Base-modified derivatives of...

Details Base-modified derivatives of... Base-modified derivatives of...

1999-12-08

2001-08-28

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S081000, C514S093000, C536S025200, C536S025600, C536S026220, C536S026260, C544S244000, C548S266800

Reexamination Certificate

active

06281201

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to synthetic analogues of naturally occurring antiviral 2′,5′-oligoadenylates wherein at least one of the nucleoside residues is replaced with a modified nucleoside.
BACKGROUND OF THE INVENTION
The discovery of the 2′-5′ oligoadenylates is connected with the study of the mechanisms of interferon action as the cellular response to virus infection [2]. The 5′-triphosphate of the (2′-5′) oligoadenylate trimer plays a most important role in the antiviral mechanism induced by interferon [3]. It is generally regarded that activation of RNase L by 2-5A is key to the antiviral defense mechanisms. Interferon induces transcription of the enzyme 2-5A synthetase which produces 2′,5′-linked oligoadenylates upon activation of double-stranded RNA.
Previously, the only known biochemical effect of 2-5A is activation of RNase L. This enzyme hydrolyzes mRNA and rRNA, thereby resulting in inhibition of protein synthesis. The activation of RNase L is transient unless 2-5A is continuously synthesized, since 2-5A is rapidly degraded. RNase L activation thus plays a critical role in inhibiting replication, and therefore in defending against infection by viruses.
Naturally occurring (2′-5′)oligoadenylates (both 5′-phosphorylated and unphosphorylated) have shown different kinds of biological activity [4][5]. Analogues of the natural (2′-5′)oligoadenylates have been synthesized to achieve new approaches to antiviral and antitumoral therapy [6-13]. Biological activities of 5′-phosphorylated (2′-5′)oligoadenylates are connected with the functioning of the (2′-5′)A system which leads to the inhibition of protein synthesis [3]. The mechanism of action of unphosphorylated (2′-5′)oligoadenylates in many cases is still unknown. Recently, certain sugar-modified trimers of (2′-5′)oligoadenylates were found to be inhibitors of HIV-1 reverse transcriptase (RT) [14-18].
SUMMARY OF THE INVENTION
The compounds of the present invention are useful in inhibiting viral infections in plants and mammals.
The compounds and the water-soluble salts thereof are of the formula wherein
m is zero, 1, 2 or 3; n is from 1 to 8, preferably 1, 2 or 3; most preferably 1 or 2;
R is independently selected from the group consisting of
 provided that all R may not be
R
1
is independently selected from the group consisting of hydroxyl and hydrogen;
R
2
is independently selected from the group consisting of oxygen and sulfur.
Preferably, all R
1
are hydroxyl and all R
2
are oxygen.
According to one preferred embodiment of the invention, R is selected from the group consisting of
According to another preferred embodiment of the invention, R is selected from the group consisting of
According to yet another preferred embodiment of the invention, the R of the 2′,3′-terminal nucleoside moiety is
Compounds of the invention include, for example, the following core compounds, the 5′-mono, di-, and triphosphates thereof, and water-soluble salts of any of them:
adenylyl-(2′-5′)-adenylyl-(2′-5′)-1-(&bgr;-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide;
adenylyl-(2′-5′)-[1-(&bgr;-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide]yl-(2′-5′)-adenosine;
1-(&bgr;-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide]yl-(2′-5′)-adenylyl-(2′-5′)-adenosine;
adenylyl-(2′-5′)-adenylyl-(2′-5′)-N
6
-benzyladenosine;
adenylyl-(2′-5′)-N
6
-benzyladenylyl-(2′-5′)-adenosine;
N
6
-benzyladenylyl-(2′-5′)-adenylyl-(2′-5′)-adenosine; and
N
6
-benzyladenylyl-(2′-5′)-N
6
benzyladenylyl-(2′-5′)-N
6
-benzyladenosine.
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 further comprises an antiviral composition comprising such a compound or water soluble salt in combination with an agricultural carrier or pharmaceutical carrier.
DETAILED DESCRIPTION OF THE INVENTION
Replacement of the adenine moiety in the (2′-5′)oligoadenylate trimer core with 1H-1,2,4-triazole-3-carboxamide (TCA) or with N
6
-(benzylamino)purine (Ade
Bn
)-moieties has resulted in a new group of inhibitors of HIV-1 replication. Trimer compounds of the present invention and their synthesis intermediates are numbered 1 through 28 as follows for purposes of identification. Compound 29 is the authentic (2′-5′)oligoadenylate trimer core.

Base
R
R
1
R
2
1
Ade
Bn
H
H
H
2
Ade
Bn
MeOTr
H
H
3
Ade
Bn
MeOTr
Bz
Bz
4
Ade
Bn
MeOTr
H
Bz
5
Ade
Bn
MeOTr
Bz
H
6
Ade
Bn
H
Bz
Bz
7
TCA
H
H
H
8
TCA
MeOTr
H
H
9
TCA
MeOTr
Bz
Bz
10
TCA
MeOTr
Bz
H
11
TCA
H
Bz
Bz
12
Ade
Bz
H
Bz
Bz

Base
1
13
Ade
Bn
14
TCA
15
Ade
Bz

Base
Base
1
16
Ade
Bn
Ade
Bz
17
Ade
Bn
Ade
Bn
18
Ade
Bz
Ade
Bn
19
TCA
Ade
Bz
20
Ade
Bz
TCA
21
Ade
Bz
Ade
Bn

Base
Base
1
Base
2
22
Ade
Bn
Ade
Ade
23
Ade
Ade
Bn
Ade
24
Ade
Ade
Ade
Bn
25
Ade
Bn
Ade
Bn
Ade
Bn
26
TCA
Ade
Ade
27
Ade
TCA
Ade
28
Ade
Ade
TCA
29
Ade
Ade
Ade
In the compounds of the present invention, each R
2
may be oxygen, each R
2
may be sulfur, or R
2
may comprise a mixture of oxygen and sulfur to provide a backbone of a 2′,5′-phosphodiester, a 2′,5′-phosphorothioate or a 2′,5′-mixed phosphorothioate/phosphodiester oligonucleotide, respectively.
The substitution of sulfur for oxygen in the 2′,5′-phosphodiester backbone referenced above, introduces chirality into the molecules and introduces a new chemistry of the backbone. The core 2′,5′-phosphorothioates exhibit increased resistance to phosphodiesterase and phosphatases and new biological activities compared to authentic 2-5A cores. The preparation of the 2′,5′-phosphorothioates, including fully resolved enantiomers thereof, is disclosed in U.S. Pat. No. 4,924,624 and is incorporated herein by reference. A mixture of phosphorothioate and phosphodiester linkages is possible in the same oligomer, providing molecules with a mixed phosphodiester/phosphorothioate backbone, as described in PCT/US95/10683, the entire disclosure of which is incorporated by reference.


REFERENCES:
patent: 4464359 (1984-08-01), Suhadolnik et al.
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
Kvasyuk, E.I. et al., Synthesis and Biological Activity of New 2′,5′-Oligonucleotides,Nucleosides&Nucleotides, 16(7-9):1351-1354 (Nov. 1997).
Kvasyuk, E.I. et al., “Synthesis and Biological Activity of New Base-Modified (2′,5′) Oligoadenylate Trimers”,Helvetica Chimica Acta, 80(4):1053-1060 (Jun. 30, 1997).
Beaucage and Iyer, “The Functionalization of Oligonucleotides Via Phosphoramidite Derivatives”,Tetrahedron, 49(10):1925-1993 (1993).

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