method for the preparation of an oligomeric compound comprising a moiety of Formula X: [ STR 48 ] wherein: W is selected independently from O and S;X is selected independently from O and S;Y is selected independently from O and NR.sup.2 ;Z is selected independently from
[ What is claimed is:] [1.] A method for the preparation of an oligomeric compound comprising a moiety of Formula X: [ STR 48 ] wherein: W is selected independently from O and S;X is selected independently from O and S;Y is selected independently from O and NR.sup.2 ;Z is selected independently from a single bond, O, and NR.sup.2 ;R.sup.1, at each occurrence, is selected independently from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, CN, NO.sub.2, Cl, Br, F, I, CF.sub.3, OR.sup.4, NR.sup.5a R.sup.5b, and phenyl;alternatively, two R.sup.1 groups, when on adjacent carbons of the phenyl ring, join to form a napthyl ring that includes said phenyl ring;R.sup.2, at each occurrence, is selected independently from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, and phenyl;R.sup.3, at each occurrence, is selected independently from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, and phenyl;R.sup.4 is selected independently from C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, and phenyl;R.sup.5a and R.sup.5b, at each occurrence, are selected independently from C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, and phenyl;n is selected independently from 0, 1, 2, and 3; andm is selected independently from 0, 1, 2, and 3;the method comprising:(a) providing a compound of Formula II: [ STR 49 ] wherein: R.sup.6, at each occurrence, is selected independently from H, a hydroxyl protecting group, and a linker connected to a solid support;R.sup.7, at each occurrence, is indepedently H, hydroxyl, C.sub.1-20 alkyl, C.sub.3-20 alkenyl, C.sub.2-20 alkynyl, halogen, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, dilulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, or one of formula XII or XIII: [ STR 50 ] wherein E is selected from C.sub.1-10 alkyl, N(R.sup.15)(R.sup.17) and N.dbd.C(R.sup.15)(R.sup.17);R.sup.15 and R.sup.17 are independently selected from H, C.sub.1-10 alkyl, dialkylaminoalkyl, a nitrogen protecting group, a tethered or untethered conjugate group, a linker to a solid support, or alternatively R.sup.15 and R.sup.17, together, are joined in a nitrogen protecting group or a ring structure that can include at least one additional heteroatom selected from N and O;q.sup.1 is from 1 to 10;q.sup.2 is from 1 to 10;q.sup.3 is 0 or 1;R.sup.16 is OR.sup.18, SR.sup.18, or N(R.sup.18).sub.2 ;R.sup.18 is selected independently from H, C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 haloalkyl, C(.dbd.NH)N(H)R.sup.19, C(.dbd.O)N(H)R.sup.19 and OC(.dbd.O)N(H)R.sup.19 ;R.sup.19 is H or C.sub.1 -C.sub.8 alkyl;L.sub.1, L.sub.2 and L.sub.3 comprise a ring system having from about 4 to about 7 carbon atoms or having from about 3 to about 6 carbon atoms and 1 or 2 hetero atoms wherein said hetero atoms are selected from oxygen, nitrogen and sulfur and wherein said ring system is aliphatic, unsaturated aliphatic, aromatic, or saturated or unsaturated heterocyclic;L.sub.4 is alkyl or haloalkyl having 1 to about 10 carbon atoms, alkenyl having 2 to about 10 carbon atoms, alkynyl having 2 to about 10 carbon atoms, aryl having 6 to about 14 carbon atoms, N(R.sup.15)(R.sup.17) OR.sup.15, halo, SR.sup.15 or CN; andq.sup.4 is, 0, 1 or 2;R.sup.8 is selected independently from NR.sup.8a R.sup.8b, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected independently from N, O, and S;R.sup.8a and R.sup.8b, at each occurrence, are selected independently from C.sub.1-10 alkyl and C.sub.3-7 cycloalkyl;X.sup.1 is selected independently from O and S;B, at each occurrence, is independently selected from a protected or unprotected naturally occurring nucleobase, and a protected or unprotected non-naturally occurring nucleobase;q is selected independently from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;p is an integer selected independently from 0 to about 50;Q, at each occurrence, is selected independently from OH, SH, and [ STR 51 ] (b) reacting the compound of Formula II with a compound of Formula III: [ STR 52 ] wherein R.sup.10 is selected independently from a hydroxyl protecting group, and a linker connected to a solid support;with the proviso that R.sup.6 and R.sup.10 are not both simultaneously a linker connected to a solid support; andp' is an integer selected independently from 0 to about 50; to form the oligomeric compound.
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이 특허에 인용된 특허 (17)
Fung Steven (Palo Alto CA) Woo Sam L. (Redwood City CA) Smith Lloyd M. (South Pasadena CA), Amino-derivatized phosphoramidite linking agents.
Agrawal Sudhir (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Process for synthesizing oligonucleotides and their analogs adaptable to large scale syntheses.
Prakash, Thazha P.; Baker, Brenda F.; Eldrup, Anne B.; Manoharan, Muthiah; Bhat, Balkrishen; Griffey, Richard; Swayze, Eric E.; Crooke, Stanley T., 2′-Fluoro substituted oligomeric compounds and compositions for use in gene modulations.
Allerson, Charles; Bhat, Balkrishen; Eldrup, Anne B.; Manoharan, Muthiah; Griffey, Richard H.; Baker, Brenda F.; Swayze, Eric E., Compositions comprising alternating 2′-modified nucleosides for use in gene modulation.
Swayze, Eric E.; Migawa, Michael T.; Wyrzykiewicz, Tadeusz Krzysztof, Gapped oligomeric compounds having linked bicyclic sugar moieties at the termini.
Esau, Christine; Swayze, Eric E.; Bhat, Balkrishen; Kinberger, Garth A., Oligomeric compounds and compositions for the use in modulation of target nucleic acids.
Bhat, Balkrishen; Dande, Prasad; Prakash, Thazha P.; Allerson, Charles; Swayze, Eric E.; Griffey, Richard H., Oligomeric compounds comprising 4′-thionucleosides for use in gene modulation.
Woolf, Tod M.; Kamens, Joanne; Salomon, William; Khvorova, Anastasia, RNA duplexes with single stranded phosphorothioate nucleotide regions for additional functionality.
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