WO2003053989A1

WO2003053989A1 - Masked phosphate containing nucleoside derivatives and their use as antivirals

Info

Publication number: WO2003053989A1
Application number: PCT/EP2002/014203
Authority: WO
Inventors: Albert Stanley Tyms; Christopher Mcguigan
Original assignee: Mrc Technology Limited
Priority date: 2001-12-13
Filing date: 2002-12-13
Publication date: 2003-07-03
Also published as: AU2002366736A1; GB0129945D0

Abstract

A compound of general formula [masked phosphate] - [sugar] - B in which B is selected from an optionally substituted cyclopentyl, pyrrolyl, diazolyl, triazolyl, indenyl, indolyl, indazolyl or benzotriazolyl group or a pharmaceutically acceptable derivative or metabolite thereof, and the compound in combination with a pharmaceutically acceptable excipient, pharmaceutical compositions containing the compound, the use of the compound in therapy/prophylaxis, for example where the use therapy/prophylaxis of viral infection, particularly in relation to infection by human immunodeficiency virus (HIV). Optional substituents for the compound include H, N02, CO, COR15, OR15, CN, O, CON(R15) 2, COO R15, S02 R15, S03 R15, SR15, NHCHO, (CH2) n N(R15) 2 or halogen where R15 is H or hydrocarbyl and n is 0, 1, 2, 3 or 4.

Description

MASKED PHOSPHATE CONTAINING NUCLEOSIDE DERIVATIVES AND THEIR USE AS ANTTVIRALS

Field of the invention

The present invention relates to a particular class of nucieoside analogues and their therapeutic and prophylactic use, for example in the therapy and prophylaxis of viral infection, particularly in relation to infection by human immunodeficiency virus (HIV), the aetiological agent of acquired immunodeficiency syndrome (AIDS).

Background to the invention There has been much interest in the use of nucieoside analogues as inhibitors of HIV. For example, 2',3'-dideoxy-2',3'- didehydrothymidine (d4T) and 3'-azido-3'-deoxythymidine (AZT) are both known inhibitors of the virus.

The inhibition of HIV by these, and other nucieoside analogues, appears to depend upon conversion of the nucieoside analogue in vivo to the corresponding 5'-triphosphate by endogenous kinase enzymes.

The absolute dependence upon endogenous host-ceil kinases to mediate activation of administered antiviral nucieoside analogues places constraints upon the structures of nucieoside analogues which can be activated. Nucieoside analogues which fall outside these strict constraints will be inactive, even if their 5'-triphosphates are potent and selective inhibitors of a viral target, such as reverse transcriptase (RT).

Thus, the dependence upon endogenous host-cell kinases to mediate activation can lead to poor activity, the emergence of resistance, and clinical toxicity.

If nucleotides could be efficiently delivered intraceliularly, the endogenous nucieoside kinase would be by-passed and the structural constraints such host enzymes impose would be obviated. In this way, wider structural variation of the nucieoside analogue would be permitted, and more specific (less toxic) inhibitors of viral function could be developed and exploited.

However, polar (charged) free nucleotides exhibit extremely poor membrane penetration.

This problem has been addressed by masking the phosphate group (McGuigan, C, Nicholls, S.R., O'Connor, T.J. and Kinchington, D. (1990) Synthesis of some novel dialkyl phosphate derivatives of 3'-modified nucleosides as potential anti-AIDS drugs. Antiviral Chem. Chemother. 1, 25-33). Here, inactive phosphate derivatives of the parent nucieoside analogue having "masked phosphates" penetrate the cell membrane and liberate the bio- active nucleotides intraceliularly. In this way, the endogenous kinases have been by-passed and delivery of nucleotide analogues intraceliularly has been achieved using several highly modified 3'-substituted nucleosides (McGuigan, C, Kinchington, D., Wang, M.F., Nicholls, S.R., Nickson, C, Galpin, S., Jeffries, D.J. and O'Connor, T.J. (1993) Nucieoside analogues previously found to be inactive against HIV may be activated by simple chemical phosphorylation. FEBS Lett. 322, 249-252; McGuigan, C, Kinchington, D., Nicholls, S.R., Nickson, C. and O'Connor, T.J. (1993) Kinase bypass: a new strategy for anti-HIV drug design. BioMed. Chem. Lett. 3, 1207-1210).

This "kinase by-pass" approach is further developed in W096/29336, which describes a particular class of nucieoside analogues having "masked phosphate" moieties. The analogues are highly potent viral inhibitors in both TX and TK+ cells, and yet retain activity against nucieoside (e.g. d4T) - resistant virus.

The masked phosphate kinase by-pass approach has now been extended to several nucieoside analogues which have modifications in the base region.

Summary of the invention

According to the present invention there is provided a compound of general formula: [masked phosphate] - [sugar] - B, wherein B is

wherein X⁷, X⁸ and X⁹ are the same or different and each is C or N, when X⁹ is N then there is no R¹⁴ group;

R ³ and R¹⁴ are the same or different and each is H, N0₂, CO, COR¹⁵, OR¹⁵, CN, O, CON(R¹⁵)₂, COOR¹³, S0₂R¹⁵, S0₃R^1S, SR¹⁵, NHCHO, (CH₂)_πN(R ⁵)_z or halogen;

R¹⁵ is H or hydrocarbyl;

n is O, 1 , 2, 3 or 4;

or a pharmaceutically acceptable derivative or metabolite thereof. As used herein, the term "masked phosphate" means an analogue or derivative of a phosphate group which has been modified such that it is membrane permeable (i.e. can enter mammalian cells by crossing the cell membrane). Preferably, the masked phosphate groups comprise phosphoramidate derivatives (e.g. aryloxy phosphoramidates).

As used herein, the term "sugar" means any sugar (or sugar analogue) and includes natural sugars (such as ribose and deoxyribose) as well as non-natural sugars.

Preferably, the sugar moiety is

wherein

X may be absent or is CH₂; X^s may be absent or is CH₂;

Q is selected from 0, NR⁶, S, CR⁶R⁷, CR^SW³ and C V , where R⁸ and R⁷ are independently selected from hydrogen, alkyl and aryl groups; and W³ and

W⁴ are heteroatoms;

T¹ and T² are independently selected from hydrogen and CH₂R⁸, where R⁸ is selected from H, OH and F; or T¹ and T² are linked together and together are selected from the groups:

\ / \ / c=c and R 10 . C — C ; R 11

\

/ \

•-

H H R⁹ R 12

where R⁹, R¹⁰, R¹\ R¹² are independently selected from H, OH, N₃, halogen, CN, NH₂, CO-alkyl and alkyl.

Preferably, the masked phosphate moiety is Ar — O — —

wherein Ar is an aryl group;

Y is oxygen or sulphur;

X¹ is selected from O, NR³, S, CR³R⁴, CR³W¹ and C ¹W² where R³ and R⁴ are independently selected from hydrogen, alkyl and aryl groups; and W¹ and

W² are heteroatoms;

X² may be absent or selected (independently of X¹) from O, NR³, S, CR³R⁴, CRW and CW¹W² where R³ and R⁴ are independently selected from hydrogen, alkyl and aryl groups; and W¹ and W² are heteroatoms;

X³ is a C-,.₆ alkyl group;

X /4 i :s oxygen or CH₂;

Z is selected from O, NR^S, S, alkyl and aryl groups, where R^s is selected from hydrogen, alkyl and aryl groups;

J is selected from hydrogen, alkyl, aryl, heterocyclic and polycyclic groups.

According to another aspect of the invention there is provided a compound of the formula (1)

wherein Ar is an aryl group;

Y is oxygen or sulphur;

X¹ is selected from O, NR³, S, CR³R⁴, CR³W¹ and CW¹W² where R³ and R⁴ are independently selected from hydrogen, alkyl and aryl groups; and W and W² are heteroatoms;

X²-X⁶ may be absent; or X⁶ is CH₂ and X² is selected (independently of X¹) from 0, NR³, S, CR³R⁴, CR³W¹ and CW¹W² where R³ and R⁴ are independently selected from hydrogen, alkyl and aryl groups; and W¹ and W² are heteroatoms;

X³ is a d-s alkyl group;

X is oxygen or CH₂;

X⁵ may be absent or is CH₂;

Z is selected from O, NR⁵, S, alkyl and aryl groups, where R⁵ is selected from hydrogen, alkyl and aryl groups;

J is selected from hydrogen, alky!, aryl, heterocyclic and polycyclic groups;

Q Is selected from O, NR⁶, S, CR^SR⁷, CR^SW³ and CW³W , where R⁶ and R⁷ are independently selected from hydrogen, alkyl and aryl groups; and W³ and W⁴ are heteroatoms; T¹ and T² are independently selected from hydrogen and CH₂R⁸, where R⁸ is selected from H, OH and F; or T¹ and T² are linked together and together are selected from the groups:

where R⁹, R¹⁰, R¹ⁱ, R¹² are independently selected from H, OH, N₃, halogen, CN, NH₂, CO-alkyl and alkyl;

wherein B is

wherein X⁷, X⁸ and X⁹ are the same or different and each is C or N, when X⁹ is N then there is no R ⁴ group;

R¹³ and R¹⁴ are the same or different and each is H, N0₂, CO, COR¹⁵, OR¹⁵, CN, O, CON(R¹⁵)₂, COOR¹⁵, S0₂R¹⁵, S0₃R¹⁵, SR^1S, NHCHO, (CH₂)_nN(R¹⁵)₂ or halogen;

R¹⁵ is H or hydrocarbyl;

n is O, 1, 2, 3 or 4;

or a pharmaceutically acceptable derivative or metabolite thereof.

Thus the compounds of the invention may contain modified pyrrole, indole, imidazoie (including e.g. benzimidazole) or indazole units in place of the natural nucleic acid bases and it is a surprising feature of the invention that the masked (i.e. phosphoramidated) nucieoside analogues containing these unusual bases (which in some cases are entirely devoid of biological activity) may exhibit selective antiviral activity at levels as low as 1μM.

Reference in the present specification to an alkyl group means a branched or unbraπched, cyclic or acyclic, saturated or unsaturated (e.g. aikenyl or alkynyl) hydrocarbyl radical. Where cyclic, the alkyl group is- referably C₃ to C₁₂, more preferably C_s to Cι_0l more preferably C₅ to C₇.

Where acyclic, the alkyl group is preferably Ci to C _6l more preferably Ci to C₆, more preferably methyl. Reference in the present specification to alkoxy and aryloxy groups means alkyl-O- and aryl-O- groups, respectively. Reference to alkoyl 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 1 substituent. Substituents may include halogen atoms and halomethyl groups such as CF₃ and CCI₃; oxygen containing groups such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkoyi, alkoyioxy, aryloxy, aryloyl and aryloyloxy; nitrogen containing groups such as amino, alkylamino, dialkylamino, cyano, azide and nitro; sulphur containing groups such as thiol, alkylthiol, sulphonyl and sulphoxide; heterocyclic groups which may themselves be substituted; alkyl groups, which may themselves be substituted; and aryl groups, which may themselves be substituted, such as phenyl and substituted phenyl. Alkyl includes substituted and unsubstituted benzyl.

Reference in the present specification to heterocyclic groups means groups containing one or more, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imida∑olidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, cou arinyl, isocoumarinyl, quinolyl, isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl and carbolinyl. References in the present specification to polycyclic groups means a group comprising two or more non-aromatic carbcyclic or heterocyclic rings which may themselves be substituted.

Reference in the present specification to halogen means a fluorine, chlorine, bromine or iodine radical, preferably fluorine or chlorine radical.

The group Ar comprises a substituted or unsubstituted aryl group, wherein the term "aryl group" and the possible substitution of said group is as defined above. Preferably, Ar is a substituted or unsubstituted phenyl group. Particularly preferred substituents are electron withdrawing groups such as halogen (preferably chlorine or fluorine), trihalomethyl (preferably trifluoromethyl), cyano and nitro groups. Preferably, Ar is phenyl, 3^5-dichloro-phenyl, β- trifluoromethyl-phenyl, p.-cyano-phenyl, or £-nitro-phenyl.

Y may be oxygen or sulphur. Preferably, Y is oxygen.

Preferably, X¹ is selected from 0,S and NR³. Preferably, X¹ is NR³. When present, R³ is preferably H. When present, W¹ and W² may independently comprise any heteroatom such as a halogen, preferably fluorine.

When present, X² is preferably oxygen. When present, R³ is preferably H. When present W¹ and W² may independently comprise any heteroatom such as halogen, preferably fluorine.

Preferably, X⁴ is oxygen.

Preferably, Z is O or NR⁵. Preferably, R⁵ is hydrogen. Most preferably, Z is oxygen.

Preferably, J is a substituted or unsubstituted alkyl group. Preferably, J is a substituted or unsubstituted

alkyl group, preferably a benzyl or methyl group.

X³ may be a Cι.₆ substituted or unsubstituted, branched or unbranched, methylene chain. Preferably, X³ is a group CR¹R² where R¹ and R² are independently selected from hydrogen, alkyl and aryl groups. Preferably, at least one of R¹ and R² is hydrogen. It will be appreciated that if R¹ and R² are different, the carbon atom to which they are bonded is an asymmetric centre. The stereochemistry at this site may be R or S or mixed. When one of R³ and R⁴ is hydrogen, the stereochemistry is preferably S.

Where present in Q, W2 and W3 are preferably halogen atoms, preferably fluorine. Preferably, Q is O, S, CH or CF₂. Most preferably, Q is oxygen. When present in T¹ and T², R⁹ is H or F and/or R ⁰, R¹¹ and R¹² are independently selected from H, F and N₃. It will be appreciated that R⁹ corresponds to the 3' - α position and R¹⁰ corresponds to the 3' - β> position.

Preferably, T¹ and T² are linked together and together form the group:

Preferably, Y is oxygen, X is NH, X is CHR , X is oxygen and Z is oxygen

It will be appreciated that the group -NH- CHR¹-C0₂J corresponds to a carboxy-protected α- amino acid. Preferably, the group R¹ corresponds to the side chain of a naturally occurring amino acid such as Alanine, Arginine, Asparagine, Aspartic Acid, Cysteine, Cystine, Glycine, Glutamic Acid, Glutamine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine. Preferably, R¹ is Me or PhCH₂ corresponding to the side chain of alanine or phenylalanine, respectively. Preferably, the stereochemistry at the asymmetric centre -CHR¹- corresponds to an L-amino acid.

According to one preferred embodiment, the present invention provides a compound of formula (3):

I

Z — J

wherein Ar, Y, X¹, X², X³, X⁴, Z, Q and B are as defined above.

More preferably, the invention provides a compound, according to formula (3), of formula (4):

wherein Ar, R¹ and J are as defined above; or a pharmaceutically acceptable derivative or metabolite thereof.

Preferably, the invention provides a compound of formula (4) in which Ar, R¹ and J are defined in accordance with Table 1.

Table 1

According to another preferred embodiment, the present invention provides a compound of formula (5)

wherein Ar, Y, X¹, X², X³, X⁴, Z, J, R⁹, R¹⁰, ¹¹, R¹², Q and B are as defined above.

More preferably, the invention provides a compound, according to formula (5), of formula (6):

wherein Ar, R¹, J, R⁹, R¹⁰, R¹¹, R¹²and B are as defined above,

According to a further preferred embodiment, the present invention provides a compound of formula (7):

wherein Ar, Y, X¹, X³, X⁴, Z, J, Q and B are as defined above and T¹ and T² are independently selected from H and CH₂R⁸ wherein R⁸ is as defined above. Preferably, T¹ is hydrogen. Preferably, T² is CH₂R⁸.

More preferably, the invention provides a compound, according to formula (7), of formula (8):

wherein Ar, R¹, J, T¹, T² and B are as defined above.

It is a feature of the compounds of the present invention that they exhibit significantly enhanced anti-viral efficacy, in both in vitro and in vivo tests, in comparison to their corresponding nucieoside analogue (9)

In addition, the compounds of the present invention exhibit significantly reduced toxicity in comparison to their corresponding analogue (9). The compounds of the present invention thus exhibit a greatly enhanced selectivity index (ratio of CC (toxicity) : EC₅₀ (activity)) in comparison to their corresponding nucieoside analogue.

The compounds of the present invention may also yield enhanced intracellular levels of nucieoside δ'-triphosphate, the enhancement being particularly significant in TX cells. Thus, the compounds of the present invention may act in part by the known metabolic pathway.

However, it has been found that the compounds of the present invention may also show surprising activity against nucieoside resistant strains of HIV. This indicates that the compounds of the present invention may also act by a pathway independent of a 5'- triphosphate metabolite.

Preferably, in B

(a) X⁷ and X⁹ are C and X⁸ is N; or

(b) R¹³ is H, X⁸ and X⁹ are N and X⁷ is C; or

(c) R¹³ is H, R¹⁴ is N0₂, X⁷ is C and X⁸ is N.

Examples of preferred moieties B are:

Other examples of B are 3 -amιnoethyl-5-nitroindole and 3-aminomethyl-4-carboxamido pyrrole. The compounds of the invention described above lead to intracellular generation of high levels of a metabolite (10). Thus, according to another aspect of the invention there is provided a compound of formula (10)

Y

wherein Ar, Y, X¹, X², X³, X⁴, X⁵, T¹, T², Q and B are as defined above, or a pharmaceutically acceptable derivative or metabolite thereof.

Metabolite (10) may also be prepared by treatment of the corresponding compound according to formula (1) with hog liver esterase.

Compounds of formula (10) may be direct inhibitors of reverse transcriptase from HIV.

The intracellular generation of anti-viral metabolites such as (10) is an important feature of the invention for several reasons. Firstly, the direct activity of (10) on RT removes the necessity for further nucleotide-kinase mediated phosphorylation, which may be slow in many cases. In cases where the nucieoside monophosphate is not a substrate for host nucleotide kinases, activation will be poor and antiviral efficacy low, even if the triphosphate is an excellent RT inhibitor. In such cases, the generation of metabolites such as (10) may lead to a very significant enhancement in antiviral action. Such compounds may be acting directly in their own right or via a rearrangement, decomposition or disproportionation product or via a contaminant.

Moreover, the structure of metabolites such as (10) may be further designed to optimise binding to the known structure of RT, and such modified metabolites could be delivered intraceliularly using technology herein described, to further enhance the anti-viral effect.

By "a pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, ester or salt of such ester or any other compound which upon administration to a recipient is capable of providing (directly or indirectly) a compound of the invention (e.g. a compound of formula (1) or (10)).

By "pharmaceutically acceptable metabolite" is meant a metabolite or residue of a compound of the invention (e.g. a compound of formula (1) or (10)) which gives rise to a nucleoside- resistance independent or nucieoside 5'-triphosphate independent mode of reverse transcriptase inhibition exhibited by the compounds of the invention.

Medical applications The compounds of the invention find application in medicine, for example in methods of therapy and/or prophylaxis.

Thus, according to a further aspect of the present invention the compound of the invention is provided in combination with a pharmaceutically acceptable excipient. Any suitable excipient may be used, including for example inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc.

In a further aspect, the invention provides a pharmaceutical composition comprising the compound of the invention. The pharmaceutical composition may take any suitable form, and includes for example tablets, elixirs, capsules, solutions, suspensions, powders, granules and aerosols. The pharmaceutical composition may take the form of a kit of parts, which kit may comprise the compound of the invention together with instructions for use. The pharmaceuticals of the invention may also comprise the compound of the invention in association (e.g. in admixture or co-packaged with) an adjunctive therapeutic. The adjunctive therapeutic may comprise an antiviral compound. In any of the foregoing pharmaceutical compositions, the compound of the invention may be present in unit dosage form.

In yet another aspect, there is provided a compound according to the invention for use in medicine, for example in therapy or prophylaxis.

According to a further aspect of the invention there is provided the use of a compound of the invention for the manufacture of a medicament for use in therapy or prophylaxis.

In a yet further aspect of the invention, there is provided a process for the manufacture of a medicament for use in therapy or prophylaxis characterized in the use of a compound of the invention (e.g. as an active ingredient). In another aspect, the invention provides a method of therapy, prophylaxis or diagnosis comprising administration to a patient an effective dose of a compound according to the invention.

Preferably, the therapy or prophylaxis is the therapy or prophylaxis of a viral infection.

The viral infection may comprise any viral infection such as herpes virus (including HSV 1 and

HSV 2), CMV, VZV, EBV, HAV, HBV, HCV, HDV, papillo a, rabies and influenza.

In particularly preferred embodiments the viral infection is an HIV infection, including for example HIV-l or HIV-II: it is a feature of the present invention that the compounds exhibit good activity against both HIV-l and HIV-ll. Thus, the invention finds application in the treatment or prevention of AIDS.

Without wishing to be bound by any theory, it is thought that the medical applications of the present invention rest on the ability of the compounds of the invention to inhibit reverse transcriptase. In particular, the compounds of the invention appear to inhibit reverse transcriptase in a nucleoside-resistance independent or nucieoside δ'-triphosphate independent manner.

Thus, according to a further aspect of the present invention there is provided use of a compound of the present invention in the manufacture of a medicament for use in the inhibition of a reverse transcriptase by a nucleoside-resistance independent or nucieoside δ'- triphosphate independent mode of action.

According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the present invention in combination with a pharmaceutically acceptable excipient.

According to a further aspect of the present invention there is provided a method of preparing a pharmaceutical composition comprising the step of continuing a compound of of the present invention with a pharmaceutically acceptable excipient.

The medicaments employed in the present invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.

For oral administration, the compounds of the invention will generally be provided in the form of tablets or capsules, as a powder or granules, or as an aqueous solution or suspension. Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.

Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a saiicylate.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.

Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p- hydroxybenzoate.

The compounds of the invention may also be presented as liposome formulations.

In general a suitable dose will be in the range of 0.1 to 300 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 150 mg per kilogram body weight per day and most preferably in the range 15 to 100 mg per kilogram body weight per day. The desired dose is preferably presented as two, three, four, five or six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1500 mg, preferably 20 to 1000 mg, and most preferably 50 to 700 mg of active ingredient per unit dosage form. According to a further aspect of the present invention there is provided a process for the preparation of a compound according to the present invention, the process comprising reaction of a compound of formula (11)

with a compound of formula (12)

Ar — O — P — CI

(12) X I,³ c = x⁴

I

Z — J

The reaction may be carried out in the tetrahydrofuran in the presence of N-methylimida∑ole.

Alternatively, the compounds of the present invention may be prepared by reaction of a compound of formula (13) or a suitable derivative thereof

with ArOH and a compound of formula (14) or suitable derivatives thereof

The invention will now be described with reference to the following exemplary embodiments, which are purely illustrative and not intended to be limiting in any way. It will be appreciated that modifications to detail may be made whilst still falling within the scope of the invention.

Examplification

The synthetic strategy used for the preparation of the aryloxy phosphoramidates closely follows published procedures (McGuigan, C, Pathirana, R.N., Mahmood, N., Devine, K.G. and Hay, A.J. (1992) Aryl phosphate derivatives of AZT retain activity against HIV1 in cell lines which are resistant to the action of AZT. Antiviral Res. 17, 311-321; McGuigan, C, Pathirana, R.N., Balzarini, J., and De Clercq, E. (1993) Intracellular delivery of bio-active AZT nucleotides by aryl phosphate derivatives of AZT. J. Med. Chem. 36, 1048-1052).

The procedure involves the initial preparation of the appropriate phosphorochloridate from phenyl phosphorodichloridate and an a ine, followed by its reaction with the parent nucieoside analogue. Thus, reaction of the phenyl methylalaninyl phosphorochloridate with pyrrole nucieoside analogue (Loakes, D. and Brown, D.M. (1994) 5-Nitroindole as a universal base analogue. Nucleic Acids Res. 22, 4039-4043) in THF containing N-methylimidazole gave [2] in moderate yield after purification by column chromatography. This was isolated as a mixture of diastereoisomers, as evidenced by the presence of two closely spaced signals in the P-31 NMR [δ_P ca. 4 ppm] - this arising from mixed stereochemistry at the phosphorus centre. The presence of these isomers was further confirmed in the H-1 NMR spectrum, where the signal due to the carboxyl-methyl group showed extra multiplicity. Carbon-13 NMR data also confirmed the structure, purity, and isomeric nature of [2].

The synthetic route to [2] is shown in Scheme 2.

Similarly prepared and derivatised was the benzimidazole nucieoside [3] and its phosphoramidate [4], which is shown in Scheme 1.

Ail spectroscopic data fully confirmed the structure and purity of these materials, in each case again being isolated as mixtures of diastereoisomers about the phosphorus centre. All samples were pure by HPLC, and entirely free of any contaminating nucieoside. The antiviral activities of compounds [1] - [4] were evaluated in MT4 and C8166 T-cell lines infected with HIV-1 RF using the MTT cell viability assay or P24 reduction assay (Tables 2 and 3).

Table 2: anti HIV-1 activity and cytotoxicity of indole and pyrrole nucleosides and nucleotides in MT-4 cells using MTT cell viability assay

In Table 2, the data show the 50% effective dose (EC₅₀) and 50% cytotoxic dose (CC₅₀) for the nucleosides and nucleotides 1-4 for HIV-1 _RF in MT-4 cells using the MTT cell viability assay.

Table 3: anti HIV-1 activity of indole and pyrrole nucleosides and nucleotides in C8166 T-cells using p24 reduction assay

In Table 3, the data show the 50% effective dose (EC₅₀) for the nucleosides and nucleotides 1-4 for HIV-1 R_F in C8166 T-cells using a p24 reduction assay.

The parent nucieoside analogues [1] and [3] were noted to be non-active against HIV-1 at the concentrations tested , with EC_S0 values of >100μM.

On the other hand, it is notable that the phosphoramidates are active at μM concentrations. The methylalaninyl phosphoramidate derivative of 3-nitropyrrole [2] showed activity with an EC₅₀ of 7.3 μM ± 2.8 μM and a CC₅₀ of 112 μM; giving it a selectivity index (SI) of 15.3 in MT- 4 cells using a cell viability assay. In C8166 T-cells using a p24 reduction assay, this compound gave an EC₅₀ of 1.5 μM.

The benzimidazole phosphoramidate [4] showed similar activity.with an EC≤o of 6.5 μM ±2.8 μM and a CC₅₀ of 60.5 μM ±6.6 μM in the MT-4 cell viability assay. The compound had an EC₅₀ of 1.0 μM in C8 66 T-cells using the p24 reduction assay. Thus, both phosphoramidates are considerably more potent than their parent nucieoside analogues [1, 3].

Thus, in conclusion the phosphoramidate derivatives of the invention are selective inhibitors of the proliferation of HIV-1 in tissue culture, whilst the parent nucieoside analogues are poorly active. This represents a further example of "kinase by-pass"; the activation of an inactive nucieoside analogue by virtue of judicious chemical phosphorylation leading to the intracellular delivery of free nucleotides and a by-pass of the dependence on nucieoside kinase-mediated activation.

Experimental methods

All experiments involving water-sensitive compounds were conducted under scrupulously dry conditions. Tetrahydrofuran was dried by heating under reflux over sodium and benzophenone followed by distillation. N-methylimidazole was purified by distillation. Nucleosides were dried by storage at elevated temperature in vacuo over P₂0₅. Proton, carbon and phosphorus Nuclear Magnetic Resonance (¹H, ¹³C, ³ P NMR) spectra were recorded on a Bruker Avance DPX spectrometer operating at 300MHz, 75.5MHz, and 121.5MHz respectively. All NMR spectra were recorded in CDCI₃ at room temperature (20^CC ±3°C). ¹H and ¹³C chemical shifts are quoted in parts per million downfield from tetramethylsilane.

J values refer to coupling constants and signal splitting patterns are described as singlet (s), broad singlet (bs), doublet (d), triplet (t), quartet (q), multiplet (m) or combinations thereof. ³¹P chemical shifts are quoted in parts per million relative to an external phosphoric acid standard. Many proton- and carbon-NMR signals were split due to the presence of [phosphate] diastereoisomers in the samples.

The mode of ionisation for mass spectroscopy unless stated was fast atom bombardment (FAB) with MNOBA as matrix. Chromatography refers to flash column chromatography and was carried out using Merck silica gel 60 (40-60 μM) as stationary phase. Thin layer chromatography was performed using Alugram SIL G/UV_2S4 aluminium backed silica gel plates. HPLC was conducted on an ACS quaternary system, using an ODS5 column and an eluant of water/acetonitrile, with 82% water 0-10 min, then a linear gradient to 20% water at 30 min, with a flow rate of 1 ml/min and detection by UV at 265 nm. General procedure for the preparation of phenyl phosphoramidates of nucieoside analogues In a round-bottomed flask provided with a magnetic stirrer and nitrogen inlet the appropriate nucieoside analogue (0.30 mmol) and N-methylimidazole (0.9 mmol) were dissolved in THF (ca. 3 ml). To this the appropriate phenyl N-alkyl phosphoryl chloride (0.36 mmol) dissolved in THF (1 ml) was added dropwise with a syringe over 5 minutes and the reaction mixture was left stirring for 14 h at ambient temperature. The mixture was dissolved in chloroform (50 ml) and washed with M HCI (20 ml), saturated NaHC0₃ (20 ml), water (20 ml), dried (MgS0₄), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica using CHCI₃-MeOH 50:1 as eluant. The title compounds were obtained as colourless oils.

l-fβ-O-nitropyrrole-l-vm-S-KN^methylalaninyl^CphenvDphosphorvπ^-deoxy-D-ribose f∑l Yield: 15.5% δ_H (CDCI₃) 1.39 (d, J = 7.0 Hz, 3H, Ala-Me), 2.25-2.60 (m, 2H, H2'), 3.73, 3.75 (2 x s, 3H, C02CH3), 4.05-4.56 (m, 6H, H3\ H4', H5\ Ala-CH, Ala-NH), 5.90 (m, H, H1"), 6.70 (dd, J = 2.2 , 2.7 Hz, 1H, pyrrole), 6.77 (dd, J = 1.9 , 2.7 Hz, 1H, pyrrole), 7.20-7.42 (m, 5H, Ph), 7.75, 7.79 (2 x dd, J = 1.9, 2.2 Hz, 1H, pyrrole); δ_c (CDCI₃) 20.64, 20.71 (Ala-Me), 41.07, 41.15 (C2'), 50.15, 50.23 (Ala-CH), 52.60, 52.66 (C0₂CH₃), 65.53, 65.59, 65.86, 65.94 (2 x d, C5'), 70.27, 70.54 (C3¹), 84.85, 84.94, 85.15, 85.24 (2 x d, C4'), 88.11, 88.36 (Cf), 105.90-120.05 (pyrrole), 125.24-129.84 (Ph), 137.42 (pyrrole), 150.34, 150.43 (Ph-ipso), 173.84, 173.89, 174.9 (C=0); δ_P (CDCI₃) 4.21, 4.57 (2:3); FAB MS m/e 470.1328 (MH⁺, C₁₉H₂₅N₃0₉P requires 470.1328, 14%); HPLC (RT) 27.17 min.

General procedure for glvcosidation via a furanoid glycal intermediate

To a stirred mixture of the corresponding heterocyclic base (1.39 mmol) in dry CH₂Cl₂ (10 mL) 2 eq of Λ/,0-bis (trimethylsilyl)acetamide (2.78 mmol) were added and the mixture was heated to reflux until the solution became clear (30 - 60 min). After allowing to cool to room temperature a solution of the furanoid glycal SV-2b-6 (0.20g, 1.16 mmol) in CH₂CI₂ (2mL) and approximately 300 mg of 4A powdered molecular sieves were added to the previous sylilated base solution. The resulting mixture was stirred for 15 min at room temperature, cooled to - 20°C and then N-iodosuccinimide (0.313 g, 1.39 mmol) was added. After being stirred for 1h, the mixture was filtered and ethyl acetate (50 mL) and 10% aqueous Na₂S₂0₃ (50 mL) were added. The organic phase was removed and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organics were dried (MgS0₄) and concentrated. The residue was purified by column chromatography (hex/ethyl acetate, 1:1) to give the corresponding 2'-iodonucleosides.

1-(2',3'-dideoxy-2'-iodo-5'-0-(pivalovπ-β-D-ribofuranosvi) benzimidazole Following the general procedure benzimidazole (0.165g, 1.39 mmol) was silylated with Λ/.O- bis (trimethylsilyl)acetamide (0.69 mL, 2.78 mmol) for 30 min and then reacted with the glycal (0.20g, 1.16 mmol) and N-iodosuccinimide (0.313 g, 1.39 mmol) for 1h. The residue, a mixture 10/1 of the b/a anomers (determined by ¹HNMR of the crude), was purified by column chromatography (hex ethyl acetate, 1:1). The fastest moving band gave the b-isomer (SV-2b- 36a) as a yellow foam (0,225g, 51 %).

¹HNMR (CDCI₃) 8.20 (1H, s, H-2), 7.89-7.33 (4H, m, aromatics), 6.46 (1 H, d, H-1', J1',2'=3.4 Hz), 4.82 (1H, m, H-4¹), 4.41-4.60 (3H, m, H-2', 2H-5'), 2.49 (2H, m, 2H-3'), 1.28 (9H, s, 3CH3) MS (ES+) 451 (M+Na, base)

1 -(2',3'-dideoxy-b-D-glvcero-pent-2-enofuranosvD-benzimidazole Cf1201 [31

The iodonucleoside (0.150g, 0.36mmol) was treated with a freshly prepared solution of MeONa in MeOH (10.8 mmol=0.25g Na in 10 mL MeOH) at room temperature for 6h. The reaction mixture was carefully neutralized with HCHN-MeOH and concentrated to dryness.

The residue was purified by column chromatography (CH₂CI₂/MeOH, 10:1) to afford (SV-2b-

37) (0.058g, 92%) as a white foam.

¹HNMR (CDCI₃) 8.01 (1H, s, H-2), 7.58-7.08 (4H, m, aromatics), 6.80 (1H, m, H-1'), 4.42 (1H, m, H-3'), 6.01 (1H, , H-2'), 5.00 (1H, m, H-4'), 3.86 (1H, m, H-5', J4',5'=3.1, J5',5'=12.5 Hz),

3.70 (1H, m, H-5', J4',5'=3.6 Hz).

¹³CNMR (CDCI₃) 142.92, 132.98 (C-4.C-5), 141.54 (C-2), 134.98 (C-3'), 125.09 (C-2'),

123.14, 122.41, 119.98, 109.78 (aromatics), 89.29, 88.36 (C-1', C-4'), 63.02 (C-5').

MS(ES+) 239 (M+Na, base). C₁₂H₁₂N₂ HPLC RT 12.71 (acetonitrile/water, 55/45)

1-(2',3'-dideoxy-5'-(phenylmethoxyalaninylphosphate)-β-D-qlvcero-pent-2-enofuranosyπ benzimidazol Cf1210 f41

Phenyl methoxyalaninyl phosphorochloridate (0.574 mmoles, 2.0 equiv) was added to a stirred solution of [3] (O.Oδg, 0.287 mmoles) and N-methylimidazole (137 μl, 1.72 mmoles, 6 equiv) in dry THF (2 mL) at ambient temperature. After 3 h water was added and the solvent removed under pressure. The residue was dissolved in CHCI₃ (10 mL), washed with 1 HCI (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried (MgS0₄) and the solvent removed in vacuo. The residue was purified by chromatotron (CH₂CI₂/MeOH, 20:1) to give SV2b63 (66 mg, 56%) as a white foam. ³¹PNMR 4.52, 4.27 (1:1)

¹HNMR (CDCI₃) 8.50, 8.30 (1H, s, H-2), 7.95-6.98 (10H, m, Aromatics, H-1'), 6.55, 6.43 (1H, m, H-3'), 6.25, 6.19 (1H, m, H-2'), 5.15 (1H, m, H-4'), 4.24 (2H, m, 2H-5'), 4.06 (1H, m, Ala- CH), 3.76 (1H, m, Ala-NH), 3.62,3.65 (3H, s, Ala-OCH3), 1.02, 1.35 (3H, d, Ala-CH3, J=7.0 Hz).

¹³CNMR (CDCI₃) 173.83, 173.74 (C02Me), 150.53, 150.45, 150.36 (Phipso-POPh), 141.22, 141.05, 132.63, 124,09, 123.83, 123.58, 119.68, 119.46, 110.57, 110.41 (Aromatics-Bzi), 134.31, 133.99 (C-3'), 129.63, 129.55 (Phmeta-POPh), 125.80, 125.77 (C-2'), 124.87, 124.30 (Phpara-OPh), 120.30, 120.22, 120.16 (d, Phorto-POPh, J_P,_C=5.5, 5.1 Hz), 89.91, 89.80 (C- 1'), 85.84, 85.79, 85.73, 85.67 (d, C-4", J_P,c=4.2, 4.4 Hz), 66.90, 66.83, 66.34, 66.28 (d, C-5', J_P,c=5.5, 4.5 Hz), 52.39, 52.33 (Ala-OCH3), 50.30, 49.98 (Ala-CH), 20.59, 20.53, 20.30, 20.23 (d, Ala-CH3, J_P,_C=4.4, 5.1 Hz). MS(ES+) 480 (M+Na, base) C₂₂H₂₄N₃0₆P requires 457.426 HPLC RT 26.03, 26.45

Antiviral Assays

The anti-HIV-1 activities and toxicities of compounds were assessed in MT-4 cells using the MTT cell viability assay as previously described (Pauwels, R., Bal∑arini, J., Schols, D., Baba, M., Desmyter, J., Rosenberg, I., Holy, A., and De Clercq, E. (1988) Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J. Virol. Methods, 20, 309-321).

Briefly, MT-4 cells were infected for 1h at room temperature at low multiplicity. The cells were then washed and distributed into triplicate wells of 96-well cell culture plates, containing different concentrations of test compounds, or no compound, at a concentration of 5 x 104 cells per well. The plates were incubated at 37°C for 6 days and then cell viability was assessed by adding 10 μl of MTT (7.5 mg/ml) in PBS to each well, and then incubating the plates for an additional hour. The formazan crystals which formed were solubilised by adding 100 μl of acidified isopropanol to each well and mixing. The absorbance was read at 540 nm, and dose-response curves of OD versus drug concentration were plotted. Cytotoxicity was assesssed in parallel by culturing uninfected ceils in the same concentrations as test compounds.

Anti-HIV activity was confirmed in C8166 T-cells infected with HIV-1 RF using a p24 reduction assay. Briefly, C8166 cells were infected with HIV-1 RF at low multiplicity for 2h at room temperature. The cells were then washed 3 times, distributed into wells of 48-well cell culture plates containing different concentrations of test compound, or no compound, and incubated at 37°C. After 3 days, the cell-free culture fluid was harvested and assayed for levels of viral p24 antigen using a commercially available ELISA (Murex), according to the manufacturer's instructions. Dose-reponse curves were plotted of p24 (% inhibition compared with untreated controls) versus drug concentration.

Equivalents

The foregoing descriptions detail presently preferred embodiments of the present invention. Numerous modifications and variations in practice thereof are expected to occur to those skilled in the art upon consideration of these descriptions. Those modifications and variations are intended to be encompassed within the claims appended hereto. Scheme 1: Cf1201 and Cf 1210 synthesis

Cf 1210 28% Scheme 2. C1073 and Cf 1105 synthesis

Claims

CLAIMS:

1. A compound of general formula:

[masked phosphate] - [sugar] - B

wherein B is

wherein X , X and X are the same or different and each is C or N, when X is N then there is no R¹⁴ group;

R¹³ and R¹⁴ are the same or different and each is H, N0₂, CO, COR¹⁵, OR¹⁵, CCNN,, OO,, CCOONN(R¹⁵)₂, COOR¹⁵, S0₂R¹⁵, S0₃R¹⁵, SR¹⁵, NHCHO, (CH₂)_nN(R¹⁵)₂ or halogen;

R¹⁵ is H or hydrocarbyl;

n is 0, 1, 2, 3 or 4;

or a pharmaceutically acceptable derivative or metabolite thereof.

2. A compound according to claim 1 wherein the sugar moiety is

X^s X⁵—

wherein

X^s may be absent or is CH₂; X^s may be absent or is CH₂; Q is selected from 0, NR⁶, S, CR^SR⁷, CR⁶W³ and CWV , where R^e and R⁷ are independently selected from hydrogen, alkyl and aryl groups; and W³ and ⁴ are heteroatoms;

T¹ and T² are independently selected from hydrogen and CH₂R^S, where R⁸ is selected from H, OH and F; or T¹ and T² are linked together and together are selected from the groups:

\ / \ / C = C and R¹⁰ - C — C —« R¹¹

/ \ / \

H H R⁹ R¹²

where R⁹, R¹⁰, R¹¹, R¹² are independently selected from H, OH, N₃, halogen, CN, NH₂, CO-aikyl and alkyl.

3. A compound according to claim 1 or claim 2 wherein the masked phosphate moiety is

Y

II ₂

Ar — O — P — X²-

A.

C = X⁴

Z — J

wherein Ar is an aryl group;

Y is oxygen or sulphur;

X¹ is selected from O, NR³, S, CR³R⁴, CR³W¹ and CW¹W² where R³ and R⁴ are independently selected from hydrogen, alkyl and aryl groups; and W¹ and W² are heteroatoms;

X³ is a C_.._β alkyl group;

X⁴ is oxygen or CH₂;

Z is selected from 0, NR⁵, S, alkyl and aryl groups, where R⁵ is selected from hydrogen, alkyl and aryl groups;

J is selected from hydrogen, alkyl, aryl, heterocyclic and polycyclic groups.

4. A compound of the formula (1)

C = X⁴

I

Z — J

wherein Ar is an aryl group;

Y is oxygen or sulphur;

X²-X⁶ may be absent; or X^s is CH₂ and X² is selected (independently of X¹) from O, NR³, S, CR³R⁴, CR³W¹ and CW W² where R³ and R⁴ are independently selected from hydrogen, alkyl and aryl groups; and W¹ and W² are heteroatoms

X³ is a C-,.₆ alkyl group; X⁴ is oxygen or CH₂;

X^s may be absent or is CH₂;

Z is selected from 0, NR^S, S, alkyl and aryl groups, where R⁵ is selected from hydrogen, alkyl and aryl groups;

J is selected from hydrogen, alkyl, aryl, heterocyclic and polycyclic groups;

Q is selected from O, NR⁶, S, CR⁶R⁷, CR⁶W³ and CWW , where R⁶ and R⁷ are independently selected from hydrogen, alkyl and aryl groups; and ³ and W⁴ are heteroatoms;

\ / \ / C = C and R¹⁰ *— C — C — « R¹¹

/ \

H H R⁹ >12

where R⁹, R , R¹¹, R¹² are independently selected from H, OH, N₃, halogen, CN, NH₂, CO-alkyl and alkyl;

wherein B is

wherein X⁷, X^s and X⁹ are the same or different and each is C or N, when X⁹ is N then there is no R¹⁴ group; R¹³ and R ⁴ are the same or different and each is H, N0₂, CO, COR¹⁵, OR¹⁵, CN, 0, CON(R¹⁵)₂, COOR¹⁵, S0₂R¹⁵, SO₃R¹⁵, SR¹⁵, NHCHO, (CH₂)_nN(R¹⁵)₂ or halogen;

R is H or hydrocarbyl;

n is O, 1, 2, 3 or 4;

or a pharmaceutically acceptable derivative or metabolite thereof.

5. A compound according to claim 4 wherein

Y is oxygen; X¹ is NH; X³ is CHR¹;

X⁴ is oxygen; and Z is oxygen.

6. A compound of formula (10)

wherein Y is oxygen or sulphur;

X²-X⁶ may be absent; or X⁶ is CH₂ and X^2' is selected (independently of X¹) from O, NR³, S, CR³R⁴, CR³W¹ and CW W² where R³ and R⁴ are independently selected from hydrogen, alkyl and aryl groups; and W¹ and W² are heteroatoms;

X³ is a C^e alkyl group;

X⁴ is oxygen or CH₂;

X^s may be absent or is CH₂;

Q is selected from O, NR^β, S, CR⁶R⁷, CRW and CW³W⁴ , where R⁶ and R⁷ are independently selected from hydrogen, alkyl and aryl groups; and W³ and W⁴ are heteroatoms;

T and T² are independently selected from hydrogen and CH₂R⁸, where R⁸ is selected from H, OH and F; or T¹ and T² are linked together and together are selected from the groups:

where R⁹, R¹⁰, R¹¹, R¹² are independently selected from H, OH, N₃, halogen, CN, NH₂, CO-alkyl and alkyl;

wherein B is

R¹³ and R¹⁴ are the same or different and each is H, N0₂, CO, COR¹⁵, OR¹⁵, CN, O, CON(R¹⁵)₂, COOR¹⁵, S0₂R¹⁵, S0₃R^1S, SR¹⁵, NHCHO, (CH₂)_nN(R¹⁵)₂ or halogen;

R¹⁵ is H or hydrocarbyl;

n is 0, 1, 2, 3 or 4;

or a pharmaceutically acceptable derivative or metabolite thereof.

7. A compound according to claim 6 wherein

Y is oxygen; X¹ is NH; X³ is CHR¹; and X⁴ is oxygen.

A compound of any one of claims 4 to 7 wherein

X is oxygen;

X /β° is- CH₂; Q is oxygen;

X⁵ is absent; and

T¹ and T² together comprise the group:

c = c / \

H H

9. A compound of any one of claims 4 to 7 wherein

X² is oxygen;

X⁶ is CH₂;

Q is oxygen;

X⁵ is absent; and

T¹ and T² together comprise the group:

10. A compound of any one of claims 4 to 7 wherein

X²- X⁶ is absent;

Q is oxygen; X⁵ is CH₂;

T¹ and T² are independently selected from hydrogen and CH₂R⁸ wherein R⁸ is selected from H, OH and F.

11. A compound according to any one of the preceding claims wherein in B

(d) X⁷ and X⁹ are C and X⁸ is N; or

(e) R¹³ is H, X⁸ and X⁹ are N and X⁷ is C; or

(f) R¹³ is H, R¹⁴ is N0₂, X⁷ is C and X^s is N.

12. The compound of any one of the preceding claims in combination with a pharmaceutically acceptable excipient.

13. A pharmaceutical composition comprising the compound of any one of claims 1 to 11.

14. A compound of any one of claims 1 to 11 for use in therapy or prophylaxis.

15. Use of the compound of any one of claims 1 to 11 for the manufacture of a medicament for use in therapy or prophylaxis.

16. A process for the manufacture of a medicament for use in therapy or prophylaxis characterized in the use of a compound as defined in any one of claims 1 to 11.

17. A method of therapy or prophylaxis comprising administration to a patient in need thereof an effective dose of a compound according to any one of claims 1 to 12 or composition of claim 13.

18. The compound of claim 14, use of claim 15, process of claim 16 or method of claim 17 wherein the therapy or prophylaxis is the therapy or prophylaxis of a viral infection.

19. The compound, use, process or method of claim 18 wherein the viral infection is HIV infection.

20. The compound, use, process or method of claim 19 wherein the therapy or prophylaxis is the treatment or prevention of AIDS.

21. The compound, use, process or method of any one of claims 18 to 20 wherein the therapy or prophylaxis comprises the inhibition of a reverse transcriptase.

22. The compound, use, process or method of claim 21 wherein the inhibition of reverse transcriptase is nucleoside-resistance independent or nucieoside 5'-triphosphate independent.

23. A process for the preparation of a compound according to any one of claims 1 to 11 comprising reaction of a compound of formula (11)

with a compound of formula (12)

24. The compound, use, process or method of any one of the preceding claims wherein the compound is selected from: (a) 1-(2',3'-dideoxy-5'-(phenylmethoxyalaninylphosphate)-β-D-glycero-pent-2- enofuranosyl) benzimidazol (Cf1210); and (b) 1-[^β-(3-nitropyrrole-1-yl)]-5-[(N-(methylaianinyl))(phenyi)phosphoryl]-2-deoxy-D- ribose (Cf1105).