Aminoaklanoyl-linked conjugates of...

Details Aminoaklanoyl-linked conjugates of... Aminoaklanoyl-linked conjugates of...

1999-12-09

2002-03-26

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S102000, C536S025600, C544S244000

Reexamination Certificate

active

06362171

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to synthetic analogues of naturally occurring antiviral 2′,5′-oligoadenylates wherein the analogues are conjugated to a carrier molecule to enhance cellular uptake.
BACKGROUND OF THE INVENTION
It is well established that the natural antiviral pathways ubiquitous in mammalian cells—the (2-5′)oligo(A) synthetase/RNase L cascade and the PKR antiviral pathway—are activated on virus infections, including HIV-1 [2-5]. Both pathways require dsRNA. which on the one hand activates (2′-5′)oligo(A) synthetase converting ATP into 2′-5′-linked oligoadenylates (“2-5A”) with a 5′-terminal triphosphate function. These unusual oligonucleotides bind and activate RNase L leading to the degradation of viral RNA and subsequent inhibition of protein synthesis [3][4]. On the other hand, dsRNA-dependent PKR (p68 kinase) undergoes autophosphorylation and catalyzes phosphorylation of the &agr;-submit of eIF-2, thereby inhibiting initiation of protein synthesis [6]. Although, (2′-5′)oligoadenylates are rapidly inactivated by two different nucleases, the (2′-5′)oligo(A)system represents a chemotherapeutic possibility for the control of virus and cell growth.
Many (2′-5′)oligo(A)derivatives have been synthesized with the aim to increase biological activity and to avoid premature decomposition of the antivirally active substance. One of the modified (2′-5′)oligo(A)analogues is the cordycepin-trimer core (2′-5′)d
3′
(A-A-A) [7][8]; U.S. Pat. No. 4,464,359 which was found to be biologically active, metabolically stable, and not toxic to cells [9]. Although, the trimer-cordycepin core effects no activation of RNase L [10]; this substance inhibits HIV-1 production [11] probably by weakening the complex formation of primer tRNA
Lys,3
to HIV-1 reverse transcriptase [5][12][13].
One of the major problems in application of oligonucleotides to cells and biological systems is their polyanionic structure which renders them difficult to penetrate cell membranes. Numerous efforts have been made to improve the cellular uptake of oligonucleotides, e.g., incorporation in liposomes [14] or syntheses of lipophilic conjugates [15-17]. The attachment of cholesterol, various vitamins, and lipids to the 2′-O- and 5′-O-position of the sugar moiety of monomeric and trimeric cordycepin has been described [18-20].
SUMMARY OF THE INVENTION
Compounds of the following formula are provided, useful in treating viral infection in plants and animals:
wherein:
n is from 1 to 8, preferably 1, 2 or 3, most preferably 1 or 2;
R
1
is selected from the group consisting of
wherein m is zero, 1, 2, or 3; and
wherein q is from 1 to 20, preferably from 2 to 8, most preferably from 3 to 7;
R
2
is independently selected from the group consisting of oxygen and sulfur;
R
3
is independently selected from the group consisting of hydrogen and hydroxyl; and
R
4
is selected from the group consisting of hydrogen, hydroxyl and
R
5
is selected from the group consisting of hydroxyl and
R
6
is selected from the group consisting of
and
wherein x is from 1 to 20, preferably from 2 to 16, most preferably 10 to 14;
provided that one of R
1
, R
4
and R
5
is
wherein R
6
is defined as above;
or water soluble salt thereof.
Preferably, the compounds of the invention include at least one nucleotide residue which is cordycepyl, that is, either R
4
is hydrogen or at least one of R
3
hydrogen. Most preferably, the compounds of the present invention comprise conjugates of 2′,5′-oligocordycepin wherein the internucleotide linkages comprise phosphodiester groups, that is, all R
2
are oxygen, R
4
is hydrogen, and all R
3
are hydrogen.
The invention also comprises a method of treating viral infection in mammals or plants by administering an antivirally effective amount of a compound according to the above formula, or a water-soluble salt thereof. The invention also comprises an antiviral composition comprising such a compound or water soluble salt in combination with an agricultural carrier or pharmaceutical carrier.
Compounds of the invention include, for example, the following compounds, the 5′-mono-, di-, and triphosphates thereof, and water-soluble salts of any of them:
3′-deoxyadenylyl-(2′-5′)-3′-deoxyadenylyl-(2′-5′)-3′-deoxy-2′-O-[6-(tetradecanoylamino)-hexanoyl]adenosine;
3′-deoxyadenylyl-(2′,5′)-3′-deoxyadenylyl-(2′-5′)-3′-deoxy-2′-O-{-[(3&agr;,7&agr;, 12&agr;-trihydroxy-5&bgr;-cholan-24-oyl)-amino]hexanoyl}adenosine;
3′-deoxyadenylyl-(2′-5′)-3′-deoxyadenylyl-(2′-5′)-2′-O-{6-{{N-{4-{[(2-amino-1,4-dihydro-4-oxopteridin-6-yl)methyl]amino}benzoyl}-L-&ggr;-glutanyl}amino}hexanoyl}-3′deoxy]adenosine;
Compounds of the invention further include, for example, the following compounds, and water-soluble salts thereof:
3′-deoxy-5′-O-[6-(tetradecanoylamino)hexanoyl]adenylyl-(2′-5′)-3′-deoxyadenylyl-(2′-5′)-3′-deoxyadenosine;
3′-deoxy-5′-O-{6-[(3&agr;, 7&agr;, 12&agr;-trihydroxy-5&bgr;-cholan-24-oyl)amino]hexanoyl}adenylyl-(2′-5′)-3′-deoxyadenylyl-(2′-5′)-3′-deoxyadenosine; and
5′-O-{6-{{N-{4-{[(2-amino-[,4-dihydro-4-oxopteridin-6-yl)methyl]amino}benzoyl}-L-&ggr;-glutanyl}amino}hexanoyl}-adenylyl-(2′-5′)-3′-deoxyadenylyl-(2′-5′)-3′-deoxyadenosine.


REFERENCES:
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patent: 4859768 (1989-08-01), Suhadolnik et al.
patent: 4924624 (1990-05-01), Suhadolnik et al.
patent: 4981957 (1991-01-01), Lebleu et al.
patent: 2 002 773 (1979-02-01), None
patent: WO 89/12380 (1989-12-01), None
patent: WO 93/17692 (1993-09-01), None
patent: WO 96/08256 (1996-03-01), None
Wasner et al.:“6-Aminohexanoyl-Linked Conjugates of Monomeric and Trimeric Cordycepin”; Helve.Chim.Acta, 80/4, 1061-72(Jun. 30, 1997).*
Horndler et al., “59. Nucleotides”,Helvetica Chimica Acta, 80:767-785 (May 12, 1997).
Wasner et al., “55. Nucleotides”,Heletica Chimica Acta, 79:619-633 (May 8, 1996).
Wasner et al., “79. Nucleotides”,Heletica Chimica Acta, 80:1061-1072 (Jun. 30, 1997).
Wasner et al., “156. Nucleotides”,Heletica Chimica Acta, 77:1757-1767 (1994).
Wasner et al., “54. Nucleosides”Heletica Chimica Acta, 79:609-618 (May 8, 1996).
Wasner and Pfleiderer, “Synthesis of Trimeric Cordycepin-Vitamin Conjugates as Improved Antiviral Agents”,Nucleosides&Nucleotides, 14 (3-5):1101-1104 (1995).
Beaucage and Iyer, “The Functionalization of Oligonucleotides Via Phosphoramidite Derivatives”,Tetrahedron, 49(10):1925-1963 (1993).
Horndler and Pfleiderer,Heletica Chimica Acta, 79:718-726 (May 8, 1996).

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