Backbone modified oligonucleotide analogs and preparation thereof through reductive coupling
First Claim
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1. A method for forming between adjacent sugar moieties a covalent linkage having structure CH═
- N--RA --CH2, CH2 --RA --N═
CH, or RA --N═
CH--CH2 where RA is O or NR1, comprising the steps of;
(a) providing synthons having structure;
##STR4## (b) contacting said synthons for a time and under reaction conditions effective to form said covalent linkage;
wherein;
Z1 and Y2 are selected such that(i) Z1 is C(O)H and Y2 is CH2 RA NH2 ;
or(ii) Z1 is CH2 RA NH2 and Y2 is C(O)H;
or(iii) Z1 is RA NH2 and Y2 is H(O)CCH2 ;
R1 is H or alkyl having 1 to about 10 carbon atoms;
BX1 and BX2 are, independently, nucleosidic bases;
Q1 and Q2 are O; and
X1 and X2 are, independently, H;
OH;
F;
or O-alkyl having 1 to about 10 carbon atoms.
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Abstract
Methods for preparing oligonucleotide analogs which have improved nuclease resistance and improved cellular uptake are provided. In preferred embodiments, the methods involve reductive coupling of 3'"'"'- and 4'"'"'-substituted or 4'"'"'- and 3'"'"'-substituted nucleosidic synthons.
600 Citations
20 Claims
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1. A method for forming between adjacent sugar moieties a covalent linkage having structure CH═
- N--RA --CH2, CH2 --RA --N═
CH, or RA --N═
CH--CH2 where RA is O or NR1, comprising the steps of;(a) providing synthons having structure;
##STR4## (b) contacting said synthons for a time and under reaction conditions effective to form said covalent linkage;wherein; Z1 and Y2 are selected such that (i) Z1 is C(O)H and Y2 is CH2 RA NH2 ;
or(ii) Z1 is CH2 RA NH2 and Y2 is C(O)H;
or(iii) Z1 is RA NH2 and Y2 is H(O)CCH2 ; R1 is H or alkyl having 1 to about 10 carbon atoms; BX1 and BX2 are, independently, nucleosidic bases; Q1 and Q2 are O; and X1 and X2 are, independently, H;
OH;
F;
or O-alkyl having 1 to about 10 carbon atoms. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10)
- N--RA --CH2, CH2 --RA --N═
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11. A method for forming between adjacent sugar moieties a covalent linkage having structure CH2 --NR1 --RA --CH2, CH2 --RA --NR1 --CH2, RA --NR1 --CH2 --CH2 where RA is O or NR2, comprising the steps of:
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(a) providing synthons having structures;
##STR5## (b) contacting said synthons for a time and under reaction conditions effective to form an intermediate linkage; and(c) reducing said intermediate linkage to form said covalent linkage; wherein; Z1 and Y2 are selected such that (i) Z1 is C(O)H and Y2 is CH2 RA NH2 ;
or(ii) Z1 is CH2 RA NH2 and Y2 is C(O)H;
or(iii) Z1 is RA NH2 and Y2 is H(O)CCH2 ; R1 and R2 are, independently, H or alkyl having 1 to about 10 carbon atoms; BX1 and BX2 are, independently, nucleosidic bases; Q1 and Q2 are O; and X1 and X2 are, independently, H;
OH;
F;
or O-alkyl having 1 to about 10 carbon atoms. - View Dependent Claims (12, 13, 14, 15, 16, 17, 18, 19, 20)
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Specification
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Current AssigneeISIS Pharmaceuticals Incorporated
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Original AssigneeISIS Pharmaceuticals Incorporated
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InventorsCook, Phillip D., Sanghvi, Yogesh S.
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Primary Examiner(s)Rollins, John W.
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Assistant Examiner(s)Wilson, James O.
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Application NumberUS08/040,903Time in Patent Office671 DaysField of Search536/23.1, 536/25.3, 536/25.33, 536/25.34, 536/25.6US Class Current536/25.3CPC Class CodesA61K 31/70 Carbohydrates; Sugars; Deri...A61K 47/549 Sugars, nucleosides, nucleo...C07D 405/04 directly linked by a ring-m...C07D 405/14 containing three or more he...C07F 7/1804 Compounds having Si-O-C lin...C07H 19/04 Heterocyclic radicals conta...C07H 19/06 Pyrimidine radicalsC07H 19/10 with the saccharide radical...C07H 19/16 Purine radicalsC07H 21/00 Compounds containing two or...
