Chemical compounds

Details Chemical compounds Chemical compounds

1999-08-24

2002-09-24

Berch, Mark (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S086000, C544S105000, C544S118000, C544S243000, C544S244000

Reexamination Certificate

active

06455513

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a new class of nucleoside analogues and their therapeutic use in the prophylaxis and treatment of viral infection, for example by human immunodeficiency virus (HIV), which is believed to be the aetiological agent in human acquired immunodeficiency syndrome (AIDS).
BACKGROUND OF THE INVENTION
There has been much interest in the use of nucleoside analogues as inhibitors of HIV. 2′,3′-dideoxy-2′,3′-didehydrothymidine (d4T) and 3′-azido-3′-deoxythymidine (AZT) are both known inhibitors of HIV [Hitchcock et al., Antiviral Chem. Chemother. (1991), 2, 125; Mansuri et al., Antimicrob. Agents Chemother., (1990), 34, 637.]. The inhibition of HIV by these, and other nucleoside analogues, is conventionally thought to depend upon conversion of the nucleoside analogue in vivo to the corresponding 5′-triphosphate by (host-cell) kinase enzymes. However, this absolute dependence upon (host-cell) kinase-mediated activation can lead to poor activity, the emergence of resistance, and clinical toxicity.
In order to reduce the dependence on kinase enzymes the use of masked phosphate pro-drugs of the bioactive nucleotide forms of several chemotherapeutic nucleoside analogues has been suggested [McGuigan et al., Nucleic Acids Res., (1989), 17, 6065; McGuigan et al., Ibid., (1989), 17, 7195; Chawla et al., J. Med. Chem., (1984), 27, 1733; Sergheraert et al., J. Med. Chem. (1993), 36, 826-830.]. In particular, McGuigan et al [J. Med. Chem. 36, 1048-1052 (1993)] have reported the preparation of aryl ester—phosphoramidate derivatives of AZT. In vitro evaluation of these compounds revealed the compounds to have anti-HIV activity. However, in “normal” thymidine kinase rich (TK
+
) cells, the activity of such compounds was at least an order of magnitude less than the parent nucleoside AZT. Only in TK-deficient (TK
−
) cells, in which the activity of the aryl ester—phosphoramidate derivatives was virtually maintained but the activity of AZT was reduced, did the activity of the derivatives exceed that of AZT.
McGuigan et al [Bioorganic & Medical Chemistry Letters, 3,(6), 1203-1206 (1993)] have also reported preparation of triester phosphate derivatives of d4T. Again, in vitro evaluation of these compounds revealed that whilst the compounds have significant anti-HIV activity, the activity is less than that of the parent nucleoside d4T in TK
+
cells.
Abraham and Wagner (Nucleosides and Nucleotides 13 (9). 1891-1903 (1994)) have reported the preparation of nucleoside phosphoramidate diesters and triesters but do not report any biological activity.
The acyclic nucleoside analogue 9(2-phosphonomethoxyethyly adenine (PMEA), and analogues thereof, have been demonstrated to show activity against herpes viruses and retroviruses including HIV (Calio et al., Antiviral Res., (1994), 23(1), 77-89; Balzarini et al., AIDS, (1991), 5(1), 21-28).
To date, the approach of providing masked phosphate pro-drugs has failed to enhance the anti-viral activities of the parent nucleoside analogues such as AZT and d4T in TK
+
cells. Furthermore, the emergence of resistance to the nucleoside analogues in their bioactive 5′-triphosphate form has rendered the reported masked phosphate pro-drugs and their parent nucleoside analogues potentially ineffective.
DESCRIPTION OF THE INVENTION
It has now been found that a particular class of masked nucleoside analogues are highly potent viral inhibitors in both TK
−
and TK
+
cells, and yet retain activity against nucleoside (e.g. d4T)-resistant virus.
According to the present invention there is provided a compound of the formula (1)
wherein Ar is an aryl group;
Y is oxygen or sulphur;
X
1
is selected from O, NR
3
, S, CR3R
4
, CR
3
W
1
and CW
1
W
2
where R
3
and R
4
are independently selected from hydrogen, alkyl and aryl groups; and W
1
and W
2
are heteroatoms;
X
2
and Y
6
together are direct bond; or X is CH
2
and X
2
is selected (independently of X
1
) from O, NR
3
, S, CR
3
R
4
, CR
3
W
1
and CW
1
W
2
where R
3
and R
4
are independently selected from hydrogen, alkyl and aryl groups; and W
1
and W
2
are heteroatoms;
X
3
is a alkylene of 1 to 6 carbon atoms (e.g., alkenyl);
X
4
is oxygen or CH
2
;
X
5
may be absent or is CH
2
;
Z is selected from O, NR
5
, S, alkylene and arylene (e.g., alkenyl) groups, where R
5
is selected from hydrogen, alkyl and aryl groups;
J is selected from hydrogen, alkyl, aryl, heterocyclic and polycyclic groups;
Q is selected from O, NR
6
, S, CR
6
R
7
, CR6W
3
and CW
3
W
4
where R
6
and R
7
are independently selected from hydrogen, alkyl and aryl groups; and W
3
and W
4
are heteroatoms;
T
1
and T
2
are independently selected from hydrogen and CH
2
R
8
, where R
8
is selected from H, OH and F; or T
1
and T
2
are linked together and together are selected from the groups
where R
9
is selected from H, halogen, CN, NH
2
, CO-alkyl and alkyl; and R
10
, R
11
, R
12
are independently selected from H, N
3
, halogen, CN, NH
2
, CO-alkyl and alkyl;
B is a purine or pyrimidine base;
or a pharmaceutically acceptable derivative or metabolite thereof.
The compounds of the present invention are potent anti-viral agents. In particular, they are highly active against HIV in both TK
−
and TK
+
cells. Particularly surprising is the activity of the compounds of the present invention against nucleoside-resistant HIV. These observations indicate that the activity of these compounds is not wholly dependent upon the conventional mode of action (requiring hydrolysis of the phosphate aryl ester and P-X
1
bonds followed by kinase-dependent conversion to the 5′-triphosphate derivative), but arises from an entirely different mode of action. The experimental data presented herein indicates that the compounds and metabolites of the present invention are directly acting as reverse transcriptase (RT) inhibitors via a previously unrecognised metabolic pathway and mechanism of action.
Reference in the present specification to an alkyl group means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical. Where cyclic, the alkyl group is preferably C
3
to C
12
, more preferably C
5
to C
10
, more preferably C
5
to C
7
. Where acyclic, the alkyl group is preferably C
1
to C
16
, more preferably C
1
to C
6
, more preferably methyl. Reference in the present specification to alkoxy and aryloxy groups means alkyl-O- and aryl-O- groups, respectively. Reference to alkanoyl and aryloyl groups means alkyl-CO- and aryl-CO-, respectively.
Reference in the present specification to an aryl group means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more, preferably one, heteroatom, such as pyridyl, pyrrolyl, furanyl and thiophenyl. Preferably, the aryl group comprises phenyl or substituted phenyl.
The alkyl and aryl groups may be substituted or unsubstituted, preferably unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1substituent. Substituents include halo, halomethyl (such as CF
3
and CCl
3
), oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, arloxy, arloyl, aryloyloxy, amino, alkylamino, dialkylamino, cyano, azide, nitro, thiol, alkylthiol, sulphonyl, sulphoxide, heterocyclic, alkyl, benzyl, and aryl (such as phenyl and substituted phenyl).
Reference in the present specification to heterocyclic groups means groups containing one or more, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benz

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