2'modified nucleoside and nucleotide compounds

• US 5,466,786 A
• Filed: 05/10/1994
• Issued: 11/14/1995
• Est. Priority Date: 10/24/1989
• Status: Expired due to Term

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: Gilead Sciences Inc.
• Inventors: Buhr, Chris A., Matteucci, Mark
• Primary Examiner(s): Robinson, Douglas W.
• Assistant Examiner(s): Wilson, James O.
• Application Number:
  US08/240,508
• Time in Patent Office: 553 Days
• Field of Search: 514/45, 514/46, 514/49, 514/50, 514/51, 536/22.1, 536/23.1, 536/25.3, 536/25.32, 536/16.8, 536/25.34, 536/26.7, 536/26.8, 536/27.21, 536/28.1
• US Class Current: 536/26.26
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• 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
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/3517 Marker; Tag
• CPC Class Codes: C12N 2310/3527 Other alkyl chain
• CPC Class Codes: C12N 2310/353 linked to the nucleic acid via an atom other than carbon
• CPC Class Codes: C12N 2310/3535 Nitrogen

Abstract

Oligomers which have substituents on the 2'"'"' position are resistant to oligonucleases and furthermore can be derivatized to deliver reagents or drugs, to carry label, or to provide other properties.

Claims

1. A monomer having the formula:

##STR7## wherein B is a purine or pyrimidine moiety;

W₁ is H, (PO₃)_m^-2 wherein m is an integer of 1-3;

a protecting group, or an intermediate moiety in the formation of an internucleotide link which when reacted with the appropriate --OH results in Z wherein Z is selected from the group consisting of P(O)O^--, P(O)S, P(O)NR₂, P(O)R, P(O)OR'"'"', CO, and CNR₂, wherein R is H or alkyl (1-6 C) and R'"'"' is alkyl (1-6 C);

W₂ is H, PO₃^-2 a protecting group or an intermediate moiety in the formation of an internucleotide link which when reacted with the appropriate --OH results in Z wherein Z is selected from the group consisting of P(O)O^--, P(O)S, P(O)NR₂, P(O)R, P(O)OR'"'"', CO, and CNR₂, wherein R is H or alkyl (1-6 C) and R'"'"' is alkyl (1-6 C);

X is O, S, NR, or CR₂ wherein each R is independently H or alkyl (1-6 C);

Y is a drug moiety selected from the group consisting of netropsin, anthramycin, quinoxaline antibiotics, actinomycin, and pyrrolo (1-4) benzodiazepine.

2. The monomer of claim 1 wherein X is O or S.

3. The monomer of claim 1 wherein X is NR.

4. The monomer of claim 1 wherein X is CR₂.

5. The monomer of claim 1 wherein W₂ is a phosphonate moiety or a salt thereof.

6. The monomer of claim 1 wherein W₁ is a protecting group.

7. The monomer of claim 5 wherein said salt is a triethylammonium salt.

8. A monomer having the formula:

##STR8## wherein B is a purine or pyrimidine moiety;

W₁ is H, (PO₃)_m^-2 wherein m is an integer of 1-3;

a protecting group, or an intermediate moiety in the formation of an internucleotide link which when reacted with the appropriate --OH results in Z wherein Z is selected from the group consisting of P(O)O^--, P(O)S, P(O)NR₂, P(O)R, P(O)OR'"'"', CO, and CNR₂, wherein R is H or alkyl (1-6 C) and R'"'"' is alkyl (1-6 C);

W₂ is H, PO₃^-2 a protecting group, or an intermediate moiety in the formation of an internucleotide link which when reacted with the appropriate --OH results in Z wherein Z is selected from the group consisting of P(O)O^--, P(O)S, P(O)NR₂, P(O)R, P(O)OR'"'"', CO, and CNR₂, wherein R is H or alkyl (1-6 C) and R'"'"' is alkyl (1-6 C);

X is O, S or CR₂ wherein each R is independently H or alkyl (1-6 C);

Y is selected from the group consisting of substituted or unsubstituted alkyl (2-20 C), substituted or unsubstituted alkenyl (2-20 C), substituted or unsubstituted aryl (6-20 C), wherein the substituents are selected from the group consisting of a hydroxyl, an amino, a mercaptyl, a carboxy or a keto moiety, --CH₂ COOH, --CH₂ COONH₂, --CH₂ COOEt, --CH₂ CONHCH₂ CH₂ NH₂ and SiR"₃ wherein R" is alkyl (2-6 C).