CA2132303A1

CA2132303A1 - Antiviral phosphonic acid derivatives of purine analogues

Info

Publication number: CA2132303A1
Application number: CA002132303A
Authority: CA
Inventors: Halina Teresa Serafinowska; Michael Raymond Harnden; Stuart Bailey
Original assignee: Individual
Current assignee: SmithKline Beecham Ltd
Priority date: 1992-03-18
Filing date: 1993-03-18
Publication date: 1993-09-30
Also published as: JPH07504666A; KR950701638A; WO1993019075A1; EP0631583A1; AU3760793A; GB9205917D0

Abstract

Compounds of formula (I), or a pharmaceutically acceptable salt thereof wherein X is -CH2O, -CH2 or -CH(CH2OR6)O where R6 is hydrogen or acyl; Y is O or S; R1 is hydroxy or amino;
R2 is amino or hydrogen; R3 is hydrogen or, when X is CH2O and Y is O, R3 may be CH2OR7 where R7 is hydrogen or acyl;
and R4 and R5 are both phenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2-acetoxyphenyl or 2-methylphenyl; and their pharmaceutical use in the treatment of viral diseases.

Description

p3() .5~ 3 0 ~3 P~-~AR~ CEUTICALS

n.e present invention rel;ltes to novel compounds which ~rc ot po[~n[i~l u~ as 5 antiviral agents, [o prucesses lor Lheir prepara~ion and to their use ~s ph~rm~ccuticals.

EP-A-319228 and EP-A-353955 (Beecham Group p.l.c.) disclose a oroup of purine derivatives containing a 9-[2-(phosphoncmethoxy)alkoxy] substituent. which are described as having antiviral activity.

- EP-A-3S3955 (Ceslcoslovenska akademie ved) discloses a group of 9-(phosphonomethoxyalkyl)adenines, which are described as havin~ antiviral activity.

'Nucleotide An~looues as Antiviral Agents' ACS Symposium Series 401, Editor J.C.
15 Martin, published by the American Chemical Society, Washington DC (1989) Chapters 4 and 5 discloses, a number of (phosphonometho~yalkyl) derivatives of purines and pyrimidines and their antiviral activity.

Particular compounds of interest are adenine or guanine having a 9-substituent as 2~ follows:

(HO)2POCH20cH2cH2o- Ex.2, EP-A-319~
(HO)2POCH20CH2CH(CH20H)O- Ex.16, EP-A-206~59 (H0)2POCH20CH2CH2- PMEA/PMEG
- (H0)2POCH20CH(CH20H)c~2- HPMPA/HPMPG

It nas now been discovered that certain derivatives of these compounds are prodru~,s therefor, having improved gastrointestinal absorption properties.

`3 '`' ~c~

O 93/19075 2 ~ ' 2 3 ~ 2 - rC~ /GI;93/005~' Accordingly, ~he present invennon provides a compound of fomlula (I), or a pharmaceutically accep~able salt thereof:

o ~XN~'1R

S (I) wherein X is -CH2O, -CH2 or -CH(CH20R6)0 where R6 is hydrogen or acyl;
YisOo~S;
10 Rl is hydroxy or amino;
R2 is amino or hydrogen;
R3 is hydrogen or, when X is CH2O and Y is O, R3 may be CH20R7 where R7 is hydrogen or acyl; and R4 and Rs are both phenyl, ~bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2-lS acctoxyphenyl or 2^me~ylphenyl. :

When Rl is hydroxy and R2 is amino9 the compound of formula (~) is a guaninedcrivative;

20 When Rl is amino and R2 is hydrogen, the compound of foImula (I) is an adenine deriva~ve;

Whcn Rl is hydroxy and R2 is hydrogen, the compound of formula (1) is a h~xanthine denvahve; and 25 - ~
Whcn Rl and R2 aIe both arnino groups, thc compound of formula (1) is a 2,6 diaminopmine desivative~

Often, d~e compound of formula (I) is a guanine or adenine derivative.
R4 and Rs arc prcfesably both phenyl.

~13~3~3 93/1907' PCI /GB9.~/()O~

Suitable examples of R6/R7 when acyl include ca~>oxylic acyl, such as Cl 7 aLkanoyl and benzoyl optionally substituted in ~e phenyl nng by one, two or three groups or atoms selected from halogen, such as fluoro, chloro, bromo, and Cl 4 alkyl or Cl 4 5 aL~coxy whereln the alkyl moiety is selected from methyl, ethyl, n- and iso-propyl, n-, sec-. is~ and tert-butyl. Prefe~ed acyl groups include acetyl, propionyl, butyryl, heptanoyl and hexanoyl.

There are groups of compounds of interest wherein:
i) X is ~CH2O and R3 is hydrogen.
ii) X is -CHzO and R3 is CH20R7 as defined.
iii) X is -CH2(CH20R6)0 as defined and R3 is hydrogen.
iv) X is -CH2 and R3 is hydrogen.

v) X is -CH2 and R3 is C~H20R7 as defined.
Y is preferably O.

Examples of pharmaceutically acceptable salts of the compound of formula (I) are acid ~ddition salts formed with a phannaceu~cally acceptable acid such as hydrochloric 25 ~d, or~ophosphoric acid and sulphuric acid. Pha~naceu~acally acceptable s~ts also include ~ose fo~med with organic bases, preferably with amines, such as ethanol~es or diamines; and alkali metals, such as sodium and po~ssium.

It will be ap~ated that some o~ the compounds of formula (1), especially those 30 whercin R3 is o~er dlan hydrogen, have an asymmetric centre, and therefore are capablc of cxis~ng in more than one stereoisomeric f~nn. The inven~on extends toeach o~ thcsc f~ms individually and to mixtures thereof, including racemates. The isome~s may be scparatcd convcntionally by chromatographic methods or using a rcsohnng agent. Altematively, dle individual isomers may be prepared by asymmc~ric 35 sSmthcsis using chiral intelmediates.

Thc compounds of fc~rmula (I) including their alka.li metal salts may form solvates such as hydrates and thesc are included wherever a compound of folmula (I) or a salt thsrcof wo 93l1907~ pcrtGB9~ o~
2 ~ 3 æ 3 9 4 is herein refelTed tO.

It will be appreciated that, when Rl is hydroxy in formula (I~ the compound exists in the predominant tautomeric form of structure (LA):
S O

< X'',l R3 :
(l[A) .. , The invention also provides a process for the preparation of a compound of formula (I), 10 or a pharmaceutically acceptable salt thereof, which pr~cess comprises reacting a compound of formula ~

<
o N N R2 Cl~ll , PCH2YCH X
~1 1 with R40H and RsOH and Rl, R2, and R3 are as defined in formula (I), and thereafter optionally fo~ning a pharmaceutically acceptable salt thereof.
. . .
The reaction takes place in a suitable inert solvent such as dichloromethane at 20 tcmperatures with cooling 0 to 3C, under an inert atmosphere.

As appropriate or necessary, Rl/R2/R3 may be pr~tected. Suitable examples of protecting groups and their removal, are as described in EP-A-242482. A par~cularly suitable protecting group for R3 when other than hydrogen is the t-butyldiphenylsilyl ~.

)93/19075 - - ~ 10 .3 PCT/GB93/00560 group removable by conventional methods.

The compounds of formula (~) may be generated from the co~esponding compounds of formula (I~, but wherein R4/Rs is replaccd by an ethyl group, by trea~nent with 5 bromotrimethylsilane in dichloromethane followed by chlorina~on with PCls in dichl~methane: caIbon tetrachlo~ide.

It will bc appreciated th~t the aboYe convcrsions may takc place in any desired or neccssary order, having rcgard t~ thc final desired compound of formula (1).

Thc R4~ = edlyl compounds of the formula (1) are prepared as described in A-313289 and the aforcmentioned publications, the subject matter of which are inc~npora~ herein by rcfcrcncc.

15 Whcn R6~R7 is hydroxy, appropriate selective protection may be required, eg using acetate.
.
Pharmaceutically acceptable salts may be prepared in conventional manner, for cxample, in d~e case of acid addition salts, by reaction with the appropriate ~rganic o~
20 inorganic acid.

lt will be appreciated that the inv~ntion provides a process for the preparation of a compound of fonnula (I) wherein R6J~7 is hydrogen which process comprises the deprotection of a correspondin~ compound of f~ula (I) wherein Rg/Rg is protected25 hy~xy. Methods for deprotec~on, are conventiona~ for the protecting group conccrne~

The compounds of ~e invcnnon are of potendal use in the ~eatment of infections - caused by viruses, in pa~cular DNA viruses and ~ oviruses. Examples of DNA
30 viruses include he~pesviruses such as herpes simplex types 1 and 2, varicdla-zoster virus, Eps~ Ba~ virus and ~rtomegalo~us. Examples of retr~viruses include len~iviruses such as visna ~nrus and human imIslunodeficiency virus (strains 1 and 2).

The compounds may also be inhibitors of tumorogenic viruses and~or of potential use 35 in thc =ent of ncoplastic diseases, i.e. cancer.

WO 93/19075 PCl /ÇR93/0056' `~ 3~3~3 -6-Compounds of the invention may be fo~nulate~ for use in a pharrnaceutical composition. Accordingly, in a further aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of formula (I) or pharmaceuticaDy acceptable salt thereof together with a pharmaceutically acceptable 5 ca~Ticr or excipicn~

A composidon which may be administered by the oral route to humans may be Impoonded in thc form of a syrup, tablct o~ capsule. ~Vhen thc composition is in the foIm of a tablct, any pharmaccutical calTicr suitablc fo~ fo~mulating such solid10 c~ositions may be uscd, for examplc magncsium stearate, starch, lactosc, glucose, r,icc, flour and chall~ Ibe composidon may also be in the form of an ingcstible capsulc, for cxample of gclatin, to contaîn thc compound, or in thc fo~m of a syrup, a soludon ora suspcnsion. Suitablc liquid pharmaccutical camers include ethyl alcohol, glyc~inc, saline and watcr to which flavouring o~ colouring agents may be added to 15 form syrups. Thc compounds may also be prcscnted with a sterile liquid ca~ier for injcction.

lhc composition may also be fo~mulated for topical apph;cation to the skin or cyes.

20 For topical application to thc sl~n, the composition may be in the form of a cream, lotion o~ ointmen~ These fo~mulations may be conventional foqmulations well known in thc art, f~3r cxample, as dcscribed in standard books of pharmaccutics and cosmctics, such as Ha~y's Cosmeticology published by Lconard Hill Books and the British Pharmacopaeia Thc composition for application to the eyes may be a conventional eye-drop composition well h~own in the art, or an ointmenl composition.
Preferably, the composition of this invention is in unit dosage fo~m or in some other form ~at may be administcr~ in a single dose. A suitable dosage unit might contain 30 fr~m 50 mg to 1 g of active ingredient, for example 100 to 500 mg.

- Such doses may be ad~nisterd 1 to 4 times a day or more usually 2 or 3 dmes a day.
The cffcc~ve dose of compound will in general be in the range of from 1.0 to 20 mg/kg of body wdght pcr day or more usually 2.0 to 10 mg/lcg per day.
No unacceptablc to~icological effcctsi are indicated at the above dcscribcd dosagc lc~rcls.

393/1907s ~ 3 ~ 3 r~/GB9~/00560 The invention also provides a method of treating viral infections/diseases in a human or non-human animal, which comprises administering to the animal an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
S
Ihc invcntion also provides a compound of formula (I) or a pharmaceutically acccptablc salt dlereof for use as an active the~apcutic substance, in particular for the t~cnt of viral infections/discases`.

The compounds of the invcntion are also believed to exhibit a synergistic antiviral - ~
cffcct in conjuncdon with intcrfcrons; and combination products comprising these two ~ --- componcnts for sequcntial or concomitant administration, by the same or differcnt routcs, arc thcrcfo~c ~ithin the ambit of the present invention 15 Thc following cxamplcs illustrate the invention.
.:
,-'~'.

wo 93/19û75 ~, pcr/GB93/ou56 Examples The following compoun~ls of ~ormula (I) are prepared.
Example R1 R2 R~ R~, X Y
NH2 H H C~ 2 II NH2 H H ~Br-C~ I20 0 m NH2 H H 4-CH~,-C~ H20 0 IV N~I2 H H ~CH?,~C~H4 CH~O O
V NH2 H H 2,-CH~C02-C~H4 CH20 0 VI NH2 H H 2~ C~

In cxamples I-VI, the follo~g general synthehc pr~cedure was used:
~NH2 i)~MSBr,CH2CI2 1 2 ~N iD~ ~~ cc~ <N_lî N
~ J~ d iii)ROH.Et3N,CH2cl2~ NJ~ ~J
O N N l-met~yl~nidazole 1l I N
(EtO)21lVO l (R)2PV l R = C6H5 -~

II R = 4-Br-C6H4 m ~ = 4 cH3-C6H4 IV R = 4-CH30 C6H4 V R = 2- CH3CQ C6H4 VI R = 2-CH3-C6H4 .-.

) 93/1907~ 3 PCI /GB9?./00~i6() , ~xamples I-Vl To a solution of the diethyl ester ( 1 .45Ir~nol) in dry dichloromethane (5ml) bromotnmethylsilane (14.5mmol) was added. The reaction mixture was stiITed at RTS for 2h and the solvents were evaporated. The residue was coevaporated with drytoluene (2x5ml) and the resulting glass was dissolvcd in dry dichloromethane: carbon tetrachloridc ~.olution (3:1, lOml). Phospho¢us pentachloride (3.045mmol) was then addcd and the rcaction mixture was stirrcd at RT for 3h. The solvcnts were evaporated. ~-the rcsiduc was coevaporated with dry toluene (lxlOml). The resulting phosphonyldichloridatc dcri~rativc was suspendcd in dry dichloromcthane (lOml), the appropriate `~
aloohol (3.045mmol) was added and thc solution was coolcd to 0-3C undcr argon.Thc reaction mixture was thcn treated with triethylamine (3.625mmol) followed by 1-methylimidazole (5.8mmol), stirred at 0 -3C for lOmin and then at RT for l.Sh. The plecipitate was filtered, washed with dichloromcthane and the solvents were ~ ~ -cvaporatcd. Thc residue was coevaporated with tolucne (2x20ml), dissolved in chlorofoIm (801rd), washed succcssivcly with aqueous sodium hydrogen car'oonate (2x20ml) and water (2x20ml). The product was purified by column chromatography on silica gd dudng with chlorofonn-ethanol to give the compound examples I-VI in12-40% yicld.
Example I, R=C6Hs, 36% yield ~H t(CD3)2SO~ 3.97 (2H, m, C~20CH2P)? 4.35 (2H, d, J--7.15Hz, CH2P), 4.55 (2H, ~-m, NOCH2), 7.21-7.44 (12H, m, Ar and NH2. D20 exchangeable), 8.15 (lH, s, H-2), 8.31 (lH, s, H-8).
Found: C, 50.84; H, 4.20; N, 14.59%. C2bH20osp x 0.35 CHC13 requires C, 50.59, H, 4.24; N, 14.49%.

Example II, R=4-Br-C6H4, 31% yield ~H [(CD3)2S01 3.96 (2H, m~ CH2OCH2P), 4.38 (2H, d, J=7.42Hz, CH2P), 4.54 (2H, m, NOCH2), 7.2()-7.63 (8H, m, Ar), 7.39 ~2H, br.s, D20 cxchangeable, NH2), 8.15 (lH, s, H-2), 8.31 (lH, s, H-8).
Found: C, 38.50; H, 2.88; N, 10.84%. C2~ gNsOsPBr2 x 0.3 CHCl3 requires C, 38.4, H, 2.90, N, 10.87%.
Elcamplc m, ~CH3-C~14, 12% yield WO 93/1907-~ PCI /~ 9~/~)0~

H ((CD3)2SO] 3.31 (6H, s, CH3), 3.94 (2H, m, Ç~2ocH2p)7 4.38 (2H, d, J=7.15Hz, CH2P), 4.54 (2H, m, NOCH2), 7.08-7.21 (~H, m, Ar), 7.38 (2H, br.s, D20 exchangeable, NH2), 8.15 (lH, s, H-2), 8.31 (lH, s, H-8).
Found: M+H (C.I.) 470.1594; C22H24NsOsP requires M~H 470.1594.

Example IV, R~CH3~C6H4, 26% yield ~H [(CD3)2SO] 3.73 (6H, s, OCH3), 3.95 (2H, m, ~120C~I2P). 4.27 (2H, d, J=7.15Hz, CH2P), 4.55 (~ m, NOCH2), 6.68-7.32 (8H, m, Ar), 7.38 (2H, b~.s, D20 exchangeable, NH2), 8.15 (lH, s, 2-H), 8.33 (lH, s, 8-H).
- Found: C, 50.37; H, 5.50, N, 13.92%, M+H (C.I.) 502.1492; C22H24NsO7P x H20 - s~quires C, 50.87; H, 5.05; N, 13.48%, M+H 502.1492. ~:

Exampl~ V, R=2-CH3(~O2-C6H4, 14% S ield ~H [(CD3)2S03 2.20 (6H, s, CH3C02), 3.96 (2H, m, ~120CH2P~t 4.36 (2H, d, J=6.87H~, CH2P), 4.55 (2H, m. NOCH2), 7.27-7.84 (lOH, m, Ar and NH2, D~O
exchangeable), 8.15 (lH, s, H-23, 8.30 (lH, s, H-8).
Found: C, 50.50; H, 4.31; N, 12.21%. C24H24NsOgP x 0.1 CHCl3 requires C,50-84;H, 4.26; N, 12.30%.

Example VI, R=2-CH3-C6H4, 40% yaeld ~H 1(CD3)2S0~ 3-32 (6H, s, CH3), 3.98 ~2H, m, ~20CH2P), 4.38 (2H, d, J--7.25Hz, CH2P), 4.54 (2H, m, NO~H2), 7.09-7.25 (8H, m, Ar), 7.33 (2H, br.s, D2C) exchangeable,NH2), 8.15 (lH, s, H-2), 8.31 (lH, s, H-8).
- Found: C, 53.14; H, 5.80; N, 13.87%. C22H24NsOsP x l.S H20 requ~res C, 53.23;
H, ~.48; N, 14.10%.

213~30~
~ 93/1907~ r~ /Gss~

- 1 l -9-[2-lBis(phenoxy)phosphorylmethoxy lethoxy~adenine (alternative preparation method) A mixture of 9-[1phosphonomethoxy)ethoxy]adenine (1.0 g, 3.46 mmol) and thionyl chlo~ide (50 ml) was heated undcr reflux for 2 h. The solution was cooled to room temperature and the solvent was removed under reduc~d pressure (wi~h exclusion of moisn~re) to give an oily residue. The residue was coevapolated with dry dichlc~romethane and then it was redissolved in dry dichloromethane ~15 ml). Phenol (Q.72 g, 7.61 mmol) was added to the solution and the rcsulting mixture was cooled to 0C under argon. Tnethylamine (1.06 ml, 7.61 mmol) was added dropwise (over 2 min) followed by l-medlylimidazole (l.1 ml, 13.84 mmol). The reactants were sti~ed at 0C fc~r 15 min and dlen at room temperature for 1 h. The precipitate was filte~ed off, washed with cold dichloromethane (lO ml). The combined filsrate and washingw~e diluted with dichloromedlane (100 ml), washed with san~rated ~queous NaHCO3 (30 ml), water (30 ml) and dried (MgSO4). The solYent was removed under reduced pressure, the ~duct was p~ified by column chromatogra~hy, elu~ng with 6% edlanolin chloroform, to gi~re thé title compound as a colourless gum; yield 0.52 g, 34%.

lH NMR ~ (DMSO-d6) 3.97 (2H,m,CH2CH2O), 4.35 (2H,d,J=7.42,CH2P), 4.55 (2H,m,CH2CH2O), 7.22-7.44 (12H,m,aromatic protons and NH2,D20 exchangeable), 8.15 and 8.31 (lH,s and lH,s~-2 and H-8). Pound: (CI),M+,441.1202;C2~H2oNsOs P r~quires M+, 441.1201 - Anal. Calcd for C2~H20Nsos PØ2 CHC13: C,52. 15; H, 4.38; N, 15.05. Found: C, 25 52.37; H, 4.42; N, 14.83.

wO 93/1907~ pcr/GB9~/oo~
c~,~ 3'~ 12 -9-[2-Bis(phenoxy)phosphorylmethoxylethoxy~adenine hydrochloride 9-[2-Bis(phenoxy)phospho~ylrnethoxy]ethoxy~adenine (l.S g, 3.4 mmol) was dissolved in dry dichloromethane (10 ml) and a saturated (0C) solution of hydrogen chloride in S dichloromethane (30 ml) was addcd. Aft:er being stirred at rt>om temperature for 5 min, ~e solution was conccntrated (with exclusion of moisture) and d~e residue was coevaporated vnth dry dichloromethane (3 ~c 50ml) to give the diphenyl ester hydr~chlo~idc as a colourless solid; yicld 1.6 g (99%). A sample of the compound (S0 mg) was evaporated ~vith dry tolucnc (20 ml) and dried in ~acuo to give a crystalline soL 139-143C.

H NMR ~ ~DMSO d6) ' ..:,.

4.01 (2H,m,CH2CH20), 4.32 (2~d,J=7.42,CH2P), 4.62 (2H,m,CH2CH20), 7.1~7.44 (lOH,m,a~ma~ic protons), 8.49 and 8.69 (lH,s and lH,s, H-2 and H-8), 8.7-9.25 (2H,v.b.d,NFI2,DzO oxchangeable). Found: (CI), MH+, 442.1280; ~2tjH20Nsos P
equircs MH+, 442.1280. Anal. Calcd for (: 2bH2bNsOs P.H2O. 1.2 HCl: C, 47.74; H,4.64; N, 13.92; Cl, 8.45. Found: C, 47.42; H, 4.54; N, 13.90; Cl, 8.~2.

2 1 3~303 93/l907:~ PCl /C~E~93/00~i60 Biological Evaluation Procedures Compounds were administered by oral gavage to female Balb/C mice weighing 20g, as single 0.1ml doses of 0~mmoVkg. These solu~ons were made by dissolving the 5 compounds in DMP and diluting with 1% carboxymethyl cellulose and 1% Tween 80,to a final DMF concentration of 5%. Pood was withheld from the mice for 18 hoursprior to thc start of thc e~cpe~iment. Blood was collectcd by cardiac puncturc using hcpa~inised syringcs 15, 60 and 180 mins aftcr dosing. Equal volumes (0.2ml) ~om 3 rnice werc pooled at each timc point and 0.6ml of ice-cold ethanol was added.
10 Following chilling at -20C and centrigugation, 0.5ml of supernatant was dried undcr - ~eduoed p~ssure. Thc samplc was then rcconstituted with 0.5ml of 0.4M NH4OAc (pH 6.0) and analysed by HPLC.

Thc results arc as shown in thc table below 9-12-(Phosphonometho~cy)etho~y]adenine concn. (~lM) in blood at time (min) after dosing : Compound of Example No. 15 60 m 4 ~
IV 9 1 : .

- V~l ~ 10 5

Claims

WO 93/19075 PCT/GB93/0056?

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

(I) wherein X is -CH2O, -CH2 or -CH(CH2OR6)O where R6 is hydrogen or acyl;
Y is O or S;
R1 is hydroxy or amino;
R2 is amino or hydrogen;
R3 is hydrogen or, when X is CH2O and Y is O, R3 may be CH2OR7 where R7 is hydrogen or acyl; and R4 and R5 are both phenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxypenyl, 2-acetoxyphenyl or 2-methylphenyl.

2. A compound according to claim 1 wherein R1 is hydroxy and R2 is amino.

3. A compound according to claim 1 wherein R1 is amino and R2 is hydrogen.

4. A compound according to any one of claims 1 to 3 wherein R4 and R5 are both phenyl.

5. A compound to any one of claims 1 to 4 wherein X is -CH2O and R3 is hydrogen.

6. A compound according to any one of claims 1 to 4 wherein X is -CH2O and R3 is CH2OR7 as defined in claim 1.

7. A compound according to any one of claims 1 to 4 wherein X is -CH(CH2OR6)O as defined in claim 1 and R3 is hydrogen.

8. A compound according to any one of claims 1 to 4 wherein X is -CH2 and R3 is hydrogen.

9. A compound according to any one of claims 1 to 4 wherein X is -CH2 and R3 is CH2OR7 as defined in claim 1.

10. A compound as described herein with reference to any one of the Examples.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, and a pharmaceutically acceptable carrier.

12. A compound according to any one of claims 1 to 10 for use as an active therapeutic substance.

13. A compound according to any one of claims 1 to 10 for use in treating viraldiseases.

14. Use of a compound according to any one of claims 1 to 10 in the manufactureof a medicament for use in the treatment of viral diseases.

15. A method of treatment of viral diseases in mammals, which comprises the administration to mammal in need of such treatment, an effective amount of a compound according to any one of claims 1 to 10.

16. A compound, use or method according to any one of claims 13, 14 or 15 wherein the viral infection is a human immunodeficiency virus infection.

17. 9-[2-Bis(phenoxy)phosphorylmethoxy]ethoxy]adenine hydrochloride.