2′-substituted nucleosides and oligonucleotide...

Details 2′-substituted nucleosides and oligonucleotide... 2′-substituted nucleosides and oligonucleotide...

2001-01-03

2003-12-30

McGarry, Sean (Department: 1635)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C435S091100

Reexamination Certificate

active

06670468

ABSTRACT:

AREA OF INVENTION
The present invention relates to an oligonucleotide derivative which comprises at least one nucleoside building block which is substituted at the 2′ position. The invention furthermore relates to intermediates, to processes for preparing the oligonucleotide derivatives, to their uses and to pharmaceutical compositions.
BACKGROUND TO THE INVENTION
As chemotherapeutic agents, oligonucleotides and oligonucleotide derivatives open up effective possibilities for treating many different pathological states which are characterized by expression of a protein or an RNA molecule, for example hyperplastic or neoplastic changes in a cell or a tissue. They can exert their effect, in particular, by way of the so-colled antisense mechanism. Oligonucleotides and oligonu employed in this manner are consequently termed “antisense oligonucleotides”. Alternatively, an oligonucleotide can exert its effect by way of the so-called triplex mechanism. Such oligonucleotides and oligonucleotide derivatives are termed “triplex-forming oligonucleotides”.
For an oligonucleotide or oligonucleotide derivative to be advantageously suitable for use as an antisense oligonucleotide or as a triplex-forming oligonucleotide, it should possess specific properties. Thus, for example, it should have adequate binding affinity for a target nucleic acid, possess adequate resistance to nucleases, in particular towards endogenous nucleases, and, in the case of exerting an effect by way of an antisense mechanism, completely or partially inhibit the translation of a target DNA by means of the formation of a hybrid and subsequent cleavage of the target RNA strand by endogenous nucleases, such as RNAse H, or by means of the formation of a hybrid and subsequent complete or partial inhibition of the ribosomal translation process (so-called translation arrest), or, in the case of exerting an effect by way of a triplex mechanism, the transcription of a particular double-stranded gene segment or DNA segment should be completely or partially inhibited by means of the formation of a triple helix. Furthermore, the oligonucleotide or oligonucleotide derivative should be taken up to an adequate extent by the cell to be treated, should exert an effect which is as sequence-specific as possible, and possess adequate bioavailability (cf., for example, S. T. Crooke, “Therapeutic Applications of Oligonucleotides”, R. G. Landes Company Publisher (1995); Plum, G. E., Annu. Rev. Biophys. Biomol. Struct. 24 (1995), 319-350; Cohen, J. S. et al., Sci. Am. (1994), 50-55; Stull, R. A. et al., Pharm. Res. 12 (1995), 465-483).
In order to obtain oligonucleotides or oligonucleotide derivatives which possess one or more of the abovementioned properties, substitutions have, for example, been performed on the nucleoside building blocks or the internucleosidic bonds from which the oligonucleotides and oligonucleotide derivatives are assembled.
There is a particular need for additional or improved oligonucleotide derivatives in the antisense field or the triplex field.
Ready industrial accessibility to such oligonucleotide derivatives, for example a simple or economic preparation method, would be a further advantage.
An object of the present invention is consequently to make available additional or improved oligonucleotide derivatives which, particularly in relation to their use as antisense oligonucleotides or triplex-forming oligonucleotides, have advantageous properties with regard to one or more of the following criteria:
binding affinity
resistance to nucleases
sequence-specific effect
inhibition or modulation of expression
uptake by the cell
bioavailability.
Another object of the present invention is to make available compounds which ensure ready industrial accessibility to oligonucleotide derivatives according to the invention.
A further object lies in the provision of an oligonucleotide derivative or a pharmaceutical which can be used in a mammalian subject, including man, to treat, in particular, pathological states which are characterized by the expression of a protein or an RNA molecule.
SUMMARY OF THE INVENTION
The invention provides an oligonucleotide derivative which comprises at least one nucleoside building block which has a substituent of the type described below at the 2′-O position.
The invention also provides a nucleoside compound which can be used as an intermediate in the preparation of the novel oligonucleotide derivatives.
The invention also provides processes for preparing the novel oligonucleotide derivatives and processes for preparing the nucleoside compounds and also other intermediates which are used.
The invention furthermore provides a pharmaceutical composition which comprises the novel oligonucleotide derivatives and also a use of these oligonucleotide derivatives for therapeutic treatment, for modulating the expression of a protein or an RNA molecule, and in diagnostic methods.
The invention also provides the use of the novel nucleoside compounds in pharmaceutical compositions and for therapeutic treatment.
PRECISE DESCRIPTION OF THE INVENTION
Surprisingly, it has been ascertained that one or more of the above-described objects is/are achieved by a novel oligonucleotide derivative according to the present invention.
Consequently, the invention provides an oligonucleotide derivative which comprises at least one nucleoside building block of the formula I
in which
A is a radical of the formula —C(H)(R
3
)—N(R
1
)(R
2
), in which
R
1
and R
2
are, independently of each other
H,
C
1
-C
10
alkyl,
a radical of the formula II
—(CH
2
—CH
2
—X)
m
—R
5
  (II),
in which each X is, in each case independently of each other, O or N(R
6
), R
5
and R
6
are, in each case independently of each other, H, C
1
-C
10
alkyl, amino-C
2
-C
10
alkyl, N-mono-C
1
-C
10
alkylamino-C
2
-C
10
alkyl or N,N-di-C
1
-C
10
alkylamino-C
2
-C
10
alkyl, and m is an integer from 1 up to and including 3, amino-C
3
-C
10
alkyl, N-mono-C
1
-C
10
alkylamino-C
3
-C
10
alkyl, or N,N-di-C
1
-C
10
alkylamino-C
3
-C
10
alkyl; or in which —N(R
1
)(R
2
) are together a radical of the formula (III),
 in which Y is O, S, SO
2
or N(R
7
), and R
7
is H or —CH
3
;
R
3
is H, —CH
3
, —CH
2
CH
3
, —CH
2
OH or —CH
2
—O—C
1
-C
4
alkyl; or
A is a radical of the formula (IVa) or (IVb)
in which R, independently, has the meaning of R
1
or R
2
, and U is O or CH
2
;
R
4
is H, —CH
3
, —CH
2
CH
3
, —CH
2
OH or —CH
2
—O—C
1
-C
4
alkyl;
n is 0, 1 or 2;
B is the radical of a nucleic acid base; and
V and W are, independently of each other, the same or different radicals of an internucleosidic bridging group or are a terminal radical;
or a salt thereof;
where those compounds are excepted in which, in the radical A, two heteroatoms are linked to the same carbon atom.
In a further embodiment of the radical of formula (III) Y is SO.
The expression “oligonucleotide derivative” is familiar to the skilled person and will only be explained here for the sake of completeness. Within the context of the present invention, the expression “oligonucleotide derivative” denotes, in particular, a derivatized oligonucleotide. An oligonucleotide per se is preferably an oligomer which consists of a sequence of natural nucleoside building blocks which are connected to each other by way of natural internucleosidic bridging groups. A natural nucleoside as such preferably consists of a sugar, in particular a &bgr;-D-erythropentofuranose, in particular &bgr;-D-ribose, together with a natural nucleic acid base which is linked to it in the P position. Within the context of the present invention, nucleic acid base preferably denotes a base which, in relation to a naturally occurring nucleoside, is capable of forming Watson-Crick base pairing (for antisense oligonucleotides) or of forming Hoogsteen or reverse Hoogsteen base pairing (for triplex-forming oligonucleotides). Examples of natural nucleic acid bases are adenine, guanine, cytosine, thymine and uracil and also other bases with which the skilled person is familiar. In an oligonucleotide, a natural internucleosi

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