Anti-viral pyrimidine nucleoside analogues

Details Anti-viral pyrimidine nucleoside analogues Anti-viral pyrimidine nucleoside analogues

2000-01-06

2003-06-03

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S027110, C536S027130, C536S027140

Reexamination Certificate

active

06573247

ABSTRACT:

The present invention relates to a new class of nucleoside analogues and to their therapeutic use in the prophylaxis and treatment of viral infection for example by varicella zoster virus (VZV). Varicella zoster virus is the aetiological agent in chickenpox and shingles which can cause considerable human illness and suffering.
There has been considerable interest in the development of 5-substituted pyrimidine deoxynucleosides as putative antiviral agents.
Tetrahedron Letters, 22, 421, 1981, M. J. Robins and P. J. Barr describes a method of coupling terminal alkynes with protected 5-iodouracil nucleotides in the presence of a catalyst to give the corresponding 5-(alkyn-1-yl) uracil nucleosides.
J. Med. Chem. 26, 661, 1983, E. de Clercq, J. Descamps, J. Balzarini, J. Giziewicz, P. J. Barr and M. J. Robins describes a catalytic process for coupling terminal alkynes with 5-iodo-1-(2,3,5,-tri-O-p-toluyl-&bgr;-D-arabinofuranosyl)uracil and 5-iodo-3′,5′-di-O-p-toluyl-2′-deoxyuridine. A cyclized by-product having methyl substituted at the 6-position was isolated and characterised spectroscopically.
J. Org. Chem. 48, 1854, 1983, M. J. Robins and P. J. Barr describes catalytic coupling of terminal alkynes with 5-iodo-1-methyluracil and 5-iodouracil nucleotides protected as their p-toluyl esters. The article also describes the conversion of 5-hexynyl-2′-deoxyuridine to cyclized 6-n-butyl-3-(2-deoxy-&bgr;-D-erythro-pentofuraosyl)furano[2,3-d]pyrimidin-2-one.
Tetrahedron Letters 29, 5221, 1988, K. A. Cruickshank and D. L. Stockwell describes the catalytic condensation of 5′-dimethoxytrityl-5-iodo-2′-deoxyuridine with N-trifluoroacetyproparglyamine and subsequent conversion to the 3′-phosphoramidite.
J. Heterocyclic Chem. 28, 1917, 1991, R. Kumar, E. E. Knaus and L. I. Wiebe describes a reaction employing 5-(1-fluoro-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine and producing a compound having the formula:
J. Org. Chem. 1993, 58, 6614, G. T. Crisp and B. L. Flynn describes palladium catalysed couplings of terminal alkynes with a variety of oxyuridines. One coupling described is that between 5-ethynyl-2′-deoxyuridine and a range of fluorinated aryl compounds.
Nucleic Acids Research 1996, 24, 2470, J. Woo, R. B. Meyer and H. B. Gamper describes a process for the preparation of 3-(2′-deoxy-&bgr;-D-ribofuranosyl)-pyrrolo-[2,3-d]-pyrimidine-2(3H)-one.
Can. J. Chem. 74, 1609, 1996, R. Kumar, L. I. Wiebe, E. E. Knaus describes a range of deoxyuridine compounds and their various anti-viral activity. A compound of the formula:
was found to be inactive in the vitro assays against HSV-1, HSV-2, VZV and CMV.
JP 62255499 (Teijin Ltd) describes the preparation of fluorescent nucleosides or nucleotides and their use for DNA hybridization probes. The compounds described have the general formula:
wherein X
1
and Y
1
are HO[P(O)(OH)O]n, Z
1
is H or HO[P(O)(OH)O]m, with m and n=0 to 3, W1 is H or HO and R
1
and R
2
are H or C
1
to C
10
alkyl.
Nippon Kagaku Kaishi 7, 1214, 1987 describes the synthesis of fluorescent dodecadeoxy ribonucleotides having the general formula:
where R can be H or butyl.
It is an object of the present invention to provide a novel class of nucleoside analogues.
It is a further object of the present invention to provide a novel class of nucleoside analogues for therapeutic use in the prophylaxis and treatment of viral infection for example by varicella zoster virus.
According to a first aspect of the present invention there is provided a compound having formula I as follows:
wherein
R is selected from the group comprising C
5
to C
20
alkyl, C
5
to C
20
cycloalkyl, halogens, aryl and alkylaryl;
R′ is selected from the group comprising hydrogen, alkyl, cycloalkyl, halogens, amino, alkylamino, dialkylamino, nitro, cyano, alkyoxy, aryloxy, thiol, alkylthiol, arylthiol, and aryl;
R″ is selected from the group comprising hydrogen, alkyl, cycloalkyl, halogens, alkyloxy, aryloxy and aryl;
Q is selected from the group comprising O, S and CY
2
, where Y may be the same or different and is selected from H, alkyl and halogens;
X is selected from the group comprising O, NH, S, N-alkyl, (CH
2
)
n
where n is 1 to 10, and CY
2
where Y may be the same or different and is selected from hydrogen, alkyl and halogens;
Z is selected from the group comprising O, S, NH and N-alkyl;
U″ is H and U′ is selected from H and CH
2
T, or U′ and U″ are joined so as to provide a ring moiety including Q wherein
U′-U″ together is respectively selected from the group comprising —CTH—CT′T″— and —CT′═CT′—, so as to provide ring moieties selected from the group comprising
 wherein
T is selected from the group comprising OH, H, halogens, O-alkyl, O-acyl, O-aryl, CN, NH
2
and N
3
;
T′ is selected from the group comprising H and halogens and where more than one T′ is present they may be the same or different;
T″ is selected from the group comprising H and halogens; and
W is selected from the group comprising H, a phosphate group and a phosphonate group.
It is to be understood that the present invention extends to compounds according to formula I wherein the group W is modified to any pharmacologically acceptable salt or derivative of —H, phosphates or phosphonates. The present invention also includes any compound which is a pro-drug of the compound according to formula I, any such pro-drug being provided by modification of the moiety W, wherein W is selected from phosphates and derivatives thereof, and phosphonates and derivatives thereof.
Each of R, R′ and R″ may be substituted or unsubstituted and may be branched or unbranched. When any of R, R′ and R″ are alkyl or cycloalkyl they may be saturated or unsaturated. The nature, position and number of any substituents and unsaturation present may be varied. R may contain aryl or heteroaryl groups which may vary in nature, position or number. A preferred position is the terminus position in R. Examples of suitable substituents include OH, halogens, amino, CN, CHOH, CO
2
alkyl, CONH
2
, CONHalkyl, SH, S-alkyl and NO
2
, wherein alkyl is suitably C
1
to C
5
. Suitably any substituent in R when R is alkyl or cycloalkyl is non-polar, more suitably any such substituent is additionally hydrophobic.
Preferably R is an alkyl group. More preferably R is a C
7
to C
20
alkyl group, which may optionally carry substituents such as halogens. Even more preferably R is a C
8
to C
14
group, particularly preferred is R being straight chain C
10
H
21
.
When R is aryl or alkylaryl it can be substituted. Alkylaryl can be aryl with one or more C
1
to C
10
groups attached which themselves can be substituted or unsubstituted. Aryl groups can include benzyl groups and heterosubstituted 5, 6 or 7 numbered rings. Either an aryl or an alkyl portion of an alkylaryl group can be attached to the ring structure. If desired R can, optionally substituted as above, for example be —(CH
2
)
n
-aryl-(CH
2
)
m
H, where n and m are each more than 1 and n+m≦10 and the aryl is preferably C
6
H
4
. R cannot be any radical equivalent to 4-FC
6
H
5
, C
6
F
5
, 4 MeOC
6
H
5
, 3,5-(CF
3
)
2
C
6
H
4
, 3,5-F
2
C
6
H
4
, 4-CF
3
C
6
H
5
or C
6
H
5
.
Suitably R′ is selected from the group comprising C
1
to C
10
alkyl, C
3
to C
10
cycloalkyl, C
1
to C
10
alkylamino, C
1
to C
10
dialkylamino, C
1
to C
10
alkyloxy, C
6
to C
10
aryloxy, C
1
to C
10
alkylthiol, C
6
to C
10
arylthiol and C
6
to C
10
aryl. Suitably R″ is selected from the group comprising C
1
to C
10
alkyl, C
3
to C
10
cycloakyl, C
1
to C
10
alkyloxy, C
6
to C
10
aryloxy and C
6
to C
10
aryl.
Preferably each of R′ and R″ is a small alkyl i.e. a C
1
to C
2
alkyl group or H. More preferably each of R′ and R″ is H.
Throughout the present specification “halogen” is taken to include any of F, Cl, Br and I.
Preferably Q is CH
2
, S or O

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