Bifunctional nucleosides, oligomers thereof, and methods of making and using the same

• US 5,892,024 A
• Filed: 03/13/1997
• Issued: 04/06/1999
• Est. Priority Date: 03/31/1993
• Status: Expired due to Fees

• Current Assignee: Sanofi
• Original Assignee: Sanofi
• Inventors: Chaturvedula, Prasad Venkata Chala, Saha, Ashis Kumar
• Primary Examiner(s): Elliott, George C.
• Assistant Examiner(s): LARSON, THOMAS GEORGE
• Application Number:
  US08/816,708
• Time in Patent Office: 754 Days
• Field of Search: 435/6, 435/375, 514/44, 536/21.3, 536/24.3, 536/24.5, 536/25.3, 536/27.21, 536/27.6, 536/27.81, 536/28.4, 536/28.5, 536/28.53, 536/28.54
• US Class Current: 536/27.6
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

Disclosed are novel bifunctional nucleoside analogs and oligonucleosides of 3-4 bases (trimers and tetramers) and longer containing at least two consecutive internucleoside linkages of two carbon-one nitrogen atom or two carbon-one oxygen atom (3'"'"'-NCC-5'"'"', 3'"'"'-CNC-5'"'"', 3'"'"'-OCC-5'"'"') internucleoside linkages. The bifunctional nucleosides are useful for preparing the trimers and tetramers, which, in turn, are useful, together with the nucleosides, in preparing oligonucleosides as well as chimeric oligonucleotide analogs, preferably antisense oligonucleosides and oligonucleotide analogs, of 6 to about 60 bases having at least two consecutive internucleoside linkages of two carbon atoms and one nitrogen atom or 2 carbon atoms and one oxygen atom in the oligonucleoside backbone.

Claims

1. A compound having the structural formula ##STR7## or a salt thereof, wherein:

Q is selected from the group consisting of H, NHZ, Z, SZ,CHO, COOR, halogen, phosphonium salt and phosphonate;

L is selected from the group consisting of SZ, CHO, COOR, phosphonium salt and phosphonate;

Q-(HCR)_n - can also be replaced independently by;

##STR8## L-(HCR)_m - can also be replaced independently by;

##STR9## each R is independently selected from the group consisting of H, lower alkyl, lower alkenyl, and acyl;

each Z is independently selected from the group consisting of H, lower alkyl, lower alkenyl, aryl, acyl, and protecting groups for O-, S-, and N-;

each E is independently selected from the group consisting of H, and OZ;

m is 0 or an integer from 1 to 4;

n is an integer from 1 to 5; and

each B is independently selected from the group consisting of adenine, cytosine, guanine, thymine and uracil or a modification thereof that does not substantially interfere with the affinity of an oligonucleoside or chimeric oligonucleotide analog for its antisense counterpart wherein the bases of the antisense counterparts are selected from the group consisting of adenine, cytosine, guanine, thymine and uracil.

2. The compound of claim 1 ##STR10## wherein:

Q is selected from the group consisting of H, NHZ, SZ, COOR, halogen, phosphonium salt and phosphonate;

L is selected from the group consisting of SZ, CHO, COOR, phosphonium salt and phosphonate;

each Z is independently selected from the group consisting of H, lower alkyl, lower alkenyl, aryl, acyl, and protecting groups for S-, and N-; and

E is H.

3. The compound of claim 1, wherein Q is COOR, is 2, and m is 0.