US 5,969,135 AGranted

Oligonucleotide analogs with an amino acid or a modified amino alcohol residue

AssigneeICN Pharmaceuticals, Inc.

InventorsKandasamy Ramasamy, Wilfried E. Seifert

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Abstract

The present invention provides various novel oligonucleotide analogs having one or more properties that make the subject compounds superior to conventional oligonucleotides for use in procedures employing oligonucleotides. The compounds of the invention are oligonucleotide analogs in which the furanose ring of a naturally occurring nucleic acid is replaced with an amino acid or a modified amino alcohol residue. Some embodiments of the novel compounds of the invention are particularly useful for the antisense control of gene expression. The compounds of the invention may also be used as nucleic acid hybridization probes or as primers. Another aspect of the invention is to provide monomeric precursors of the oligonucleotide analogs of the invention. These monomeric precursors may be used to synthesize the subject polynucleotide analogs. Another aspect of the invention is to provide formulations of the subject polynucleotide analogs that are designed for the treatment or prevention of disease conditions. Yet another aspect of the invention is to provide methods for treating or preventing diseases, particularly viral infections and cell growth disorders. The subject disease treatment methods comprise the step of administering an effective amount of the subject polynucleotide analogs for use as antisense inhibitors.

A monomer of formula 1 in any of Groups I-V, which, when polymerized, adopts a rigid conformation via intramolecular Hydrogen bonding, and thereby mimics ribose puckering:

##STR6## Group I, where:
X is CHR.sub.2 OH where R.sub.2 is H, lower alkyl amine or lower alkyl imidazole;
Y is Base-(CH.sub.2)n-, where Base is a non-halogenated purine, and n is 1 to 7 C atoms;
A is carbonyl;
Z is H or OR.sub.3, where R.sub.3 is H, lower alkyl, lower alkyl amine or lower alkyl imidazole;
W is CHR.sub.4 OH, where R.sub.4 is H or lower alkyl amine or lower alkyl imidazole;
N is N (nitrogen);
and
L is nothing;
Group II, where:
X is Base-(CH.sub.2)n-, where Base is a non-halogenated purine, and n is 1 to 7 C atoms;
Y is CHR.sub.2 OH where R.sub.2 is H, lower alkyl amine or lower alkyl imidazole;
A is carbonyl or CH.sub.2 ;
Z is H or OR.sub.3, where R.sub.3 is H, lower alkyl, lower alkyl amine or lower alkyl imidazole;
W is CHR.sub.4 OH, where R.sub.4 is H or lower alkyl amine or lower alkyl imidazole;
N is N (nitrogen);
and
L is nothing;
Group III, where:
X is CHR.sub.2 OH where R.sub.2 is H, lower alkyl amine or lower alkyl imidazole;
Y is Base-(CH2)n-, where Base is a non-halogenated purine, and n is 1 to 7 C atoms;
A is CH.sub.2 ;
Z is OH or OR.sub.3 and R.sub.3 is H, lower alkyl, lower alkyl amine or lower alkyl imidazole;
W is CHR.sub.4 OH, where R.sub.4 is H or lower alkyl amine or lower alkyl imidazole;
N is N (nitrogen);
and
L is nothing;
Group IV, where:
X is Base-(CH.sub.2)n-, where Base is a non-halogenated purine, and n is 1 to 7 C atoms;
Y is COOH or CHR.sub.2 OH where R.sub.2 is H, lower alkyl amine or lower alkyl imidazole;
A is carbonyl or CH.sub.2 ;
Z is CH.sub.2 ;
W is CH.sub.2 ;
N is N (nitrogen);
and
L is CHNHR.sub.5 where R.sub.5 is H, OH or OR.sub.3, and R.sub.3 is H, lower alkyl, lower alkyl amine or lower alkyl imidazole;
and
Group V, where:
X is CH.sub.2 OH, CH.sub.2 NH.sub.2, CONH.sub.2 or COOH;
Y is nothing;
Z is CH.sub.2 or CHO-L.sub.1 -B;
W is O, S or CH.sub.2 ;
N is CH;
and
L and A are independently COOH, CHCOOH, CHCH.sub.2 COOH, NH.sub.2, CHNH.sub.2, L.sub.1 -NH-L.sub.2 -B or CH-L.sub.1 -NH-L.sub.2 -B;
where B is H or a purine, and L.sub.1 and L.sub.2 are independently (CH.sub.2).sub.n or (CH.sub.2).sub.n CO, where n=-0, 1, 2 or 3.

43 more elements

Abstract

Claims9