(1R,CIS)-4-(4-AMINO-7H-PYRROLO'2,3-I(D) ! PYRIMIDINE-7-YL)-2-CYCLOPENTENE-1-METHANOL DERIVATIVES AS ANTIVIRAL

Abstract: The present invention relates to (1R, cis)-4-(4-Amino-7H-pyrrolo[2,3-<i>(d)</i>]pyrimidine-7-yl)-2-cyclopentene-1-methanol derivatives for the treatment of viral infections.

Description: ( 1R , CIS ) -4- (4 -AMINθ- 7H- PYRR0 0 ' 2 , 3 - I ( D ) ! PYRIMIDINE-7-YL) -2-CYCL0PENTENE-1- METHANOL DERIVATIVES AS ANTIVIRAL FIELD OF THE INVENTION The present invention relates to phosphoramidates of (1 R, cis)-4-(4-amino-7H- pyrrolo[2,3-σ]pyπmidine-7-yl)-2-cyclopentene-l -methanol anc | t eir use j n medical therapy. BACKGROUND OF THE INVENTION Retroviruses form a sub-group of RNA viruses which, in order to replicate, must first "reverse transcribe" the RNA of their genome into DNA ("transcription" conventionally describes the synthesis of RNA from DNA). Once in the form of DNA, the viral genome may be incorporated into the host cell genome, allowing it to take advantage of the host cell's tianscription/translation machinery for the purposes of replication. Once incorporated, the viral DNA is virtually indistinguishable from the host's DNA and, in this state, the virus may persist for the life of the cell. A species of retrovirus, the Human immunodeficiency virus (HIV) has been reproducibly isolated from patients with AIDS (acquired immunodeficiency syndrome) or with the symptoms that frequently precede AIDS. AIDS is an immunosuppressive or immunodestructive disease that predisposes subjects to fatal opportunistic infections. Characteristically, AIDS is associated with a progressive depletion of T-cells, especially the helper-inducer subset bearing the CD4 surface marker. HIV is cytopathic and appears to preferentially infect and destroy T-cells bearing the CD4 marker, and it is now generally recognized that HIV is the etiological agent of AIDS. Clinical conditions such as AIDS- related complex (ARC), progressive generalized lymphadenopathy (PGL), Karposi's sarcoma, thrombocytopenic purpura, AIDS-related neurological conditions, such as AIDS dementia complex, multiple sclerosis or tropical paraparesis, and also anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients, are also conditions which may be treated by appropriate anti-viral therapy. Another RNA virus which has been recognized as the causative agent of an increasingly serious international health problem is the non-A, non-B hepatitis virus. At least 80°/o of cases of chronic post-transfusional non-A, non-B hepatitis have been shown to be due to the virus now identified as hepatitis C and this virus probably accounts for virtually all cases of post-transfusional hepatitis in clinical settings where blood products are screened for hepatitis B. Whereas approximately half of the cases of acute hepatitis C infection resolve spontaneously over a period of months, the remainder become chronic and in many if not all such cases chronic active hepatitis ensues with the potential for cirrhosis and hepatocellular carcinoma. The structure of the hepatitis C virus genome has been elucidated and the virus has been characterized as a single stranded RNA virus with similarities to flaviviruses. Hepatitis B virus (HBV) is a small DNA containing virus which infects humans. It is a member of the class of closely related viruses known as the hepadnaviruses, each member of which selectively infects either mammalian or avian hosts, such as the woodchuck and the duck. Recent insights into the mechanism of replication of the hepadnavirus genome indicate the importance of reverse transcription of an RNA intermediate, suggesting that the reverse transcriptase is a logical chemotherapeutic target. HBV is a viral pathogen of major world-wide importance. The virus is etiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of the world's liver cancer. Clinical effects of infection with HBV range from headache, fever, malaise, nausea, vomiting, anorexia and abdominal pains. Replication of the virus is usually controlled by the immune response, with a course of recovery lasting weeks or months in humans, but infection may be more severe leading to persistent chronic liver disease outlined above. WO 96/29336 discloses masked monophosphate nucleoside analogues for the treament of HIV. It has now been discovered that certain phosphoramidates of (1 R, cis)-4-[4-amino-7H- pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-l -methanol are useful for the treatment of viral infections, particularly hepatitis B and retroviral infections, especially HIV. Compounds of the present invention have pharmacokinetic properties which render them advantageous as therapeutic agents. SUMMARY OF THE INVENTION The present invention features a compound of formula (I) (I) wherein: R 1 is hydrogen; Cs-uaryl; or heteroaryl, optionally substituted with one or more substituents selected from the group consisting of G-salkoxy, nitro, halogen, amino, hydroxy, carboxylate and esters thereof, carboxyalkyl, -CONHR 6 , and -CONR 6 R 7 , wherein R 6 and R 7 , which may be the same or different, are independently selected from Ci-salkyl, G- salkylaryl or Cs-uaryl; R 2 and R 3 are independently selected from hydrogen; or G-βalkyl, C3-scycloalkyl, C∑-sal enyl, C5-8cycloalkenyl, Cs-uaryl, or aralkyl wherein each Ci-salkyl, C3-scycloalkyl, C2-8alkenyl, Cs- βcycloalkenyl, Cs-uaryl or aralkyl may be optionally substituted with one or more substituents selected from the group consisting of Ci-salkyl, halo, hydroxy, alkoxy, amino, aminoalkyi, aminodialkyl, -SH, thioalkyl, carboxylate and esters thereof, carboxyalkyl, -CONHR 6 , and -C0NR 6 R 7 , wherein R 6 and R 7 , which may be the same or different, are independently selected from Ci-salkyl, G-salkylaryl or Cs-uaryl; or R 2 and R 3 can together form a 3- to 8-membered ring; R 4 is -OR 8 , -NR 8 R 9 or -SR 8 , where R 8 and R 9 , which may be the same or different, are independently selected from hydrogen, or Ci-salkyl, C3-8cycloalkyl, C2-salkenyl, Cs- scycloalkenyl, heterocycle, aralkyl, Ce-uaryl or Ci-salkylaryl wherein each Ci-salkyl, C3- δcycloalkyl, C2-salkenyl, Cs-scycloalkenyl, heterocycle, aralkyl, Cs-uaryl or Ci-salkylaryl may be optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, amino, aminoalkyl, aminodialkyl, -SH, thioalkyl, carboxylate and esters thereof, carboxyalkyl, -CONHR 6 , and -CONR 6 R 7 , wherein R 6 and R 7 , which may be the same or different, are independently selected from G-salkyl, G-salkylaryl or Cs-uaryl; R 5 is hydrogen; G-salkyl; or Cs-uaryl; or R 2 and R 5 may together form a 5- or 6-membered ring; or R 3 and R 5 may together form a 5- or 6-membered ring; or a pharmaceutically acceptable derivative thereof and their use in the treatment of viral infections. DETAILED DESCRIPTION OF THE INVENTION The present invention features a compound of formula (I) (I) wherein: R 1 is hydrogen; Cs-uaryl; or heteroaryl, optionally substituted with one or more substituents selected from the group consisting of G-salkoxy, nitro, halogen, amino, hydroxy, carboxylate and esters thereof, carboxyalkyl, -CONHR 6 , and -C0NR 6 R 7 , wherein R 6 and R 7 , which may be the same or different, are independently selected from G-βalkyl, Ci- salkylaryl or Cs-uaryl; R 2 and R 3 are independently selected from hydrogen; or G-salkyl, G-βcycloalkyl, G-salkenyl, Cs-scycloalkenyl, Cs-uaryl, or aralkyl wherein each G-salkyl, G-scycloalkyl, C2-salkenyl, G- scycloalkenyl, Cs-uaryl, or aralkyl may be optionally substituted with one or more substituents selected from the group consisting of G-salkyl, halo, hydroxy, alkoxy, amino, aminoalkyl, aminodialkyl, -SH, thioalkyl, carboxylate and esters thereof, carboxyalkyl, - CONHR 6 , and -CONR 6 R 7 , wherein R 6 and R 7 , which may be the same or different, are independently selected from G-salkyl, G-salkylaryl or Cs-uaryl; or R 2 and R 3 can together form a 3- to 8-membered ring; R 4 is -OR 8 , -NR 8 R 9 or -SR 8 , where R 8 and R 9 , which may be the same or different, are independently selected from hydrogen, or G-salkyl, C3-scycloalkyl, G-salkenyl, Cs- scycloalkenyl, heterocycle, aralkyl, Cε-uaryl or G-salkylaryl wherein each G-salkyl, G- βcycloalkyl, G-salkenyl, G-βcycloalkenyl, heterocycle, aralkyl, Cs-uaryl or G-salkylaryl may be optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, amino, aminoalkyl, aminodialkyl, -SH, thioalkyl, carboxylate and esters thereof, carboxyalkyl, -CONHR 6 , and -CONR 6 R 7 , wherein R 6 and R 7 , which may be the same or different, are independently selected from G-βalkyl, G-salkylaryl or Cs-uaryl; R 5 is hydrogen; G-salkyl; or Cs-uaryl; or R 2 and R 5 may together form a 5- or 6-membered ring; or R 3 and R 5 may together form a 5- or 6-membered ring. or a pharmaceutically acceptable derivative thereof. The compounds of the present invention include diastereomers differing in the absolute configuration at phosphorus. Diastereoisomers may be present as a single isomer or as mixtures of diastereoisomers. The term "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 1 to about 10, more preferably from 1 to about 8 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like. The term "aryl" refers to a carbocyclic aromatic radical (such as phenyl or naphthyl) containing the specified number of carbon atoms, preferably from 6-14 carbon atoms, and more preferably from 6-10 carbon atoms, optionally substituted with one or more substitutents selected from G-s alkoxy (for example, methoxy), nitro, halogen (for example chloro), amino, carboxylate and hydroxy. Examples of aryl radicals include, but are not limited to phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the like. The term "alkenyl," alone or in combination with any other term, refers to a straight-chain or branched-chain mono- or poly-unsaturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 2- 10 carbon atoms and more preferably, from 2-6 carbon atoms. Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutyenyl, pentenyl, hexenyl, hexadienyl and the like. The term "alkoxy" refers to an alkyl ether radical, wherein the term "alk/l" is defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, with methoxy being preferred. The term "halo" or "halogen" refers to a radical of fluorine, chlorine, bromine or iodine. The term "heterocycle", alone or in combination with another term, refers to a stable 3-7 membered monocyclic heterocyclic ring or 8-1 1 membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which may be optionally benzofused if monocyclic. Each heterocycle consists of one or more carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen a d sulfur. As used herein, the terms "nitrogen and sulfur heteroatoms" include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. A heterocyclyl radical may be attached at any endocyclic carbon or heteroatom which results in the creation of a stable structure. Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8- 10 membered bicyclic heterocycles. Examples of such groups include imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoqinolyl, indolyl, indazolyl, indazolinolyl, perhydropyridazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl sulfone, oxazolyl, benzoxazolyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, isoxozolyl, isothiazolyl, furazanyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thiadiazoyl, dioxolyl, dioxinyl, oxathiolyl, benzodioxolyl, dithiolyl, thiophenyl, tetrahydrothiophenyl, sulfolanyl, dioxanyl, dioxolanyl, tetahydrofurodihydrofuranyl, tetrahydropyranodihydrofuranyl, dihydropyranyl, tetradyrofurofuranyl and tetrahydropyranofuranyl. The term "pharmaceutically acceptable derivative", as used herein, meε'is any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Compounds of formula (I) and their pharmaceutically acceptable derivatives may hereinafter be referred to as compounds according to the invention. In another aspect of the present invention there is provided compounds of formula (I) wherein R 1 is hydrogen or Cs-uaryl; R 2 and R 3 are independently hydrogen, G-salkyl or aralkyl; R 4 is -OR 8 wherein R 8 is hydrogen, G-salkyl, G-salkylaryl or Cs-uaryl and R 5 is hydrogen; or a pharmaceutically acceptable derivative thereof. A further aspect of the present invention features compounds selected from: (1 R, cis)-4-[4-amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol-0- [phenyl (methoxy L-alaninyl)]phosphoramidate; (1 R, cis)-4-[4-amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol-O- [phenyi (methoxy α, α-dimethylglycinyl)]phosphoramidate; (1 R, cis)-4-[4-amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol-0- [phenyl (methoxy L-phenylalaninyl)]phosphoramidate; and (1 R, cis)-4-[4-amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol-0- [phenyl (benzyloxy L-alaninyl)]phosphoramidate; or a pharmaceutically acceptable derivative thereof. Physiologically acceptable salts of the compounds of the present invention include salts of a basic or acidic portion of the molecule. Salts of a basic moiety are formed by organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic, and succinic acids, organic sulphonic acids, such as methanesulphonic, ethanesulphonic, benzenesulphonic and p-toluenesulphonic acids and inorganic acids, such as hydrochloric, sulphuric, phosphoric and sulphamic acids. Salts of an acidic moiety are formed by an appropriate base , such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium, calcium), ammonium and ammonium salts. For therapeutic use, salts of compounds according to the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base. However, salts of acids which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid, are within the scope of the present invention. The present invention includes mono-, di- and tri-phosphates of compounds of formula (II). The O-monophosphate of a compound of formula (II) may be prepared by treating a compound of formula (II) with an appropriate phosphorγlating agent, e g. phosphoryl chloride as in M. Yoshikawa, T. Kato and T. Takenishi, Bulletin Chem. Soc Japan, 1969, 42, 3505. The corresponding O-di- and O-triphosphates may be prepared by the method of N. C. Mishra and A. D. Broom, J. Chem. Soc, Chem. Commun., 1991 , 1276 or by the methods described in "Nucleotide Analogs" K.H. Sheit, John Wiley and Sons, New York 1980, pp.21 1 -215, and D. E. Hoard and D. G. Ott, J. Amer, Chem Soc. 1965, 87, 1785. Compounds of formula (I) may be made by modifications of the procedures described in Biochem. Biophys. Res. Commun. 225:363-369, 1996. Compounds of the present invention may be preapared by a process which comprises reaction of a compound of formula (II) with a compound of formula (Ill) wherein R 1 - R 5 are as hereinbefore defined. The reaction may be carried out under dry conditions at ambient temperature in tetrahydrofuran in the presence of N-methylimidazole, or by using t-butyl magnesium chloride in solvents such as pyridine, pyridine-tetrahydrofuran, or acetonitrile and an excess of the appropriate phosphochloridate reagent (Balzarini et al., Biochem. Biophys. Res. Comm. 225:363-369 (1996). The phosphochloridate reagent may be prepared according to WO 96/29336. Compounds of formula (II) may be prepared according to Example 1 or 2. Separation of isomers may be accomplished by methods known in the art, for example, by high-pressure liquid chromatography with chiral columns, particularly using liquid carbon dioxide as the mobile phase, or by crystallization of salts with chiral acids or bases. Phosphate isomers may be separated with Supercritical Fluid Chromatography using a Chiralpak ? AS column, 25% methanol in carbon dioxide as the eluent. flow rate 2 mL/min, temperature 40° C, and pressure 3000 psi. A further aspect of the present invention features the compounds according to the invention for use in medical therapy, particularly for the treatment of retroviral infections and hepatitis B virus and hepatitis C virus infections. Another aspect of the present invention features the compounds according to the invention for use in the manufacture of a medicament for the treatment of viral infections, particularly for the treatment of retroviral infections and hepatitis B virus and hepatitis C virus infections. In a further aspect of the present invention there is provided a method for the treatment of retroviral infections and hepatitis B virus infections and hepatitis C virus infections in a host comprising administering to said host a therapeutically effective amount of a compound according to the invention. Examples of retroviral infections which may be treated or prevented in accordance with the invention include human retroviral infections such as human immunodeficiency virus (HIV), HIV-1 , HIV-2 and human T-cell lymphotropic virus (HTLV), for example, HTLV-I or HTLV-II infections. The compounds according to the invention are especially useful for the treatment of AIDS and related clinical conditions such as AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), AIDS-related neurological conditions, such as multiple sclerosis or tropical paraparesis, anti-HIV antibody-positive and HIV- positive conditions and thrombocytopenic purpura. The compounds according to the invention are particularly applicable for the treatment of asymptomatic infections or diseases in humans caused by or associated with human retrovi ruses. The compounds according to the invention may be stable towards acid-mediated hydrolytic decomposition and thus, advantageous as therapeutic agents for oral administration, because the compounds are likely to withstand the acidic environment of the stomach. The compounds according to the invention may be employed in combination with other therapeutic agents for the treatment of the above infections or conditions. Other therapeutic agents may include agents that are effective for the treatment of viral infections or associated conditions such as reverse transcriptase inhibitors, for example, zidovudine or abacavir; (1 alpha, 2 beta, 3 alpha)-9-[2,3- bis(hydroxymethyl)cyclobutyl]guanine [(-)BHCG, SQ-34514]; oxetanocin-G (3,4-bis- (hydroxymethyl)-2-oxetanosyl]guanine);acyclic nucleosides (e.g. acyclovir, valaciclovir, famciclovir, ganciclovir, penciclovir); acyclic nucleoside phosphonates (e.g. (S)-1 -(3- hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC) or PMEA or PMPA; ribonucleotide reductase inhibitors such as hydroxyurea, 2-acetylpyridine 5-[(2- chloroanilino)thiocarbonyl) thiocarbonohydrazone; other 2',3'-dideoxynucleosides such as 2',3'-dideoxycytidine, 2',3'-dideoxyadenosine, 2',3'-dideoxyinosine, 3'-deoxy-2',3'- didehydrothymidine (d4T); protease inhibitors such as saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, tipranavir; oxathiolane nucleoside analogues such as lamivudine, cis-1-(2-(hydroxymethyl)-1 ,3-oxathiolan-5-yl)-5-fluorocytosine (FTC); 3'-deoxy-3'- fluorothymidine, 5-chloro-2',3'-dideoxy-3'-fluorouridine, ribavirin, 9-[4-hydroxy-2- (hydroxymethyl)but-1 -yl]-guanine (H2G); tat inhibitors such as 7-chloro-5-(2-pyrryl)-3H- 1 ,4-benzodiazepin-2-(H)one (Ro5-3335), 7-chloro-1 ,3-dihydro-5-(l H-pyrrol-2yl)-3H-1 ,4- benzodiazepin-2-amine (Ro24-7429); interferons such as α-interferon; renal excretion inhibitors such as probenecid; nucleoside transport inhibitors such as dipyridamole; pentoxifylline, N-acetylcysteine (NAC), Procysteine, α -trichosanthin, phosphonoformic acid, as well as immunomodulators such as interleukin II or thymosin, granulocyte macrophage colony stimulating factors, erythropoetin, soluble CD and genetically engineered derivatives thereof; or non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine (BI-RG-587), loviride (α -APA), delavuridine (BHAP), atevirdine, efavirenz, and DPC 961/963, and phosphonoformic acid, and 1 ,4-dihydro-2H-3,1 - benzoxazin-2-ones NNRTIs such as (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl- 1 ,4-dihydro-2H-3,1 -benzoxazin-2-one (L-743,726 or DMP-266), and quinoxaline NNRTIs such as isopropyl (2S)-7-fluoro-3,4-dihydro-2-ethyl-3-oxo-1 (2H)-quinoxalinecarboxylate (HBY1293). The component compounds of such combination therapy may be administered simultaneously, in either separate or combined formulations, or at diffc ent times, for example, sequentially such that a combined effect is achieved. The compounds according to the invention, also referred to herein as the active ingredient, may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal). It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the infection and the chosen active ingredient. The amounts required of the active ingredient will depend upon a number of factors includir.g severity of the condition to be treated and the identity of the recipient and will ultimately be at the discretion of the attendant physician or veterinarian. In general however, for each of these utilities and indications, a suitable effective dose of a compound of formula (I) will be in the range of 0.01 to 100 mg per kilogram body weight of recipient per day, advantageously in the range of 1 to 70 mg per kilogram body weight per day, preferably in the range of 1 to 50 mg per kilogram body weight per day. The desired dose is preferably presented as one, two, three or four or more subdoses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing about 0.5 to 2000 mg, preferably about 5, 25, 50, 150, 200, or 250 mg of active ingredient per unit dose form. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. A further aspect of the present invention features pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier therefor. The compositions of the present invention comprise at least one active ingredient, as defined above, together with one or more pharmaceutically acceptable carriers thereof and optionally other therapeutic agents. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The compositions may conveniently be presented in unit dosage form prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing in to association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, sachets of granules or tablets (such as a swallowable, dispersible or chewable tablet) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liqircl The active ingredient may also be presented as a bolus electuary or paste. A tablet may be made by compression or moulding optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored any may be formulated so as to provide slow or controlled release of the active ingredient therein. Tablets may be enteric coated. Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. Compositions for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Compositions 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. Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solution which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multidose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. The active ingredient may also be presented in a composition comprising micrometer- or nanometer-size particles of active ingredient. Preferred unit dosage compositions are those containing a daily dose or unit daily sub- dose (as herein above recited) or an appropriate fraction thereof, of the active ingredient. It should be understood that in addition to the ingredients particularly mentioned above the composition of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents or taste masking agents. A further aspect of the invention relates to kits to be used in the treatment of patients suffering from viral infections. These kits include one or more oral dosage of a compound of formula (I) and may include one or more additional therapeutic agents. By way of illustration, a kit of the invention may include one or more tablets, capsules, caplets, gelcaps or liquid formulations containing a compound of formula (I) and one or more tablets.capsules, caplets, gelcaps or liquid formulations containing a compound of formula (I) in dosage amounts within the ranges described above. The kits may include as an insert printed dosing information for the co-administration of the agents. The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. Example 1 (+)~(1 R, cis)-4-[4-Amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol (a) (±)-cis-4-Amino-2-eyclopentene-1 -methanol hydrochloride (±)-tert-butyl N-[4-(hydroxymethyl)-2-cyclopenten-1-yl]carbamate (US Patent 5,206,435, Apr. 27, 1993, 0.84 g, 3.96 mmol) was refluxed in absolute ethanol (5 mL) with concentrated hydrochloric acid (0.4 mL, 4.8 mmol) for 2.5 hours. Evaporation of the volatiles left the title compound as a white solid; mass spectrum (ES): 1 14 (M+1); Η-rtMFi (DMSO-ds) δ 7.9 (m, 3H), 6.03 and 5.75 (two m, 2H), 4.1 1 (r , 1 H), 3.41 (d, J = 5.4 Hz, 2H), 2.8 (m, 1 H), 2.36 (m, 1 H), 1.4 (m, 1 H). This solid was used immediately in the following example. (b) (±)-4-[4-Chloro-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol (±)-ds-4-Amino-2-cyclopentene-1 -methanol hydrochloride (3.96 r:mol, from 1 a), triethylamine (1.20 g, 1 1.8 mmol), and 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (J. A. Montgomery and K. Hewson . Med. Chem. 1967, 70: 665; 1.05 g, 3.96 mmol) were refluxed in absolute ethanol (5 mL) for 4 hours. The solution was cooled, 1 N sodium hydroxide (8 mL) added, and volatiles removed under reduced pressure. The residue was chromatographed on silica gel with 10 % methanol-chloroform. Product-containing fractions were combined and concentrated to an oil which was dried at 0.1 mm Hg to a weight of 0.80 g . This oil was dissolved in dioxane (10 mL) - 1 N hydrochloric acid (3 mL) and the solution stirred at ambient temperature for 2 days, neutralized with ammonium hydroxide, and volatiles evaporated under reduced pressure. The residue was chromatographed on silica gel and title compound eluted with 5-10% methanol- chlorororm as a light tan oil (0.60 g, 60%); 1 H-NMR (DMSO-ds) δ 8.67 (s, 1 H), 7.70 and 6.69 ( two d. J = 3.65 Hz, 1 H each), 6.10 (m, 1 H), 6.0-5.8 (m, 2H), 4.77 (m, l H), 3.5 (m, 2H), 2.9 (m, 1 H), 2.7 (m, 1 H), 1.6 (m, 1 H); mass spectrum (API + ): 252(35), 250(100), 156(24), 154(73). (c) (±)-4-[4-Amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol (±)-4-[4-Chloro-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol (600 mg, 2.36 mmol) was heated in liquid ammonia (50 mL) in a Parr bomb at 65°C for 3 days. Volatiles were evaporated with 1 N sodium hydroxide (2.3 mL) and the residue c'.r ms'iographed on silica gel. Title compound was eluted with 10 r '; methanol- chloroform as a colorless oil. Evaporation of an acetonitrile solution gave title compound as white powder which was washed with hexanes (291 mg, 52%); m.p. 165- 168°C; H-NMR (DMSO-ds) δ 8.07 (s, 1 H), 7.06 and 6.56 ( two d, J = 3.5 Hz, 1 H each), 7.0 (br s, 2H), 6.10 (m, 1 H), 5.80 (m, 2H), 4.75 (m, 1 H), 3.45 (m, 2H), 2.85 (m, 1 H), 2.6 (m, 1 H), 1.45 (m, 1 H) ; mass spectrum (Cl): M+1 , 231 (100), 163(37), 135(45). Anal. Calcd. for G2H12N4OO.4O H2O: C, 60.67; H, 6.28; N, 23.59. Found: C, 60.54; H, 5.96; N, 23.73. (d) (+)-(l R, cis)-4-[4-Amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 - methanol (±)-4-[4-Amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol (part c of this example, 56 mg, 0.22 mmole) was resolved using supercritical fluid chromatography. Title compound eluted with a RT of 20.1 min from a Chiralpak AS column, 10% methanol(0.1% triethylamine)-90% carbon dioxide, 2.0 mL/min, 40°C, 3000 p i: 97.2 % enantiopure; evaporation of solvents gave title compounds as a white solid (22 mg); 1 H-NMR (DMSO-ds) identical with that of the racemate described in part c of this example. The enantiomer (-)-(l S, 4R)-4-[4-amino-7H-pyrrolo(2,3-d)pyrimidin- 7-yl]-2-cyclopentene-1 -methanol had a RT of 17.5 min. Example 2 (+)~(1 R, cis)-4-[4-Amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1-methanol (a) (1 S, 4R)- tert-Butyl 3-oxo-2-azabicyclo[2.2.l]hept-5-ene-2-carboxylate (+)-2-Azabicyclo[2.2.1]hept-5-en-3-one (Chiroscience, Cambridge, England; 54.565 g, 0.500 mole) was dissolved in dry tetrahydrofuran (350 mL). Di-tert- utyl carbonate (Aldrich, 1 14.87 g, 0.510 mole as 97%) and 4-dimethylaminopyridine (Aldrich, 600 mg) were added to the stirred mixture. The resulting solution was stirred at ambient temperature for 2 hours. Solvent was evaporated under reduced pressure and the residual orange solid was crystallized from toluene-hexanes to give title compound as white crystals (95.72 g, 91 %), m.p. 85-86°C; H-NMR (CDCb) δ 1.50 (s, 9H), 2.24 (app AB q, J = 8.4 Hz, 2H), 3.39 (br s, 1 H), 4.96 (m, 1 H), 6.66 (m, 1 H), 6.89 (m, 1 H). Anal. Calcd. For CπHisNOa : C, 63.14; H, 7.21 ; N, 6.69. Found: C, 63.20; H, 7.26; N, 6.65. (H (+)-M S, cis)-tert-Butyl N-[4-(hydroxymethyl)-2-cyclopenten-1 -yl]carbamate A solution of (1 S, 4R)- tert-butyl 3-oxo-2-azabicyclo[2.2.l]hept-5-ene-2-carboxylate (part a of this example, 95.50 g, 0.456 mole) in tetrahydrofuran (500 mL)-water (50 mL) was added over 10 minutes to a vigorously stirred solution of sodium borohydride (Aldrich, 21.96 g, 0.580 mole as 99%) in water (100 mL). The temperature was maintained below 35°C. After 2 hours, the solution was cooled to maintain the temperature below 25°C while concentrated hydrochloric acid (50 mL) was added over 10 minutes. Additional water (100 mL) was added to dissolve solid and the solution was extracted with toluene (4x300 mL). The combined organic layers were washed with 9:1 saturated sodium sulfate/saturated sodium carbonate (200 mL) and dried (sodium sulfate). Evaporation of solvents under reduced pressure left a colorless syrup which crystallized on stirring with hexanes (200 mL) to provide title compound as a fine white powder (87.16 g, 90%), m.p. 72-73°C; 1 H-NMR (DMSO-ds) δ 6.78 (d, J = 7.6 Hz, 1 H), 5.80 and 5.60 (two m, 2H), 4.58 (t, J = 5.25 Hz, 2H), 4.45 (m, 1 H), 3.35 (m overlapping water), 2.60 (m, 1 H), 2.30 (m, 1 H), 1.38 (s, 9H), 1.20 (m, 1 H); [α] BSΘ +2.80° (c 5.0, methanol). Anal. Calcd. for G1H19NO3 : C, 61.95; H, 8.98; N, 6.57. Found: G 61.87; H, 8.97; N, 6.55. (c) (+)-(! R, cis)-4-Amino-2-eyelopentene-1 -methanol hydrochloride (+)-(l S, cis)-tert-Butyl N-[4-(hydroxymethyl)-2-cyclopenten-1 -yl]carbamate (part b of this example, 9.7 g, 45.6 mmol) was refluxed in absolute ethanol (10 mL) with concentrated hydrochloric acid (4.4 mL, 52.8 mmol) for 2.5 hours. Evaporation of volatiles left title compound as a white solid; mass spectrum (ES): 1 14 (M+1); 1 H-NMR (DMSO-ds) δ 7.9 (m, 3H), 6.03 and 5.75 (two m, 2H), 4.1 1 (m, 1 H), 3.41 (d, J = 5.4 Hz, 2H), 2.8 (m, 1 H), 2.36 (m, 1 H), 1.4 (m, 1 H). This solid was used immediately in the following example. (d) (+)-(l R, cis)-4-[4-Chloro-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 - methanol In the same manner as part b of Example 1 , starting with the (+)-(1 R, cis)-4-amino-2- cyclopentene-1 -methanol hydrochloride (45.6 mmol, this Example c), the title compound was eluted from a silica gel column with 5-10% methanol-chloroform as a light tan oil (10.4 g, 91%); 'H-NMR (DMSO-ds) identical with that of the racemate described in Example 1 , part b; mass spectrum (El): M+1 , 252 (35), 250 (100); [α] sss +43.6° (c 0.0045, methanol). Anal. Calcd. for G2H12N3OCI 0.05 CHCb : C, 57.67; H, 4.92; N, 16.54. Found: C, 58.05; H, 5.07; N, 16.46. (e) (+)-(l R, cis)-4-[4-Amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 - methanol In the same manner as Example 1 , part c, (+)-(1 R, cis)-4-[4-Amino-7H-pyrrolo(2,3- d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol (1.7 g, 6.8 mmol) was heated in liquid ammonia (50 mL) in a Parr bomb at 75°C for 3 days. Volatiles were evaporated with 1 N sodium hydroxide (6.8 mL) and the residue chromatographed on silica gel. The title compound was eluted with 10 % methanol-chloroform to give after removal of volatiles 1.2 g (77 %) of a white foam; 1 H-NMR (DMSO-ds) δ: 8.07 (s, 1 H), 7.06 and 6.56 ( two d, J = 3.5 Hz, 1 H each), 7.0 (br s, 2H), 6.10 (m, 1 H), 5.80 (m, 2H), 4.75 (m, 1 H), 3.45 (m, 2H), 2.85 (m, 1 H), 2.6 (m, 1 H), 1.45 (m, 1 H) ; mass spectrum (El): M+1 , 231 ; [α] 5 s 9 +42.9° (c 0.0028, methanol). Anal. Calcd. for G2H14N4O 0.8 H2O : C, 58.91 ; H, 6.43; N, 22.90. Found: C, 58.74; H, 6.25; N, 22.72. Example 3 (1 R, cis)-4-[4-Amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol-0- [phenyl (methoxy L-aianinyl)]phosphoramidate To (+)-(l R, cis)-4-[4-amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol (Example 2e, 0.19 g, 0.8 mmoles) was added anhydrous pyridine (4 mL) and anhydrous tetrahydrofuran (3 mL). Subsequently, fert-butylmagnesiumchloride (Aldrich, 0.9 mL, 1 M solution in tetrahydrofuran) was added and the reaction stirred under nitrogen for 10 minutes at room temperature. A solution of phenyl(methoxy-L- alaniny phosphorochloridate (prepared as described by C. McGuigan et al. J. Med. Chem. 1993, 36, 1048-1052; 2.6 mmoles) in anhydrous tetrahydrofuran was added and the reaction stirred at room temperature for 12 h. The resuling mixture was concentrated to a syrup under reduced pressure. This syrup was dissolved in dichloromethane (60 mL) and the organic phase washed with water (2 x 30 mL), dried (magnesium sulfate), filtered and concentrated to a foam. This foam was purified by flash column chromatography on silica gel. The title compound was eluted with 5% methanol in chloroform to give, after removal of volatiles, 290 mg (77 %) of a white foam; 1 H-NMR (CDCb) δ 8.23 (s, 1 H), 7.22 (m, 2H), 7.10 (m, 3H), 6.88 (2 x d, 1 H), 6.27 (d, 1 H), 5.98 (m, 1 H), 5.87 (m, 1 H), 5.80 (m, 1 H), 5.35 (bs, 2H), 3.85-4.10 (m, 4H), 3.61 (s, 3H), 3.06 (m, 1 H), 2.7 (m, 1 H), 1.50 (m, 1 H), 1.28 (m, 3H); 31 P-NMR (CDCb): 2.99 and 2.80; mass spectrum (El): M+23 (Na), 494. Anal. Calcd. for C22H26N5O4P H2O: C, 53.98; H, 5.76; N, 14.31 ; Found: C, 54.32; H, 5.79; N, 14.22. Example 4 (I R, cis)-4-[4-Amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol-0- [phenyl (methoxy α,α-dimethylglycinyl)]phosphoramidate (+)-(l R, cis)-4-[4-Amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol (Example 2e, 0.20 g, 0.9 mmoles) was treated with phenyl(methoxy-α,α-dimethylglycinyl) phosphorochloridate (2.5 mL of 1 M solution in tetrahydrofuran, 2.5 mmoles; prepared as described by C. McGuigan et al. Antiviral Research 1997, 35, 195-204) as described for Example 3 to give, after silica gel chromatography with 5% methanol in chloroform, 310 mg (73 %) of the title compound as a white foam; 'H-NMR (CDCb) δ:8.35 (s, 1 H), 7.1 -7.4 (m, 5H), 6.97 (2 x d, 1 H), 6.38 (m, 1 H), 6.08 (m, 1 H), 5.97 (m, 1 H), 5.90 (m, 1 H), 5.40 (broad s, 2H), 4.00-4.20 (m, 3H), 3.73 (s, 3H), 3.15 (m, 1 H), 2.8 (m, 1 H), 2.25 (s, 1 H), 1.55 (m, 6H); 1 P-NMR (CDCb):1.73; mass spectrum (El): M+1 , 486. Anal. Calcd. for C23H28N5O5P V2 H2O: C, 55.87; H, 5.91 ; N, 14.16; Found: C, 55.93; H, 5.91 ; N, 14.16. Example 5 (1 R, cis)-4-[4-Amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol-0- [phenyl (methoxy L-phenylalaninyl)]phosphoramidate (+)-(l R, cis)-4-[4-Amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol (Example 2e, 0.20 g, 0.9 mmoles) was treated with phenyl(methoxy-L-phenylalaninyl) phosphorochloridate (2.5 mL of 1 M solution in tetrahydrofuran, 2.5 mmoles; prepared as described by C. McGuigan et al. J. Med. Chem. 1993, 36, 1048-1052) as described for Example 3 to give after silica gel chromatography with 5% methanol in chloroform 320 mg (67%) of the title compound as a white foam; 'H-NMR (CDCb) δ:8.22 (s, 1 H), 6.9-7.3 (m, 10H), 6.85(m, 1 H), 6.25 (2 x d, 1 H), 5.7 -6.0 (m, 3H), 5.35 (broad s, 2H), 4.15 (m, 1 H), 3.55-4.0 (m, 2H), 3.55 (2 x s, 3H), 2.6-2.9 (m, 5 H), 1.4 (m, 1 H); 31 P-NMR (CDCb):3.0; mass spectrum (El): M+1 , 548. Anal. Calcd. for GsHsoNsOsP 0.7 MeOH: C, 60.48; H, 5.80; N, 12.29; Found: C, 60.49; H, 5.51 ; N, 1 1.98. Example 6 (1 R, cis)-4-[4-Amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-l -methanol-0- [phenyl (benzyloxy L-alaninyl)]phosphoramidate. (+)-(l R, cis)-4-[4-Amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol (Example 2e, 0.20 g, 0.9 mmoles) was treated with phenyl benzyloxy-L-alaninyl phosphochloridate (2.5 mL of 1 M solution in tetrahydrofuran, 2.5 mmol; prepared as described by C. McGuigan et al. Bioorganic and Medicinal Chemistry Letters, 1996, 6, 2359-2362) as described for Example 3 to give after silica gel chromatography with 5 % methanol in chloroform 330 mg (69%) of the title compound as a white foam: 'H-NMR (CDCb) δ:8.34 (s, 1 H), 6.9-7.4 (m, 10H), 6.95(2 x d, 1 H), 6.35 (m, 1 H), 5.8 -6.1 (3 x m, 3H), 5.45 (broad s, 2H), 5.13 (m, 2H), 4.0-4.2 (m, 4H), 3.1 (m, 1 H), 2.75 (m, 1 H), 1.58 (m, 1 H), 1.4 (m, 3H); 31 P-NMR (CDCb):3.2 and 3.0; mass spectrum (El): M+1 , 548. Anal. Calcd. for GsHsoNsOsP 1/3 H 2 0: C, 60.92; H, 5.57; N, 12.69; Found: C, 60.93; H, 5.65; N, 12.58. Example 7 Anti-HIV Activity Compounds were tested for anti-HIV activity in MT» cells according to the method described by Averett, D.R., J. Virol. Methods, 23, 1989, 263-276. Activity of the compounds against HIV was in the range ICso 0.010 μM - 1.0 μM. Example 8 Anti-Hepatitis B Virus Activity Compounds were tested for anti- hepatitis B Virus activity according to the method described by Jansen, R. et al., Antimicrobial Agents and Chemotherapy, Vol. 37, No. 3, pp. 441-447, 1993. Anti-hepatitis B activity of the compounds was in the range ICso 0.010 μM - 2.0 μM. ICso values of the compounds according to the invention demonstrated improved activity by as much as 100-fold over that of the corresponding nucleoside analog, (1 R, cis)-4-(4-amino-7H-pyrrolo[2,3-cdpyrimidin-7-yl)-2-cyclopentene-1 - methanol. Example 9: Tablet Formulation The following formulations A, B and C are prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression. Formulation A mq/tablet Active Ingredient 250 Lactose B.P. 210 Povidone B.P. 15 Sodium Starch Glycollate 20 Magnesium Stearate 5 500 Formulation B mg/tablet Active Ingredient 250 Lactose B.P. 150 Avicel PH 101 60 Povidone B.P. 15 Sodium Starch Glycollate 20 Magnesium Stearate 5 500 Formulation C mg/tablet Active Ingredient 250 Lactose B.P. 200 Starch 50 Povidone 5 Magnesium Stearate 4 359 The following formulations, D and E, are prepared by direct compression of the admixed ingredients. The lactose in formulation E is of the direct compression type (Dairy Crest- "Zeparox"). Formulation D mg/tablet Active Ingredient 250 Pregelatinized Starch NF15 150 400 Formulation E mg/tablet Active Ingredient 250 Lactose B.P. 150 Avicel 100 500 Formulation F (Controlled Release Formulation) The formulation is prepared by wet granulation of the ingredients with a solution of povidone followed by the addition of magnesium stearate and compression. mg/tablet Active Ingredient 500 Hydroxypropylmethylcellulose 1 12 (Methocel K4M Premium) Lactose B.P. 53 Povidone B.P. 28 Magnesium Stearate 7 700 Drug release takes place over a period of about 6-8 hours and is complete after 12 hours. Example 10: Capsule Formulations Formulation A A capsule formulation is prepared by admixing the ingredients of formulation D in Example 6 above and filling into a two-part hard gelatin capsule. Formulation B (infra) is prepared in a similar manner. Formulation B mg/capsule Active Ingredient 250 Lactose B.P. 143 Sodium Starch Glycollate 25 Magnesium Stearate 2 420 Formulation C mg/capsule Active Ingredient 250 Macrogel 4000 B.P. 350 600 Capsules of formulation C are prepared by melting the Macrogel 4000 B.P., dispersing the active ingredient in the melt and filling the melt into a two-part hard gelatin capsule. Formulation D mg/capsule Active Ingredient 250 Lecithin 100 Arachis Oil 100 450 Capsules of formulation D are prepared by dispersing the active ingredient in the lecithin and arachis oil and filling the dispersion into soft, elastic gelatin capsules. Formulation E mg/capsule Active Ingredient 150.0 Vitamin E TPGS 400.0 Polyethylene Glycol 400 NF 200.5 Propylene Glycol USP 39.5 Four (4) kilograms (kg) of Vitamin E TPGS (obtained from Eastman Chemical Co.) was heated at 50°C until liquefied. To the liquified Vitamin E TPGS, 2.005 kg of polyethylene glycol 400 (PEG400) (low aldehyde, <10 ppm, obtained from Union Carbide or Dow Chemical Co.) heated to 50°C was added and mixed until a homogeneous solution was formed. The resultant solution was heated to 65°C. 1.5 kg of active in; redient was dissolved in the liquefied solution of Vitamin E TPGS and PEG 400. 0.395 kg of propylene glycol at room temperature was added and mixed until a homogenous solution was formed. The solution was cooled to 28-35°C. The solution was then de-gassed. The mixture was preferably encapsulated at 28-35°C at a fill weight equivalent to 150 mg of volatiles-free compound, into Size 12 oblong, white opaque soft gelatin capsules using a capsule filling machine. The capsule shells were dried to a constant fill moisture of 3-6% water and a shell hardness of 7-10 Newtons, and placed in a suitable container. Formulation F (Controlled Release Capsule) The following controlled release capsule formulation is prepared by excluding ingredients a, b, and c using an extruder, followed by spheronization of the extrudate and drying. The dried pellets are then coated with release-controlling membrane (d) and filled into a two- piece, hard gelatin capsule. mg/capsule (a) Active ingredient 250 (b) Microcrystalline Cellulose 125 (c) Lactose B.P. 125 (d) Ethyl Cellulose 13 513 Example 1 1 : Injectable Formulation Formulation A ma Active Ingredient 200 Hydrochloric Acid Solution 0.1 M or Sodium Hydroxide Solution 0.1 M q.s. to pH 4.0 to 7.0 Sterile water q.s. to 10 ml The active ingredient is dissolved in most of the water (35° - 40° C) and the pH adjusted to between 4.0 and 7.0 with the hydrochloric acid or the sodium hydroxide as appropriate. The batch is then made up to volume with water and filtered through a sterile micropore filter into a sterile 10 ml amber glass vial (type 1) and sealed with sterile closures and oversea Is. Formulation B Active Ingredient 125 mg Sterile, Pyrogen-free, pH 7 Phosphate Buffer, q.s. to 25 ml Example 12: Intramuscular Injection Active Ingredient 200 mg Benzyl Alcohol 0.10 g Glycofurol 75 1.45 g Water for injection q.s. to 3.00 ml The active ingredient is dissolved in the glycofurol. The benzyl alcohol is then added and dissolved, and water added to 3 ml. The mixture is then filtered througn a sterile micropore filter and sealed in sterile 3 ml amber glass vials (type 1). Example 13: Syrup Active Ingredient 250 mg Sorbitol Solution 1.50 g Glycerol 2.00 g Sodium Benzoate 0.005 g Flavor, Peach 17.42.3169 0.0125 ml Purified Water q.s. to 5.00 ml The active ingredient is dissolved in a mixture of the glycerol and most of the purified water. An aqueous solution of the sodium benzoate is then added to the solution, followed by addition of the sorbital solution and finally the flavor. The volume is made up with purified water and mixed well. Example 14: Suppository mg/capsule suppository Active Ingredient 250 Hard Fat, B.P. (Witepsol Hl 5-Dynamit Nobel) 1770 2020 One-fifth of the Witepsol Hi 5 is melted in a steam-jacketed pan at 45°C maximum. The active ingredient is sifted through a 200μm sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45° C, the remaining Witepsol H 15 is added to the suspension and stirred to ensure a homogenous mix. The entire suspension is passed through a 250μm stainless steel screen and, with continuous stirring, is allowed to cool to 45° C. At a temperature of 38° C to 40° C, 2.02 g of the mixture is filled into suitable, 2 ml plastic molds. The suppositories are allowed to cool to room temperature. Example 15: Pessaries mg/pessary Active Ingredient 250 Anhydrate Dextrose 380 Potato Starch 363 Magnesium Stearate 7 1000 The above ingredients are mixed directly. Example 16 Acid Stability The compound of Example 3 was tested for stability towards acid-mediated hydrolytic decomposition employing a test designed to simulate stomach conditions. The compound was incubated at an initial concentration of 0.27 mg/mL in dilute hydrochloric acid at pH 1 for 72 hours at 37°C. HPLC was run immediately for t = 0 and at intervals up to approximately 72 hours. The half-life of the compound of Example 3 in 0.1 N hydrochloric acid under these conditions was 36 hours. In contrast, the phosphoramidate of 2', 3'-dideoxy-adenosine (Compound 1093, PCT/GB96/00580) had entirely decomposed by t = 13 hours and 2', 3'-didehydro-2', 3'- dideoxy-adenosine (Compound 1001 , PCT/GB96/00580) had entirely decomposed at t = 0 in 0.1 N hydrochloric acid at 25°C.

Claims: Claims 1. A compound of formula (I) (I) wherein: R 1 is hydrogen; Cs-uaryl; or heteroaryl, optionally substituted with one or more substituents selected from the group consisting of G-salkoxy, nitro, halogen, amino, hydroxy, carboxylate and esters thereof, carboxyalkyl, -CONHR 6 , and -C0NR 6 R 7 , wherein R 6 and R 7 , which may be the same or different, are independently selected from G-salkyl, G- βalkylaryl or Cs-uaryl; R 2 and R 3 are independently selected from hydrogen; or G-salkyl, G-scycloalkyl, G-salkenyl, Cs-scycloalkenyl, Cs-uaryl, or aralkyl wherein each G-salkyl, G-scycloalkyl, G-salkenyl, Cs- βcycloalkenyl, Cs-uaryl, or aralkyl may be optionally substituted with one or more substituents selected from the group consisting of G-salkyl, halo, hydroxy, alkoxy, amino, aminoalkyl, aminodialkyl, -SH, thioalkyl, carboxylate and esters thereof, carboxyalkyl, - CONHR 6 , and -C0NR 6 R 7 , wherein R 6 and R 7 , which may be the same or different, are independently selected from G-salkyl, G-salkylaryl or Cs-uaryl; or R 2 and R 3 can together form a 3 to 8-membered ring; R 4 is -OR 8 , -NR 8 R 9 or -SR 8 , where R 8 and R 9 , which may be the same or different, are independently selected from hydrogen, or G-βalkyl, G-scycloalkyl, G-salkenyl, G- scycloalkenyl, heterocycle, aralkyl, Cε-uaryl or G-salkylaryl wherein each G-salkyl, G- 31 scycloalkyl, G-salkenyl, G-scycloalkenyl, heterocycle, aralkyl, Cs-uaryl or G-salkylaryl may be optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, amino, aminoalkyl, aminodialkyl, -SH, thioalkyl, carboxylate and esters thereof, carboxyalkyl, -CONHR 6 , and -CONR 6 R 7 , wherein R 6 and R 7 , which may be the same or different, are independently selected from G-salkyl, G-βalkylaryl or Cs-uaryl; R 5 is hydrogen; G-salkyl; or Cs-uaryl; or R 2 and R 5 may together form a 5- or 6-membered ring; or R 3 and R 5 may together form a 5- or 6-membered ring; or a pharmaceutically acceptable derivative thereof. 2. A compound of formula (I) according to claim 1 wherein R 1 is hydrogen, Cs-uaryl; R 2 and R 3 are independently hydrogen, G-salkyl or aralkyl; R 4 is -OR 8 wherein R 8 is hydrogen, G-ealkyl, Cs-uaryl or G-salkylaryl and R 5 is hydrogen; or a pharmaceutically acceptable derivative thereof. 3. A compound selected from (1 R, cis)-4-[4-amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol-0- [phenyl (methoxy L-alaninyl)]phosphoramidate; (1 R, cis)-4-[4-amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1-methanol-0- [phenyl (methoxy α, α-dimethylglycinyl)]phosphoramidate; (1 R, cis)-4-[4-amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol-0- [phenyl (methoxy L-phenylalaninyl)]phosphoramidate; and (1 R, cis)-4-[4-amino-7H-pyrrolo(2,3-d)pyrimidin-7-yl]-2-cyclopentene-1 -methanol-0- [phenyl (benzyloxy L-alaniny!)]phosphoramidate; or a pharmaceutically acceptable derivative thereof. 4. A method of treating a virus infection in a human comprising administering to said human an effective anti-virus treatment amount of a compound of formula (I) according to any of claims 1 to 3 or a pharmaceutically acceptable derivative thereof. 5. The method according to claim 4 wherein the virus is selected from Human Immunodeficiency Virus, hepatitis B virus, and hepatitis C virus. 6. A method of treating a hepatitis B virus infection in a human comprising administering to said human an effective anti-hepatitis B treatment amount of a compound according to any of claims 1 to 3 or a pharmaceutically acceptable derivative thereof. 7. A method of treating a HIV infection in a human comprising administering to said human an effective anti-HIV infection treatment amount of a compound according to any of claims 1 to 3 or a pharmaceutically acceptable derivative thereof. 8. A compound according to any of claims 1 to 3 wherein the pharmaceutically acceptable derivative is a salt. 9. A pharmaceutical composition comprising an effective anti-viral amount of a compound of formula (I) according to any of claims 1 to 3 or a pharmaceutically acceptable derivative thereof together with a pharmaceutically acceptable carrier therefor. 10. The pharmaceutical composition according to claim 9 , further comprising an antiviral agent other than a compound of formula (I). 1 1. A pharmaceutical composition according to claim 9 or 10 in the form of a tablet or capsule. 12. A pharmaceutical composition according to claim 9 or 10 in the form of a solution, suspension, or syrup. 13. A compound of formula (I) as claimed in claim 1 for use in medical therapy. 14. Use of a compound of formula (I) as claimed in claim 1 in the manufacture of a medicament for the treatment or prophylaxis of a virus infection. 15. A process for the preparation of compounds of formula (I) (I) wherein: R 1 is hydrogen; Cs-uaryl; or heteroaryl, optionally substituted with one or more substituents selected from the group consisting of G-salkoxy, nitro, halogen, amino, hydroxy, carboxylate and esters thereof, carboxyalkyl, -CONHR 6 , and -C0NR 6 R 7 , wherein R 6 and R 7 , which may be the same or different, are independently selected from G-salkyl, Ci- salkylaryl or Cs-uaryl; R 2 and R 3 are independently selected from hydrogen; or G-βalkyl, G-scycloalkyl, G-βalkenyl, Cδ-Bcycloalkenyl, Cs-uaryl, or aralkyl wherein each G-βalkyl, G-βcycloalkyI, G-salkenyl, G- βcycloalkenyl, Cs-uaryl, or aralkyl may be optionally substituted with one or more substitue.us selected from the group consisting of G-βalkyl, halo, hydro <y, alkoxy, amino, aminoalkyl, aminodialkyl, -SH, thioalkyl, carboxylate and esters thereof, carboxyalkyl, - CONHR 6 , and -C0NR 6 R 7 , wherein R 6 and R 7 , which may be the same or different, are independently selected from G-salkyl, Ci-salkylaryl or Cs-uaryl; or R 2 and R 3 can together form a 3 to 8-membered ring; R 4 is -OR 8 , -NR 8 R 9 or -SR 8 , where R 8 and R 9 , which may be the same or different, are independently selected from hydrogen, or G-salkyl, G-scycloalkyl, G-βalkenyl, G- scycloalkenyl, heterocycle, aralkyl, Cs-uaryl or Ci-salkylaryl wherein each G-βalkyl, G- scycloalkyl, G-salkenyl, G-βcycloalkenyl, heterocycle, aralkyl, Cs-uaryl or G-salkylaryl may be optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, amino, aminoalkyl, aminodialkyl, -SH, thioalkyl, carboxylate and esters thereof, carboxyalkyl, -CONHR 6 , and -C0NR 6 R 7 , wherein R 6 and R 7 , which may be the same or different, are independently selected from Ci-salkyl, Ci-salkylaryl or Cs-uaryl; R 5 is hydrogen; G-βalkyl; or Cs-uaryl; or R 2 and R 5 may together form a 5- or 6-membered ring; or R 3 and R 5 may together form a 5- or 6-membered ring; which comprises reaction of a compound of formula (II) (N) with a compound of formula (III) (IN) wherein R 1 - R 5 are as hereinbefore defined.

Inventors: DALUGE SUSAN MARY, GUDMUNDSSON KRISTJAN, DALUGE, SUSAN, MARY, GUDMUNDSSON, KRISTJAN
Applicants: DALUGE SUSAN MARY, GLAXO GROUP LTD, GUDMUNDSSON KRISTJAN, DALUGE, SUSAN, MARY, GLAXO GROUP LIMITED, GUDMUNDSSON, KRISTJAN
Application year: 2000
Main classification: C07F9
IPC codes: A61K9, A61K31, A61K45, A61P1, A61P31, C07F9