Aryl phosphate derivatives of d4T with potent anti-viral...

Details Aryl phosphate derivatives of d4T with potent anti-viral... Aryl phosphate derivatives of d4T with potent anti-viral...

2001-10-19

2004-11-30

Travers, Russell (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S132000, C514S414000

Reexamination Certificate

active

06825177

ABSTRACT:

FIELD OF THE INVENTION
The invention is directed to methods of treating viral infections through the administration of aryl phosphate derivatives of 2′,3′-didehydro-2′,3′-dideoxythymidine.
BACKGROUND OF THE INVENTION
One approach to treating AIDS is by inhibiting the reverse transcriptase (RT) activity of the human immune deficiency virus (HIV). Potent inhibitors of HIV RT are known and include 5′-triphosphates of 2′,3′-dideoxynucleoside (hereinafter “ddN”) analogues such as 3′-azido-3′-deoxythymidine (hereinafter “AZT”) and 2′,3′-didehydro-2′,3′-dideoxythymidine (hereinafter “d4T”). These active RT inhibitors are generated intracellularly by the action of nucleoside kinase and nucleotide kinase.
The rate-limiting step for the conversion of AZT to its bioactive metabolite AZT-triphosphate seems to be the conversion of the monophosphate derivative to the diphosphate derivative, whereas the rate-limiting step for the intracellular generation of the bioactive d4T metabolite d4T-triphosphate was reported to be the conversion of the nucleoside to its monophosphate derivative. (Balzarini et al., 1989,
J.Biol. Chem
. 264:6127; McGuigan et al., 1996,
J. Med. Chem
. 39:1748).
In an attempt to overcome the dependence of ddN analogues on intracellular nucleoside kinase activation, McGuigan et al. prepared aryl methoxyalaninyl phosphate derivatives of AZT (McGuigan et al.,
J.Med. Chem
., 36, 1048 (1993); McGuigan et al.,
Antiviral Res.
17, 311(1992)) and d4T (McGuigan et al.,
J.Med. Chem
., 39, 1748 (1996); McGuigan et al.,
Bioorg. Med.Chem.Lett
., 6, 1183 (1996)). Such compounds undergo intracellular hydrolysis to yield monophosphate derivatives that are further phosphorylated by thymidylate kinase to give the bioactive triphosphate derivatives in a thymidine kinase (TK)-independent fashion.
U.S. Pat. No. 6,030,957 (Uckun et al.) disclosed that substitution of the aryl moiety of an aryl phosphate derivative of d4T enhances the ability of the compounds to undergo hydrolysis. Such compounds are potent antiviral agents. A particularly potent compound is HI-113, (d4T-5′-[p-bromophenyl methoxyalaninyl phosphate]).
SUMMARY OF THE INVENTION
The invention is directed to aryl phosphate derivatives of 2′,3′-didehydro-2′,3′-dideoxythymidine (hereinafter “d4T”) that inhibit human immune deficiency virus reverse transcriptase (HIV RT) and exhibit potent anti-viral activity. One aspect of the invention provides methods for treating viral infections by increasing the elimination half-life of key metabolites such as d4T in a mammal. The method comprises administering an aryl phosphate derivative of d4T having an electron withdrawing substituent on the aryl group and an amino acid substituent on the phosphate group as in Formula I:
where R
1
is an aryl group substituted with an electron withdrawing group and R
2
is an amino acid or an ester of an amino acid. In one embodiment of Formula I, R
1
is a phenyl substituted with an electron withdrawing group and R
2
is an ester of an &agr;-amino acid. Preferably, Formula I is HI-113 (d4T-5′-[p-bromophenyl methoxyalaninyl phosphate]) where R
1
is phenyl group substituted with bromo at the para position and R
2
is the methyl ester of alanine.
The oral or intravenous administration of HI-113 results in the formation of two key metabolites: alaninyl-d4T-monophosphate (Ala-d4T-MP) and d4T. The administration of HI-113 results in more prolonged systemic exposure to Ala-d4T-MP as well as d4T than administration of an equimolar dose of either metabolite. Each metabolite has a significantly longer elimination half life when formed from the administration of HI-113 than when administered directly.
Another aspect of the invention provides a method for treating viral infections comprising extending the elimination half-life of d4T in a mammal by administering an effective amount of a compound of Formula IV:
where R
2
is an amino acid or amino acid ester residue. In one embodiment, R
2
is the methyl ester of alanine.
The methods of the invention can be used to treat HIV.


REFERENCES:
Mcuigan et al, 128CA:289775 , 1998.*
Periguad et al, 126CA:271667 1996.*
Valquest, BO, 30CA:856, 1935.*
Keller, R, 62CA:6881e-h, 1963.

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