Nucleic acid prodrugs and methods of use thereof
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/70
C07F-009/655
C07H-021/00
출원번호
US-0381323
(2010-07-06)
등록번호
US-9744183
(2017-08-29)
국제출원번호
PCT/US2010/041068
(2010-07-06)
§371/§102 date
20120823
(20120823)
국제공개번호
WO2011/005761
(2011-01-13)
발명자
/ 주소
Verdine, Gregory L.
., Meena
Iwamoto, Naoki
출원인 / 주소
WAVE LIFE SCIENCES LTD.
대리인 / 주소
Choate, Hall & Stewart LLP
인용정보
피인용 횟수 :
2인용 특허 :
289
초록
Described herein are nucleic acid prodrugs and nucleic acid prodrugs comprising chiral phosphorous moieties. Also described herein are methods of making and using nucleic acid prodrugs and nucleic acid prodrugs comprising chiral phosphorous moieties.
대표청구항▼
1. An oligonucleotide composition comprising a plurality of oligonucleotides of the following structure: wherein: each X-phosphonate independently has an Rp or Sp configuration;R1 is —OH, —SH, —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, he
1. An oligonucleotide composition comprising a plurality of oligonucleotides of the following structure: wherein: each X-phosphonate independently has an Rp or Sp configuration;R1 is —OH, —SH, —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —HP(O)(Re), —ORa or —SRc;Y1 is O, NRd, S, or Se;Ra is a blocking group;Rc is a blocking group;each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, —P(O)(Re)2, or —HP(O)(Re);each instance of Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—, or a cation which is Na+1, Li+1, or K+1;Y2 is O, S, or NRd wherein Rd is hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, or carbamate;each instance of R2 is independently hydrogen, —OH, —SH, —NRdRd, —N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, wherein Rb is a blocking group;each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase, wherein each modified nucleobase is independently adenine, cytosine, guanine, thymine or uracil, modified by one or more modifications by which:(1) a nucleobase is modified by one or more groups independently selected from acyl, halogen, amino, azide, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, carboxyl, hydroxyl, biotin, avidin, streptavidin, substituted silyl, and combinations thereof;(2) one or more atoms of a nucleobase are independently replaced with a different atom selected from carbon, nitrogen or sulfur;(3) one or more double bonds in a nucleobase are independently hydrogenated; or(4) one or more aryl or heteroaryl rings are independently inserted into a nucleobase; or is selected from:uracil, thymine, adenine, cytosine, and guanine having their respective amino groups protected by acyl groups, 2-fluorouracil, 2-fluorocytosine, 5-bromouracil, 5-iodouracil, 2,6-diaminopurine, azacytosine, pseudoisocytosine, pseudouracil, 8-substituted purines, xanthine, hypoxanthine, wherein:R8 is a linear or branched alkyl, aryl, aralkyl, or aryloxylalkyl group having 1 to 15 carbon atoms, andeach of R9 and R10 represents a linear or branched alkyl group having 1 to 4 carbon atoms; corrin or porphyrin, each optionally modified by one or more groups independently selected from acyl, halogen, amino, azide, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, carboxyl, hydroxyl, biotin, avidin, streptavidin, substituted silyl, and combinations thereof;phenanthrene, pyrene, stillbene, isoxanthine, isozanthopterin, terphenyl, terthiophene, benzoterthiophene, coumarin, lumazine, tethered stillbene, benzo-uracil, or naphtho-uracil, each optionally modified by one or more groups independently selected from acyl, halogen, amino, azide, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, carboxyl, hydroxyl, biotin, avidin, streptavidin, substituted silyl, and combinations thereof;3-nitropyrrole, 5-bromouracil, 5-iodouracil, or 2,6-diaminopurine, or a nucleobase of 4-acetylcytidine; 5-(carboxyhydroxylmethyl)uridine; 2′-O-methylcytidine; 5-carboxymethylaminomethyl-2-thiouridine; 5-carboxymethylaminomethyluridine; dihydrouridine; 2′-O-methylpseudouridine; beta,D-galactosylqueosine; 2′-O-methylguanosine; N6-isopentenyladenosine; 1-methyladenosine; 1-methylpseudouridine; 1-methylguanosine; 1-methylinosine; 2,2-dimethylguanosine; 2-methyladenosine; 2-methylguanosine; N7-methylguanosine; 3-methyl-cytidine; 5-methylcytidine; N6-methyladenosine; 7-methylguanosine; 5-methylaminoethyluridine; 5-methoxyaminomethyl-2-thiouridine; beta,D-mannosylqueosine; 5-methoxycarbonylmethyluridine; 5-methoxyuridine; 2-methylthio-N6-isopentenyladenosine; N-((9-beta,D-ribofuranosyl-2-methylthiopurine-6-yl)carbamoyl)threonine; N-((9-beta,D-ribofuranosylpurine-6-yl)-N-methylcarbamoyl)threonine; uridine-5-oxyacetic acid methylester; uridine-5-oxyacetic acid (v); pseudouridine; queosine; 2-thiocytidine; 5-methyl-2-thiouridine; 2-thiouridine; 4-thiouridine; 5-methyluridine; 2′-O-methyl-5-methyluridine; or 2′-O-methyluridine; andheteroaryl or heterocyclyl optionally substituted with one or more groups independently selected from acyl, halogen, amino, azide, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, carboxyl, hydroxyl, biotin, avidin, streptavidin, substituted silyl, and combinations thereof;each instance of X is H or —OCH2CH2S—S(O)2R10, —OCH2CH2S—SCH2CH2OH, —OCH2CH2CO2H, wherein at least 25% of X moieties present in the oligonucleotide are not H;wherein R10 is an alkyl group having 1 to 4 carbon atoms; R11 is alkyl, aryl, heteroaryl, heterocyclyl, or cycloalkyl; and R12 is hydrogen or alkyl;R3 is hydrogen, a blocking group, a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid;n is an integer of 10 to about 200; andwherein the composition is stereodefined in that each X-phosphonate moiety is more than 98% diastereomerically pure within the composition. 2. The composition of claim 1 wherein the diastereomeric purity is determined by 31P NMR spectroscopy or reverse-phase HPLC. 3. The composition of claim 1 wherein each X-phosphonate moiety has an RP configuration. 4. The composition of claim 1 wherein each X-phosphonate moiety has an SP configuration. 5. The composition of claim 1, wherein at least 90% of the X moieties of the oligonucleotide are independently selected from —OCH2CH2S—S(O)2R10, —OCH2CH2S—SCH2CH2OH, —OCH2CH2CO2H, wherein R10 is an alkyl group having 1 to 4 carbon atoms; R11 is alkyl, aryl, heteroaryl, heterocyclyl, or cycloalkyl; and R12 is hydrogen or alkyl. 6. The composition of claim 1, wherein each instance of X is independently selected from —OCH2CH2S—S(O)2R10, —OCH2CH2S—SCH2CH2OH, —OCH2CH2CO2H, wherein R10 is an alkyl group having 1 to 4 carbon atoms; R11 is alkyl, aryl, heteroaryl, heterocyclyl, or cycloalkyl; and R12 is hydrogen or alkyl. 7. The composition of claim 1, wherein R10 is methyl. 8. The composition of claim 1, wherein R11 is methyl. 9. The composition of claim 1, wherein R12 is methyl. 10. The composition of claim 1, wherein n is an integer of 15 to about 200. 11. The composition of claim 1, wherein n is an integer of 20 to about 200. 12. The composition of claim 1, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine. 13. The composition of claim 1, wherein Y1 is O. 14. The composition of claim 13, wherein: R1 is —OH, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, or —ORa;each instance of R2 is independently hydrogen, —OH, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, or —ORb, wherein Rb is a blocking group; andR3 is hydrogen or a blocking group. 15. The composition of claim 14, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine. 16. The composition of claim 1, wherein each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or acyl. 17. The composition of claim 16, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine. 18. The composition of claim 1, wherein Y2 is O or S. 19. The composition of claim 18, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine. 20. A pharmaceutical composition comprising a therapeutically effective amount of a composition of claim 1 and a pharmaceutically acceptable excipient. 21. The composition of claim 1, wherein: R1 is —OH or —ORa;each instance of R2 is independently hydrogen, —OH, halogen, or —ORb; andR3 is hydrogen or a blocking group;each instance of Ba is independently adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine. 22. A pharmaceutical composition comprising a therapeutically effective amount of a composition of claim 15 and a pharmaceutically acceptable excipient. 23. A pharmaceutical composition comprising a therapeutically effective amount of a composition of claim 21 and a pharmaceutically acceptable excipient.
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