CH679152A5 - - Google Patents

Description

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH 679 152 A5

description

The present invention relates to dideoxycarbocyclic nucleoside analogs. In particular, it relates to carbocyclic 2,3'-dideoxy-2 ', 3'-didehydropurine nucleoside analogs that can be used in therapy, particularly as antiviral agents.

In view of the similarity between viral and guest cell functions, it is difficult to selectively attack a virus while leaving the guest cell intact. Thus, there are relatively few agents that are effective against viruses per se, and it is difficult to find antiviral agents that have an acceptable therapeutic index, i.e. Agents that have a significant antiviral effect at a dose at which the agent has an acceptable toxicity on average and no side effects.

A group of viruses that have recently gained great importance are the retroviruses, which are responsible for the "human acquired immunodeficiency syndrome" (AIDS). Such viruses used to be assigned to different terminologies, but are now commonly referred to as "human immunodeficiency viruses" (HIV's); two such viruses, HIV-J and HIV-II, have been reproducibly isolated from patients suffering from AIDS and related conditions such as AIDS related complex (ARC) and persistent general lymphadenopathy.

Although a number of nucleosides have been identified as useful in treating conditions associated with HIV infection, only zidovudine (AZT, Retrovir) has received regulatory approval to treat such conditions. However, zidovudine is known to have severe side effects which cause bone marrow displacement, which leads to a decrease in the number of white blood cells with consequent, pronounced anemia, and there is therefore a need for effective agents that are less cytotoxic.

A new class of nucleoside analogues have now been found that have antiviral activity. According to a first feature of the invention, a compound of the formula (I)

X is hydrogen, NRR1, SR, OR or halogen,

Z is hydrogen, OR2 or NRR1;

R, R1 and R2 may be the same or different and are selected from hydrogen, Ci-4-alkyl and aryl as well as pharmaceutically acceptable salts, esters or salts thereof.

It is clear to the person skilled in the art that the compounds of the formula (I) are cis compounds, and furthermore that the cyclopentene ring of the compounds of the formula (I) contains two chiral centers 0n formula (I) shown by the asterisk *] and so in the form of two optical isomers (ie enantiomers) and mixtures thereof including racemic mixtures. All such isomers and mixtures thereof including the racemic mixtures are included in the scope of the invention. Accordingly, in the compounds of formula (I) either the chiral center to which the base is attached is in the R configuration and the chiral center to which the CH2ÖH half is attached is in the S configuration (hereinafter the D isomer) or the chiral center to which the base is attached is in the S configuration and that to which the CHaOH half is attached is in the R configuration (hereinafter the L isomer). The compounds will expediently be present either in the form of a racemic mixture or essentially as the pure D isomer. The D isomers can be represented by the formula (Ia)

(I)

wherein

2nd

CH 679 152 AS

10th

15

20th

(la)

in which X and Z are as defined in formula (I). Further reference to compounds of formula (I) includes compounds of formula (Ia).

Those skilled in the art will also recognize that various of the compounds of formula (I) can exist as a number of tautomeric forms, and all such tautomers are included in the scope of the invention.

The term "halogen" used here refers to fluorine, chlorine, bromine and iodine; if X is halogen, it is preferably chlorine.

The term "Ci - ^ - alkyl" used here refers to straight or branched alkyl groups, 25 for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. Ci-4-AlkyI is expediently methyl.

The term "aryl" as used herein refers to any mono- or polycyclic aromatic half and includes unsubstituted and substituted aryl (such as phenyl, tolyl, xylyl, anisyl) and unsubstituted and substituted aralkyl including ar- (Ci-4) alkyl such as Phen- (Ci-4) alkyl, 30 for example benzyl or phenethyl.

In the compounds of formula (I), Z is preferably amino.

In a preferred class of compounds of formula (I), X = OR, especially OH.

In a further preferred class of compounds of the formula (I), X represents NRFP, in particular NH2, or hydrogen.

35 Particularly preferred compounds of the formula (I) are those in which Z = NH2 and X = H, NH2 or especially OH. Such compounds in particular have particularly desirable therapeutic indices as antiviral agents.

In the following, the expression “a pharmaceutically acceptable derivative” is to be understood to mean any pharmaceutically acceptable salt, any pharmaceutically acceptable ester or any pharmaceutically acceptable salt of such an ester of a compound of the formula (I).

Preferred esters of the compounds of formula (I) include carboxylic acid esters in which the non-carbonyl half of the ester group is selected from hydrogen, straight or branched alkyl (eg methyl, ethyl, n-propyl, tert-butyl, n-butyl), alkoxyalkyl (eg methoxymethyl), aralkyl (eg benzyl), aryloxyalkyl (eg phenoxymethyl), aryl (eg phenyl, optionally substituted by halogen, 45 Ci_4.-alkyl or Ci-4-alkoxy); Sulfonate esters such as alkyl or aralkylsulfonyl (e.g. methanesulfonyl); Amino acid esters (e.g. L-valyl or L-isoleucyl) and mono-, di- or triphosphate esters.

With respect to the esters described above, any alkyl half present advantageously contains 1 to 18 carbon atoms, especially 1 to 4 carbon atoms, unless otherwise stated. Any aryl half present in such esters advantageously includes a phenyl group. 50 Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable, inorganic and organic acids and bases. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, 55 formic acid, naphaic acid, benzoic acid, benzoic acid -2-sulfonic acid and benzenesulfonic acid. Other acids, such as oxalic acid, although pharmaceutically unacceptable in themselves, may be useful in the preparation of salts which are useful as intermediates in the preparation of the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts of suitable bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), Am-60 monium and NR4. + (R = Ci-4-alkyl) salts.

The following references to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable derivatives.

Specific compounds of formula (I) include: (1a, 4a) -4- (6-chloro-9H-purin-9-yl) -2-cyclopentenylcarbinol; 65 (1a, 4oc) -4- (6-hydroxy-9H-purin-9-yl) -2-cyclopentenyl-carbinoI;

3rd

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH679152 A5

(1a, 4a) -4- (6-amino-9H-purin-9-yl) -2-cyclopentenyl-carbinol;

(1a, 4a) -4- (6-mercapto-9H-purin-9-yl) -2-cyclopentenyl carbinol;

(1a, 4a) -4- (2-amino-6-chloro-9H-purin-9-yI) -2-cyclopentenyl-carbinol;

(1a, 4a) -4- (2-amino-6-hydroxy-9H-purin-9-yl) -2-cyclopentenyl-carbinoI;

(1a, 4a) -4- (2,6-diamino-9H-purin-9-yl) -2-cyclopentenyl-carbinol;

in the form of a racemic mixture or a single enantiomer.

The compounds according to the invention either themselves have antiviral activity and / or can be metabolized to form such compounds. In particular, these compounds are effective in inhibiting the replication of retroviruses, including human retroviruses, such as human immunodeficiency viruses (HIV's), the causative agents of AIDS.

Certain compounds according to the invention have anti-cancer activity, especially those in which Z is hydrogen.

Accordingly, according to a further aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable derivative thereof (as defined above) is created as an active therapeutic agent, in particular as an antiviral agent, for example in the treatment of retroviral infections, or as an anti-cancer agent .

According to a further or alternative aspect, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof (as defined above) for the manufacture of a medicament for the treatment of a viral infection or an anti-cancer agent.

The compounds according to the invention which have antiviral activity are also useful in the treatment of AIDS-related conditions such as AIDS-related complex (ARC), persistent general lymphadenopathy (PGL), AIDS-related neurological conditions (such as idiocy or tropical paraparesis), anti-HIV antibody positive and HIV positive conditions, Kaposi-Sar-kom and thrombopenic purpura.

The antiviral compounds according to the invention are also valuable in preventing the advancement to clinical disease of individuals who are anti-HIV antibody or HIV antigen positive and in prophylaxis due to HIV exposure.

The antiviral compounds of formula (I) or their pharmaceutically acceptable derivatives can also serve to prevent viral contamination of physiological liquids, such as blood or semen, in vitro.

Certain compounds of formula (I) are also valuable as intermediates in the preparation of other compounds of the invention. It will be apparent to those skilled in the art that the treatment mentioned here extends both to prophylaxis and to the treatment of existing infections or symptoms.

It should further be noted that the amount of the compound of the invention required for use in the treatment is not only with the particular compound selected, but also with the route of administration, the nature of the disease to be treated and the age and condition of the patient will vary and is ultimately left to the judgment of the treating doctor or veterinarian. Generally, however, a suitable dose will range from about 1 to about 750 mg / kg, e.g. from about 10 to about 750 mg / kg body weight / day, such as 3 to about 120 mg / kg body weight of the recipient per day, preferably in the range from 6 to 90 mg / kg / day, particularly preferably in the range from 15 to 60 mg / kg / day.

The desired dose can conveniently be presented in a single dose or as divided doses which are administered at suitable intervals, for example two, three, four or more sub-doses per day.

The compound is conveniently administered in unit dosage form; for example containing 10 to 1500 mg, suitably 20 to 1000 mg, most suitably 50 to 700 mg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound of about 1 to about 75 nM, preferably about 2 to 50 nM, more preferably about 3 to about 30 pM. This can be achieved, for example, by intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or administered orally as a bolus containing about 1 to about 100 mg / kg of active ingredient. Desirable blood levels can be maintained by continuous infusion to achieve about 0.01 to about 5.0 mg / kg / h or by intermittent infusions containing about 0.4 to about 15 mg / kg active ingredient.

While it is possible that a compound according to the invention can be administered as a raw chemical for use in therapy, it is preferable to present the active ingredient as a pharmaceutical formulation.

Accordingly, the invention provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers and optionally other therapeutic and / or prophylactic ingredients. The carrier (s) must be "acceptable" in the sense that they are compatible with the other components of the formulation and not detrimental to the recipient.

Pharmaceutical formulations include those for oral, rectal, nasal, topical (single

4th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH679152 A5

finally buccal and sub-lingual), vaginal or parenteral (including intramuscular and intravenous) administration, or in a form suitable for administration by inhalation or insufflation. The formulations, where appropriate, may conveniently be presented in unit dosage form and may be prepared by any method known in the pharmaceutical industry. All methods include the step of bringing the active compound together with liquid carriers or finely divided solid carriers or both and then shaping the product into the desired formulation if necessary.

Pharmaceutical formulations suitable for oral administration may conveniently be offered as single units such as capsules, capsules or tablets, each containing a predetermined amount of the active ingredient; as powder or granules; as a solution, suspension or emulsion. The active ingredient can also be presented as a bolus, latwerge or paste. Tablets and capsules for oral administration can contain conventional excipients such as binders, fillers, lubricants, dividing agents or wetting agents. The tablets can be coated by conventional methods. Oral, liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or can be in the form of a dry product for preparation with water or a suitable other carrier before use. Such liquid preparations can contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which include edible oils) or preservatives.

The compounds according to the invention can also be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and can be present in unit dose form in ampoules, prefilled syringes or multiple containers with added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be in powder form, obtained by aseptic isolation of the sterile solid or by lyophilization from solution, for preparation with a suitable carrier, e.g. sterile, pyrogen-free water, before use.

For topical administration to the epidermis, the compounds according to the invention can be present as ointments, creams or lotions or as a transdermal patch or rag. Ointments and creams can be formulated, for example, with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base and will generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants.

Formulations suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; Pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Pharmaceutical formulations suitable for rectal administration in which the carrier is a solid are preferably unit dose suppositories. Suitable carriers include cocoa butter and other commonly used materials, and the suppositories may conveniently be formed by mixing the active compound with the softened or melted carriers, followed by vigorous cooling and molding.

Formulations suitable for vaginal administration can be present as pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, such carriers as are known in the art as suitable.

For intra-nasal administration, the compounds according to the invention can be used as a liquid spray or in the form of drops.

Drops can be formulated with an aqueous or non-aqueous base that also contain one or more dispersants, solubilizers, or suspending agents. Liquid sprays are conveniently delivered from pressure packs.

For administration by inhalation, the compounds according to the invention can expediently be supplied from an inhaler or blowing device, atomizer or pressure pack or other suitable means for delivering an aerosol spray. Pressure packs can contain a suitable propellant gas, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or another suitable gas. In the case of an aerosol under pressure, the dose unit can be determined by providing a valve that delivers a metered amount.

Alternatively, the compounds according to the invention for administration by inhalation or injection may be in the form of a dry powder composition, for example a powder mixture of the compound and a suitable powder base such as lactose or starch. The powder composition may be in unit dosage form, for example in capsules or cartridges or e.g. Gelatin or plaster packs, from which the powder can be administered with the help of an inhaler or blowing device.

If desired, the above formulations can be adapted so that there is a sustained release of the active ingredient.

5

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH 679 152 A5

The pharmaceutical compositions according to the invention can also contain other active ingredients, such as antimicrobial agents or preservatives.

The compounds according to the invention can also be used in combination with other therapeutic agents, for example with other anti-infection agents. In particular, the compounds according to the invention can be used together with known antiviral agents.

According to a further aspect, the invention thus provides a combination comprising a compound of the formula (I) or a physiologically acceptable derivative thereof, together with another therapeutically active agent, in particular an antiviral agent.

The above-mentioned combinations may suitably be in the form of a pharmaceutical formulation, and so pharmaceutical formulations containing a combination as defined above together with a pharmaceutically acceptable carrier therefor comprise another aspect of the invention.

Suitable therapeutic agents for use in such combinations include acyclic nucleosides such as aciclofir, interferons such as a-interferon, kidney secretion inhibitors such as probe nicid, nucleoside transport inhibitors such as dipyridamole, 2 ', 3'-dideoxynucleosides such as 2', 3'- Dideoxycyti-din, 2 ', 3-dideoxyadenosine, 2', 3-dideoxyinosine, 2 ', 3'-dideoxythymidine and 2', 3'-dideoxy-2 ', 3'-di-dehydrothymidine, and immunomodulators such as interleukin II (IL2) and granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin and ampligen.

The individual components of such combinations can be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.

When the compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent that is active against the same virus, the dosage of each compound may differ from that when the compound is taken alone. Suitable dosages are easily determined by a person skilled in the art.

The compounds of formula (I) and their pharmaceutically acceptable derivatives can be prepared by any known method for the preparation of compounds of analogous structure.

Suitable methods for the preparation of the compounds of formula (I) and their pharmaceutically acceptable derivatives are described below. The groups X and Z are as defined above unless otherwise stated. It should be noted that the following reactions require the use of starting materials with protected functional groups or can be used expediently, and the deprotection may accordingly be necessary as an intermediate or final step in order to obtain the desired compound. The functional groups can be protected and the protective groups split off using customary means. For example, amino groups can be protected by a group selected from aralkyl (e.g. benzyl), acyl or aryl (e.g. 2,4-dinitrophenyl); the subsequent removal of the protective group is, if desired, carried out by hydrolysis or hydrogenolysis, depending on the expediency, using standard conditions. Hydroxyl groups can be protected using any conventional hydroxyl protecting group, for example as described in "Protective Groups in Organili Chemistry", published by J.F.W. McOmie (Plenum Press, 1973), or "Protective Groups in Organic Synthesis" by Theodora W. Greene (John Wiley and Sons, 1981). Examples of suitable hydroxyl protecting groups include: groups selected from alkyl (e.g. methyl, tert-butyl or methoxymethyl), aralkyl (e.g. benzyl, diphenylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydropyranyl, acyl (e.g. acetyi or benzoyl) - and Silyl groups, such as trialkylsilyl (for example tert-butylimethylsilyl). The hydroxyl protecting groups can be removed by conventional techniques. For example, alkyl, silyl, acyl and heterocyclic groups can be removed by solvolysis, e.g. by hydrolysis under acidic or basic conditions. Aralkyl groups such as triphenylmethyl can be similarly removed by solvolysis, e.g. by hydrolysis under acidic conditions. Aralkyl groups, such as benzyl, can be split off by hydrogenolysis in the presence of a noble metal catalyst, such as palladium-on-carbon. Silyl groups can also be conveniently removed using a source of fluoride ions such as tetra-n-butylammonium fluoride.

In a first process (A), compounds of formula (I) and pharmaceutically acceptable derivatives thereof can be prepared by reacting a compound of formula (II)

6

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH 679152 A5

ff n

/ h2.

n

/ ^ / \, u z n nh y-ch

2 \ / \

i

(n)

(wherein X and Z are substituents as defined in formula (I) or protected forms thereof and Y is a hydroxyl group or a protected form thereof) or a pharmaceutically acceptable derivative thereof with a reagent selected from formic acid and reactive derivatives thereof, and below , if necessary, removal of unwanted groups introduced by this reagent and / or removal of any protecting groups present.

Examples of suitable derivatives of formic acid that can be used in process (A) above include: orthoformates (e.g. triethyl orthoformate), dialkoxymethylacetates (e.g. diethoxymethylacetate), dithio formic acid, formamide, s-triazine or formamidine acetate.

Undesired groups sensed by formic acid or a reactive derivative thereof can conveniently be removed by mild hydrolysis, for example using an inorganic acid such as aqueous hydrochloric acid.

If a trialkyl orthoformate, such as triethyl orthoformate, is used, this is also expediently the solvent for the reaction. Other solvents that can be used include amides (e.g. dimethylformamide or dimethyiacetamide), chlorinated hydrocarbons (e.g. dichloromethane), ethers (e.g. tetrahydrofuran) or nitriles (e.g. acetonitrile).

In some cases (e.g. when a trialkyl orthoformate such as triethyl orthoformate is used) the reaction may preferably be carried out in the presence of a catalyst such as a strong acid (e.g. concentrated hydrochloric acid, nitric acid or sulfuric acid). The reaction can be carried out at a temperature in the range of -25 to + 150 ° C, e.g. 0 to 100 ° C, and conveniently at ambient temperature.

In another process (B), compounds of formula (1) and their pharmaceutically acceptable derivatives or a protected form thereof are subjected to an internal conversion reaction, whereby the originally present substituent X is replaced by another substituent X and / or the originally present group Z is replaced by another group Z, and then, if necessary, removal of any protective groups present.

In one embodiment of process (B), compounds of the formula (I) in which X represents a group NRR1 (where R and R1 are as defined above) can be prepared by amination of a corresponding compound of the formula (I) in which X represents a halogen atom (eg chlorine). The amination can be accomplished by reaction with a reagent HNRR1 (wherein R and R1 are as defined above), conveniently in a solvent such as an alcohol (e.g. methanol). The reaction can be carried out at any suitable temperature, and conveniently at an elevated temperature, such as under reflux or, if liquid ammonia is used, in a sealed tube at about 50 to 80 ° C. Suitable conditions for the conversion of the halides to secondary and tertiary amines have also been proposed by I.T. Harrison et al., Compendium of Organic Synthetic Methods, Wiley-Interscience, New York (1971) on pages 250-252.

In another embodiment of process (B), compounds of formula (I) wherein X represents an OR group (R is as defined above) can be prepared by exchanging the halogen (e.g. chlorine) atom with a suitable anion RO ~. When R represents a hydrogen atom, the exchange reaction can be carried out by hydrolysis in water or in a mixture of water and a water-miscible solvent such as an alcohol (e.g. methanol or ethanol), an ether (e.g. dioxane or tetrahydrofuran) Ketone (eg acetone), an amide (eg dimethylformamide) or a sulfoxide (eg dimethylsulfoxide), expediently in the presence of an acid or base. Suitable acids include organic acids such as p-toluenesulfonic acid and inorganic acids such as hydrochloric, nitric or sulfuric acid. Suitable bases include inorganic bases such as alkali metal hydroxides or carbonates (e.g. sodium or potassium hydroxide or carbonate). Aqueous acid or base can also be used as a reaction solvent. The hydrolysis can conveniently be carried out at a temperature in the range from -10 to + 150 ° C, e.g. under reflux. If R is a C 1-4 alkyl or aryl group, the anion RO ~ is used7

5

10th

15

20th

25th

30th

35

40

45

50

55

CH679 152 A5

bulky formed from a corresponding alcohol ROH using an inorganic base such as an alkali metal (e.g. metallic sodium) or an alkali metal hydride (e.g. sodium hydride). The reaction with the anion formed in situ can expediently be carried out at ambient temperature.

In a further embodiment of process (B), compounds of the formula (I) in which X is a group SH can be prepared by reacting the halogen compound of the formula (I) with thiourea in a suitable solvent, such as an alcohol (for example n-propanol) ), at elevated temperature (e.g. reflux) and subsequent alkaline hydrolysis. Suitable bases that can be used include alkali metal hydroxides (e.g. sodium hydroxide). The reaction can conveniently be carried out according to the method of G.G. Urquart et al., Org. Syn. Coll., Vol. 3, 363 (1953), e.g. by refluxing the intermediate with aqueous NaOH for about 0.25 to about 5 hours.

In another embodiment of process (B), compounds of formula (I) in which X represents a hydrogen atom can be prepared by reducing the halogen compound of formula (!) Using a reducing system that does not attack the rest of the molecule. Suitable reducing agents that can be used to effect the desired dehalogenation reaction include metallic zinc / water using those described by J.R. Marshall et al., J. Chem. Soc., 1004 (1951). Alternatively, the reaction can be carried out by photolysis in a suitable solvent, such as tetrahydrofuran, containing 10% triethylamine, and expediently in a Rayonet photochemical reactor (2537A) according to the method of V. Nair et al., J. Org. Chem., 52.1344 ( 1987).

In yet another embodiment of process (B), compounds of formula (I) wherein X is a halogen atom can be prepared from another halogen compound of formula (I) by conventional halide-halide exchange methods. Alternatively, when X is chlorine, this substituent can be replaced with another halogen atom using various p- (halo) benzene diazonium chlorides by known methods.

Compounds of the formula (I) in which X is a group SH, where R is a Ci-4-alkyl or aryl group, can be obtained from the corresponding thiols using standard methods of alkylation or arylation, for example as in US -PS 4383 114 described.

Compounds of formula (I) in which Z represents a hydroxyl group can conveniently be prepared from a corresponding compound of formula (I) in which Z represents NH2 by reaction with nitrous acid, for example using the method described by J. Davoll in J. Amer . Chem. Soc., 23, 3174 (1951).

Many of the reactions described above have been described in detail in connection with purine nucleoside synthesis, for example in Nucleoside Analogs »Chemistry, Biology and Medicai Applications, R.T. Walker et al., Eds., Plenum Press, New York (1979), pages 193-223, the disclosure of which is incorporated by reference herein.

Pharmaceutically acceptable salts of the compounds according to the invention can be prepared in accordance with US Pat. No. 4,383,114, the disclosure content of which is incorporated by reference. For example, if it is desired to prepare an acid addition salt of a compound of formula (i), the product of any of the above methods can be salted by treating the resulting free base with an appropriate acid using conventional methods. Pharmaceutically acceptable acid addition salts can be prepared by reacting the free base with a suitable acid, optionally in the presence of a suitable solvent, such as an ester (e.g. ethyl acetate) or an alcohol (e.g. methanol, ethanol or iso-propanol). Inorganic base salts can be prepared by reacting the free base with a suitable base such as an alkoxide (e.g. sodium methoxide), optionally in the presence of a solvent such as an alcohol (e.g. methanol). Pharmaceutically acceptable salts can also be prepared from other salts including other pharmaceutically acceptable salts of the compounds of formula (I) using conventional methods.

A compound of formula (I) can be converted to a pharmaceutically acceptable phosphate or other ester by reaction with a phosphorylating agent, such as poci3, or a suitable esterifying agent, such as an acid halide or anhydride, as appropriate. An ester or salt of a compound of formula (I) can be converted to the parent compound, for example by hydrolysis.

The compounds of formula (II) and salts thereof are new compounds and form a further feature of the present invention.

The compounds of formula (II) in which Z represents hydrogen or hydroxyl can be obtained directly from compound 2a

8th

CH679152 A5

20th

30th

45

55

60

wh2

^ a!

28

10 are prepared by reaction with an excess of a pyrimidine of the formula (III)

. x

à / "2-

I B (III)

/ \ / V

z n y

(where Y is a halogen atom, e.g. chlorine and Z is hydrogen or hydroxyl) in the presence of an amine base such as triethylamine and in an alcoholic solvent (e.g. n-butanol), conveniently under reflux.

25 Compounds of formula (II) wherein Z is NH2 can be prepared using the compound of formula 2a by reaction with an excess of a pyrimidine of formula (IV)

/ \ (iv)

! 1

ss / \ / \

h2n n y

[wherein Y is as defined in formula (III) above] under conditions similar to those described above for the preparation of compounds of formula (II) wherein Z is hydrogen or hydroxyl 40 to a compound of formula (V)

50 h2n n t |! H ho-CH2v

// \

N •

i 1 cv)

f \ / \

I i

<•

to be diazotized using a diazonium salt ArN2 + E ~ (where Ar represents an aromatic group, e.g. p-chlorophenyl, and E ~ denotes an anion, e.g. a halide such as chloride) in a solvent such as water, an organic acid, such as acetic acid, or a mixture thereof, advantageously at about ambient temperature, to give a compound of the formula (VI)

65

9

5

10th

15

20th

25th

30th

35

40

45

50

55

60

CH 679152 A5

X

• i

// \ /

K'sN-Ar

8th

(VI)

(where Ar is as previously defined) which can be converted into the desired compound of formula (II) by reduction using, for example, a reducing metal such as zinc in the presence of an acid, e.g. Acetic acid, can be transferred. It should be noted that the selection of the reducing agent will depend on the nature of group X.

Compound 2a can be prepared from the Versatil precursor, 1a-acetylamino-3a-acetoxy-methylcyclopent-2-ene (1a), by hydrolysis in the presence of a weak base such as an alkaline earth metal hydroxide.

A particularly useful synthesis of the compounds of formula (I) via 6-chloro compounds of formula (II) is listed below.

10th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH679152 A5

Cl

AcO—. •

{/

K'HAc

\

NH.

la

Cl htla |

lj

* 2a

?

7 / \ ti h2n n

5a

A

N

j

/ a / k *

—N = K— • .r ~ \ -ci

I «" »- vwV

/ \ / \ A A

^ h2n n \

nh h

"1a ■,

! 1 • =

6a nh t \

n

! ■

A A

z n nh iQ — t •

V

\

3a

1

î

/ \ / '

N

I II CH

* / vV

h0n4 • •

l I

CI)

// \

/ \\ / \ H, M N \

H0 _) /

"H

\

4a

Compound 2a and compounds of formulas (V) and (VI) are new intermediates. The compounds of the formulas (V) and (VI) form further objects of the present invention.

Compound 1a is a known compound described in U.S. Patent 4,138,562.

If the compound of formula (I) is desired as the only isomer, it can be obtained either by resolution of the final product or by stereospecific synthesis from isomerically pure starting material or any suitable intermediate.

The splitting of the end product or an intermediate or starting material can therefore be effected by any method known in the art: see, for example, “Stereo

11

5

10th

15

20th

25th

30th

35

40

45

50

55

60

CH679152 A5

chemistry of Carbon Compounds »from E.L. Eliei (McGraw Hill, 1962), and "Tables of Resolving Agents" by S.H. Wilen.

An expedient method for achieving chiral-pure compounds of the formula (1) consists in the enzymatic conversion of a racemic mixture of the compound or a precursor thereof. Such a method can be used to obtain both (+) and (- ^ - compounds of the formula (I) in optically pure form. Suitable enzymes include deaminases, such as adenosine deaminase,

The invention is further described with reference to the following detailed examples, wherein the elemental analyzes were performed by M-H-W Laboratories, Phoenix, AZ. The melting points were determined on a Mel-Temp apparatus and are corrected. The nuclear magnetic resonance spectra were obtained on Jeol FX 90QFT or Nicollet NT300 spectrometers and determined in DMSO-De. Chemical shifts are expressed in ppm downfield from Me ^ Si. IR spectra were determined as KBr pellets with a Nicollet 50XC FT-IR spectrometer, and UV spectra were measured on the Beckmann DU-8 spectrophotometer. ' Mass spectra were obtained using an AEI Scientific Apparatus Limited MS-30 mass spectrometer. Thin layer chromatography (TLC) was performed on 0.25 mm layers of Merck silica gel (230-400 mesh). All chemicals and solvents are reagent grade unless otherwise noted. The term "active ingredient" as used in the examples means a compound of formula (I) or a pharmaceutically acceptable derivative thereof.

example 1

fiW1a.4rcV4-iï5-Amin0-6-chl0r-4-pvrimidinvh-amin0l-2-cvcl0Dentenvlcarbin0l (3aì

A mixture of 1 ~ acetylamino-3a-acetoxymethyl-cyclopent-2-ene (1a) (3.0 g, 15 mmol) and aqueous barium hydroxide (0.5N, 300 ml) was heated under reflux overnight. After cooling, it was neutralized with dry ice. The precipitate was filtered off and the aqueous solution was evaporated to dryness. The residue was extracted with absolute ethanol and concentrated again to give 2a as a colorless syrup, 1.6 g (14 mmol).

To this syrup were added 5-amino-4,6-dichloropyrimidine (4.59 g, 28 mmol), triethylamine (4.2 g, 42 mmol) and n-butanol (50 ml) and the mixture was under for 24 hours Reflux heated. The volatile solvents were removed, the residue was absorbed on silica gel (7 g) packed in a flash column (4.0 x 12 cm) and eluted with CHCl3-MeOH (20/1) and gave 2.69 g (74%) of compound 3a; Mp 130-132 ° C. An analytical sample was obtained by recrystallization from ethyl acetate (EtOAc); Mp 134-135 ° C.

MS (30 ev, 200 ° C): m / e 240 and 242 (M + and M ++ 2), 209 (M + ~ 31), 144 (B +);

IR: 3600-2600 (OH), 1620.1580 (C = C, C = N);

Analysis: (C10H13CIN4O) C, H, N.

Example 2

(±) - (1a.4a) -4-r (2-Amino-6 * chloro-4-Dvrimidinvl) -aminol-2-cvcloDentenvlcarbinol (4a)

To 14 mmol of crude 2a (Example 1) were added 2-amino-4,6-dichloropyrimidine (3.74 g, 22.8 mmol), triethylamine (15 ml) and n-butanoi (75 ml) and the mixture became 48 h heated under reflux. The volatile solvents were removed and the residue treated with methanol to separate the undissolved by-product (the double pyrimidine nucleoside). The methanolic solution was absorbed on silica gel (8 g) packed in a column (4.0 x 14 cm) and eluted with CHCl3-MeOH (40/1) to give 1.52 g (42%) of crude 4a . The product was recrystallized from ethyl acetate to give 4a; Mp 132-134 ° C.

MS (30 ev, 200 ° C): m / e 240 and 242 (M * and M ++ 2), 209 (M + -31), 144 (B +);

1R: 3600-3000 (NH2, OH), 1620.1580 (C = C, C = N);

Analysis (C10H13CIN4) C, H, N.

Example 3

f ± Vf1a.4KÎ-4-fiï2-amino-6-chloro-5-f4-chlorophenvn-azoT-4-pvrimidinvl-aminoi-2-cvclopenìenvlcarbinol (5aY

A cold diazonium salt solution was prepared from p-chloroaniline (1.47 g, 11.5 mmol) in 3N HCl (25 ml) and sodium nitrite (870 mg, 12.5 mmol) in water (10 ml). This solution was added to a mixture of 4a (2.40 g, 10 mmol), acetic acid (50 ml), water (50 ml) and sodium acetate trihydrate (20 g). The reaction mixture was stirred at room temperature overnight. The yellow precipitate was filtered and washed with cold water until neutral, then it was air dried in the hood to give 3.60 g (94%) 5a, mp 229 ° C (dec.). The analytical sample was obtained from acetone-methanol (1/2), mp. 241-243 ° C (dec.).

12

5

10th

15

20th

25th

30th

35

40

45

50

55

CH679152 A5

MS (30 ev, 260 ° G): m / e 378 and 380 (M * and M ++ 2), 282 (B +);

IR: 3600-3000 (NH2, OH), 1620.1580 (C = C, C = N);

Analysis: (C16H16CI2N6O)

Example 4

feW 1 a.4aV4- [Y2.5-Diamino-6-chloro-4-pvrimidinvh-aminol-2-cvclopentenvlcarbinol (6a)

A mixture of 5a (379 mg, 1 mmol), zinc dust (0.65 g, 10 mmol), acetic acid (0.32 ml), water (15 ml) and ethanol (15 ml) was refluxed under nitrogen for 3 h . The zinc was removed and the solvents were evaporated. The residue was absorbed on silica gel (2 g) packed in a 2.0 x 18 cm column and eluted with CHGl3-MeOH (15/1). A pink syrup was obtained. Further purification from methanol ether gave 6a as pink crystals, 170 mg (66%), mp. 168-170 ° C.

MS (30 ev, 220 ° C): m / e 255 and 257 (M + and M ++ 2), 224 (M + -31), 159 (B +);

IR: 3600-3000 (NH2, OH), 1620.1580 (C = C, C = N);

Analysis: (C10H14CIN5) C, H, N.

Example 5

(+ W1 ct.4ccV4- (6-chloro-9H-purine-9-vh-2-cvclopentenvlcarbinol / 7a)

A mixture of 3a (1.30 g, 5.4 mmol), triethyl orthoformate (30 ml) and hydrochloric acid (12N, 0.50 ml) was stirred overnight at room temperature. The solvent was evaporated at 35 ° C in a vacuum. Aqueous hydrochloric acid (0.5N, 30 ml) was added to the residue and the mixture was stirred for 1 h. The mixture was neutralized to pH 7-8 with 1N sodium hydroxide and absorbed on silica gel (8 g) packed in a column (4.0 x 8 cm) and eluted with CHCÌ3-MeOH (20/1) to give white Crystals of 7a, 1.12 g (82%). The crude product was recrystallized from ethyl acetate and gave 7a, mp. 108-110 ° C.

MS (30 ev, 200 ° C): m / e 250 and 252 (M + and M + +2), 219 (M + "31), 154 (B +);

IR: 3600-2800 (OH), 1600 (C = C, C = N);

Analysis: (C11H11CIN4O) C, H, N.

Example 6

f + H1a.4ai-4-f6-Hvdroxv-9H-Purin-9-vD-2-cvclopentenvlcarbinol (8ai

A mixture of 7a (251 mg, 1 mmol) and aqueous sodium hydroxide (0.2N, 10 ml) was heated to reflux for 3 h. After cooling, the reaction mixture was adjusted to pH 5-6 with acetic acid. The reaction mixture was absorbed on silica gel (2 g) packed in a column (2.0 x 11 cm) and eluted with CHCfe-MeOH (10/1) to give 105 mg (45%) 8a. The white crude product was recrystallized from water-methanol (3/1) and gave 8a, mp. 248-250 ° C (dec.).

MS (30 ev, 300 ° C): m / e 232 (M +), 214 (M + -18), 136 (B +);

IR: 3600-2600 (OH), 1680.1600 (C = 0, C = C, C = N);

Analysis: (C11H12N4O2) C, H, N.

Example 7

feW1a.4aV4- (6-Amino-9H-purin-9-vB-2-cvclopentenvlcarbinol (9ai

Liquid ammonia was passed into a bomb containing a solution of 7a (250 mg, 1 mmol) in methanol (5 ml) at -80 ° C. The bomb was sealed and heated at 60 ° C for 24 hours. Ammonia and methanol were evaporated and the residue was recrystallized from water and gave whitish crystals of 9a, 187 mg (81%), mp. 198-200 ° C.

MS (30 ev, 210 ° C): m / e 231 (M +), 213 (M + -18), 135 (B +);

IR: 3600-2600 (NH2, OH), 1700.1600 (C = C, C = N);

Analysis: (CnHt3N50) C, H, N.

Example 8

teVf1a.4aV4-f6-Mercapto-9H-Purin-9-vn-2-cvclopentenvlcarbinol (10a)

A mixture of 7a (125 mg, 0.5 mmol), thiourea (40 mg, 0.64 mmol) and n-propanol (5 ml) was heated to reflux for 2 h. After cooling, the precipitate was isolated by filtration, washed with n-propanol and dissolved in sodium hydroxide (1N, 5 ml). The solution was adjusted to pH 5 with acetic acid

13

5

10th

15

20th

25th

30th

35

40

45

50

55

en

CH 679 152 A5

set. The crude 10a (90 mg, 73%) was isolated again, mp. 260-262 ° C (dec.), And from N, N-Dime-

recrystallized thylformamide and gave 10a, mp. 263-265 ° C (dec.).

MS (30 ev, 290 ° C): m / e 248 (M +), 230 (MM8), 152 (B +);

IR; 3600-3200 (OH), 3100.2400 (Sch), 1600 (C = C, C = N);

Analysis: (C11H12N4OS) C, H, N.

Example 9

f ± W1rc.4rcV4- (2-amino-6-chloro-9H-Durin-9-vn-2-cvclopentenvlcarbinol 113a)

A mixture of 6a (1.41 g, 5.5 mmol), triethyl orthoformate (30 ml) and hydrochloric acid (12N, 1.40 ml) was stirred overnight. The suspension was dried in vacuo. Dilute hydrochloric acid (0.5N, 40 ml) was added and the mixture reacted for 1 h at room temperature. The mixture was neutralized to pH 8 with 1N sodium hydroxide and absorbed on silica gel (7.5 g) packed in a column (4.0 x 10 cm) and eluted with GHCb-MeOH (20/1) to give whitish Crystals from 13a, 1.18 g (80%). The crude product was recrystallized from ethanol and gave 13a, mp. 145-147 ° C.

MS (30 ev, 220 ° C): m / e 265 and 267 (M + and M ++ 2), 235 (m + "30), 169 (B +);

IR: 3600h-2600 (NHa, OH), 1620-1580 (C = C, C = N);

Analysis: (CtiHi2N50CI.3 / 4H20) C, H, N.

Example 10

fe) -f1 «.4a) -4- (2-Amino-6-hvdroxv-9H-purin-9-vl) -2-cvclopentenvlcarbinol (14a)

A mixture of 13a (266 mg, 1 mmol) and aqueous sodium hydroxide (0.33N) was refluxed for 5 h on silica gel (2 g) packed in a column (2.0 x 7.5 cm), absorbed and eluted with CHCI3-MeOH (5/1). The crude product was recrystallized from methanol-water (1/4) and gave white crystals of 14a, 152 mg (61%), mp. 254-256 ° C (dec.).

MS (30 ev, 200 ° C): m / e 247 (M +), 217 (M + "30), 151 (B +);

IR: 3600-2600 (NHa, OH), 1700.1600 (C = 0, C = C, C = N);

Analysis: (C11H13N5O2.3 / 4H2O) C, H, N.

Example 11

f ± V (1 cc.4ot) -4- (2.6-diamino-9H-purin-9-vl) -2-cvclopentenvlcarbinol (15a)

Liquid ammonia was passed into a solution of 13a (265 mg, 1 mmol) in methanol (10 ml) at -80 ° C in a bomb. The bomb was sealed and heated to 75 ° C for 48 h. Ammonia and methanol were evaporated. The residue was absorbed on silica gel (2 g) packed in a column (2.0 x 10 cm) and eluted with CHCIsMeOH (15/1). The crude product was recrystallized from ethanol to give 196 mg (80%) 15a, mp 152-155 ° C.

MS (30 ev, 200 ° G): m / e 246 (M +), 299 (M + -17), 216 (M + -30), 150 (B +);

IR: 3600-3000 (NH2, OH), 1700.1650.1600 (C = 0, C = C, C = N);

Analysis: (CnH ^ NeO) C, H, N.

Example 12

(1S.4R) -4- (2.6-Diamino-9H-purine-9-vl) -2-cvclopentenvlcarbinol

[(1 S, 4R) -4- (2,6-diamino-9H-purin-9-yl) -2-cyclopentene methanol]

fa) Intermediate connection 1:

(1 R, 2S, 3R, 5R) -3- [6-amino-9H-purin-9-yl] -5 - [((1,1-dimethylethyl) dimethylsilyloxy) methyl] -1,2-cyclo -pentanediol (-) aristeromycin (1 Journal of the American Chemical Society 1983, volume 105, 4049-4055) (12.505 g), tert-butyldimethylsilyl chloride (7.8 g) and imidazole (12.96 g) in dry dimethylformamide ( 85 ml) were stirred at ambient temperature for 2 h. The resulting solution was diluted with ethyl acetate (500 ml), then washed with water (3 x 100 ml) and brine (50 ml) before a white solid crystallized out. This was collected by filtration, washed with ethyl acetate, then dried in vacuo to give the title product (3.92 g).

1H NMR (DMSO-de) 8.15 (1H), 8.09 (1H), 7.19 (2H), 5.00 (1H), 4.72 (1H), 4.69 (1H), 4.36 (1H), 3.85 (1H), 3.67 (2H), 2.23 (1H), 2.09 (1H), 1.79 (1H), 0.89 (9H), 0 , 07 (6H).

14

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH679152 A5

(b) Interconnection 2:

(4R, 3aS, 6R, 6aR) -4- [6-amino-9H-purin-9-yl] -6 - [((1,1-dimethylethyl) dimethylsilyloxy) methyl] -3a, 5,6, 6a-tetrahydro-4H-cyclopenta-1,3-dioxol-2-thione

A stirred suspension of Intermediate 1 (3.45 g) in dry dimethylformamide (56 ml) was treated with 1,1-thiocarbonyldiimidazole (3.3 g) to give a yellow solution. After 15 h at ambient temperature, the resulting solution was combined with that from a previous experiment (6% weight) and the solvent was removed by evaporation. The remaining oil was diluted with ethyl acetate (100 ml), then washed with water (2 x 20 ml) and brine (2 x 20 ml), dried (MgSO4) and evaporated to a yellow solid. This was washed with diethyl ether (25 ml), then collected by filtration, further washed with ether (25 ml), then dried in vacuo to give the title product as a pale cream solid (3.61 g);

Xmax (ethanol) 240.0 nm (E ^ 459);

1H NMR (DMSO-d6) 8.27 (1H), 8.13 (1H), 7.33 (2H), 5.81 (1H), 5.37 (1H), 5.28 (1H), 3.78 (2H), 2.60 (1H), 2.28 (2H), 0.90 (9H), 0.09 (6H).

foi intermediate connection 3:

(1'R, 4'S) -9- [4 - (((1, l-dimethylethyl) dimethylisilyloxy) methyl) -2-cyclopenten-1-yl] -9H-purine-6-amine

A solution of intermediate 2 (3.57 g) in dry tetrahydrofuran (25 ml) was treated with a solution of 1,3-dimethyl-2-phenyI-1,3,2-diazaphospholidine (4.94 g) in dry tetrahydrofuran ( 10 ml) treated, then stirred for 8% h at ambient temperature. The solvent was removed by evaporation. The remaining oil was combined with that from a previous experiment (40% weight), then subjected to column chromatography on silica (200 g, Merck 7734), with chloroform, then with chloroform-ethanol mixtures, and gave a white solid. This solid was washed with diethyl ether (25 ml) and then collected by filtration. The solid was washed further with ether (10 ml) then dried in vacuo to give the title product (1.47 g).

Jirnax (ethanol) 261.4 nm (Ej ^ 443)

1H-NMR (DMSO-de) 8.14 (1H), 8.00 (1H), 7.20 (2H), 6.12 (1H), 5.95 (1H), 5.60 (1H), 3.66 (2H), 2.96 (1H), 2.69 (1H), 1.65 (1H), 0.74 (9H), 0.02 (6H).

(d) Interconnection 4:

1'R, 4'S) -9- [4 - (((1,1-DimethylethyI) -dimethyIsilyIoxy) -methyl) -2-cyclopenten-1-yI] -9H-purine-6-amine,

1-oxide

A solution of intermediate 3 (1.37 g) in chloroform (30 ml) was treated with 80-90% m-chloroperoxybenzoic acid (1.29 g), then stirred at ambient temperature for 3 hours. The solvent was removed by evaporation and the remaining gum was dissolved in ethyl acetate (10 ml). A white solid crystallized out. This solid and the material obtained by evaporating the filtrate were dissolved in chloroform (100 ml), then washed with saturated aqueous sodium bicarbonate solution (3x10 ml) and brine (2x10 ml). The washings were back extracted with chloroform (50 ml). The combined organic solutions were dried (MgSO4) and then evaporated to a solid. This solid was washed with diethyl ether (25 ml) and then collected by filtration. The white solid was further washed with ether (10 ml) then dried in vacuo to give the title product (1.16 g).

w (ethanol) 235.4 nm (E ^ 1324), 263.2 nm (E ^ 248), 300.2 nm (£ ^ 75);

1H NMR (CDCIs) 8.72 (1H), 8.02 (1H), 7.16 (2H), 6.21 (1H), 5.87 (tH), 5.72 (1H), 3, 68 (2H), 3.04 (1H), 2.82 (1H), 1.74 (1H), 0.89 (9H), 0.06 (6H).

fe) Interconnection 5:

(1 'R, 4'S) -7- [4 - (((1,1-dimethylethyl) dimethylisilyloxy) methyl) -2-cyclopenten-1-yl] -2-imino-1,2-dihydro [1, 2,4] oxadiazolo [3,2-i] -9H-purine hydrobromide

A stirred, ice-cooled suspension of intermediate 4 (1.08 g) in methanol (20 ml) was treated with a solution of cyanogen bromide (0.34 g) in methanol (20 ml), which was added over 5 minutes. After 15 minutes the suspension was allowed to warm to ambient temperature and provided a solution. After 90 min the solvent was removed by evaporation. The residue was washed with

15

5

10th

15

20th

25th

30th

35

40

45

50

55

60

CH679152 A5

Washed diethyl ether (25 ml) and then collected by filtration. The solid was washed further with ether (25 ml) then dried in vacuo to give the title product (1.37 g).

w (ethanol) 228.2 nm (E ^ 530), 285.2 nm (E ^ 445);

1H NMR (CDCIs) 10.20 (IH), 10.02 (1H), 8.37 (1H), 6.25 (1H), 6.01 (1H), 5.90 (1H), 3, 69 (2H), 3.05 (1H), 2.86 (1H), 1.73 (1H), 0.86 (9H), 0.03 (6H).

ffV intermediate connection 6:

(1 'R, 4'S) -9- [4 - (((1,1-dimethylethyl) dimethylsilyloxy) methyl) -2-cycIopenten-1-yl] -6-cyanoimino-1,6-dihydro-1 - methoxy-9H-purine

A solution of intermediate 5 (1.36 g) in dimethylformamide (10 ml) was stirred at ambient temperature and then treated with triethylamine (1.2 ml). After 40 minutes, iodomethane (0.54 ml) was added to give a yellow solution. After 3% h the solvent was removed by evaporation. The residue was partitioned between ethyl acetate (100 ml) and water (20 ml). The organic solution was further washed with water (2 x 20 ml) and brine (20 ml), dried (MgSO4) and evaporated to a solid. This solid was washed with diethyl ether (25 ml) and then collected by filtration. This white solid was washed further with ether (10 ml) then dried in vacuo to give the title product (0.865 g).

Xmax (ethanol) 227.2 nm (E ™ ^), 287.0 nm (E ^ 544);

1H NMR: 8.23 (1H), 7.96 (1H), 6.24 (1H), 5.85 (1H), 6.65 (1H), 4.21 (3H), 3.66 ( 2H), 3.04 (1H), 2.77 (1H), 1.68 (1H), 0.88 (9H), 0.05 (6H).

fai intermediate 7:

(l'R, 4'S) -9- [4 - (((1,1-Dimethylethyl) dimethylsilyloxy) methyl) -2-cyclopenten-1-yl] -6-methoxyamino-9H-purine-2-amine

A solution of intermediate 6 (802 mg) and 1,8-diazabicyclo [5,4,0] undec-7-ene (0.45 ml) in ethanol (80 ml) was stirred and heated to reflux. After 9 hours the heating was stopped and the solution was left overnight at ambient temperature. The solvent was removed by evaporation. The remaining oil was combined with that from a previous experiment (4% weight), then subjected to column chromatography on silica (40 g, Merck 9385), eluted with chloroform, then with chloroform-ethanol mixtures and gave a foam. This foam was triturated with diethyl ether (10 ml) and the resulting solid was collected by filtration. The solid was washed further with ether (5 ml) then dried in vacuo to give the title product (594 mg).

Xmax (ethanol) 282.2 nm (Ej ° ^ 409);

1H NMR (DMSO-de) 9.76 (1H), 7.32 (IH), 6.53 (2H), 6.08 (1H), 5.88 (1H), 5.26 (1H), 3.72 (3H), 3.61 (2H), 2.90 (1H), 2.50 (IH), 1.52 (1H), 0.83 (9H), 0.02 (6H).

(hY intermediate connection 8:

(1St4R) -4- [2-Amino-6-methoxyamino-9H-purin-9-yl] -2-cyclopentene-methanol

A solution of intermediate 7 (356 mg) in tetrahydrofuran (35 ml) was stirred at ambient temperature and then treated with tetabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 1.4 ml). After 90 min the reaction mixture was quenched with water (1 ml) then the solvents were removed by evaporation. The remaining oil was subjected to column chromatography on silica (20 g, Merck 7734), eluting with chloroform, then with chloroform-ethanol mixtures, to give the tiite product as a solid (243 mg).

W (pH6 buffer) 280.2 nm (E *% 534);

1H NMR (DMSO-de) 9.75 (1H), 7.39 (1H), 6.52 (2H), 6.10 (1H), 5.84 (1H), 5.27 (1H), 4.73 (1H), 3.40 (2H) f 2.83 (1H) 2.55 (1H), 1.52 (IH).

(1S.4RV4-r2.6-Diamino-9H-Durin-9-vl1-2-cvcloDentencarbinol

A stirred, ice-cooled solution of intermediate 8 (210 mg) in water (10 ml) and tetrahydrofuran (50 ml) was treated with aluminum amalgam [from aluminum (237 mg) and 0.5% aqueous mercury (II) chloride]. Solution] treated, which was added in small pieces over 15 min. After 40 minutes the stirred mixture was allowed to warm to ambient temperature. After 15 hours the resulting mixture was filtered through diatomaceous earth to remove insolubles. These were

16

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH 679 152 A5

water / tetrahydrofuran (1/5, 60 ml). The combined filtrates were evaporated. The residue was subjected to column chromatography on silica (10 g, Merck 9385), eluted with chloroform-ethanol mixtures and gave the title product as a foam (159 mg);

[<x] d = -81 ° (c = 1.04, methanol).

W (pH6 buffer) 255.0 nm (E ^ 302,) 280.8 nm (Ej ^ 381);

1H NMR (DMSO-de) 7.61 (1H), 6.66 (2H), 6.10 (1H), 5.87 (1H), 5.76 (2H), 5.38 (1H), 4.76 (1H), 3.45 (2H), 2.87 (1H), 2.60 (11-0.1.60 (IH).

Example 13

(1S.4Ri-4-f2-Amino-6-hvdroxv-9H-Durin-9-vh-2-cvclopentenvl-carbinol

(1 'R, 4'S) -2-amino-1,9-dihydro-9- [4-hydroxymethyl-2-cyclopenten-1-yl] -6H-purin-6-one

A cloudy solution of the title compound of Example 12 (144 mg) in 0.1 M pH6 buffer (10 ml) (from 28.4 g disodium orthophosphate in 2 l water, adjusted with orthophosphoric acid) was treated with a solution of adenosine desaminase (0.5 ml, 778 units) in 50% glycerol 0.01 M potassium phosphate (pH 6.0), then stirred and heated to 37 ° C. After 18% h the resulting suspension was cooled. The collected solid was recrystallized from water and provided the title product as a white solid (86 mg);

[oc] d = -49 ° (c = 0.5, dimethyl sulfoxide).

W (pH6 buffer) 252.6 nm (E ™ ^ 531);

1H NMR (DMSO-de) 10.60 (1H), 7.60 (1H), 6.47 (2H), 6.10 (1H), 5.86 (1H), 5.33 (1H), 4.72 (1H), 3.45 (2H), 2.59 (1H), 1.58 (1H).

Example 14

Preparation of enantiomers of (1a.4ai-4- (2-Amino-6-hvdroxv-9H-purine-9-vlV2-cvclopentenvl-carbinol faY (1S.4Ri-4- (2-Amino-6-hvdroxv-9H- ourin-9-vh-2-cvclopentenvl-carbinol

The diamino analog (100 mg) (Example 11) was dissolved in 3 ml of 0.05 M K2P04 buffer (pH 7.4) with heating (50 ° C.). The solution was cooled to room temperature and 40 units of adenosine desaminase (Sigma, type VI, calf intestinal mucosa) were added. After 3 days of incubation at room temperature, a precipitate formed which was removed by filtration, yield 18.2 mg. The filtrate was concentrated to 1.5 ml and cooled for 2 days. Additional solid was obtained by filtration, yield 26.8 mg. The two solid fractions were recrystallized from water and gave the pure title product, mp. 269-272 ° C;

[et] * 4 = -62.1 ° (c = 0.3, MeOH).

(bl (1 R.4SV4-f2-Amino-6-hvdroxv-9H-Purin-9-vli-2-cvcloDentenvl-carbinol

The filtrates from the preparation of the 1S, 4R isomer (Example 14a) were combined and evaporated to dryness. The unchanged diamino starting material was separated on a silica gel flash column using 10% methanol / chloroform. The diamino compound was dissolved in 0.05 M K2P04 buffer (pH 7.4) (15 ml) and 800 units of adenosine deaminase were added. The solution was incubated at 37 ° C for 96 h. TLC indicates that some unreacted product was left. The solution was heated in boiling water for 3 minutes and filtered to remove denatured protein. Another 800 units of adenosine deaminase were added and the process repeated. The deproteinized solution was evaporated to dryness and the product crystallized from water. The title product was collected as a white solid by filtration from water, mp. 265-270 ° C; [<x] g * = + 61.1 ° (c = 0.3, MeOH).

Example 15

f ± W1 «.4cei-4- (2-amino-6-hvdroxv-9H-purìn-9-vn-2-cvclopentenvlacetoxv-carbinol

To a suspension of the product of Example 10 (130 mg, 0.50 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in a mixture of acetonitrile (6 ml) and triethylamine (0.09 ml, 0.66 mmol) was added acetic anhydride (0.06 ml, 0.6 mmol). The mixture was stirred at room temperature for 3 hours. Methanol (1 ml) was added to quench the reaction mixture. The solution was put in17

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH 679 152 A5

concentrated and absorbed silica gel (1.5 g) packed on a column (2.0 x 12 cm), eluted with CHCfe-MeOH (20/1). The product fractions were collected and concentrated to give a white solid. The solid product was washed with MeOH-AcOEt, yield 123 mg (85%). Further purification from methanol gave the title product as needle-like crystals, mp. 237-239 ° C.

Analysis: (C13H15N5O3) C, H, N.

Example 16

(1S.4RV4-f2-Amino-9H "Purine-9-vn-2-cvclopentenvl-carbinol

A stirred, ice-cooled solution of (1S, 4R) -4- [2-amino-6-methoxyamino-9H-purin-9-yl] -2-cyc [o-pentenemethanol (intermediate 8, Example 12) (1.202 g) in tetrahydrofuran (250 ml) and water (50 ml) was added with aluminum amate [from aluminum (1.761 g) and 0.5% aqueous mercury (II) chloride solution], which was added in small pieces over 1 h 47 min was treated. After 35 minutes, the stirred mixture was allowed to warm to ambient temperature. After 16 h 50 min, further aluminum amalgam (from 235 mg aluminum) was added over the course of 14 min. After a further 4 h 10 min, the resulting mixture was filtered through diatomaceous earth to remove insolubles. These were washed with tetrahydrofuran / water (5/1) (300 ml). The combined filtrates were evaporated to a yellow foam. The foam was subjected to column chromatography on silica (33.8 g, Merck 7734) made in chloroform and eluted with chloroform-ethanol mixtures to give several fractions (578 mg, 420 mg and 40 mg). The two larger fractions were crystallized separately from isopropanoi. The filtrates were combined with the smallest column fraction and subjected to preparative thin layer chromatography (Merck 5717), developed three times in 10/1 chloroform / methanol. The plates were eluted with ethyl acetate and ethyl acetate / ethanol (1/1) to give a brown solid (45 mg). The solid was subjected to column chromatography on silica (2.7 g, Merck 7734) made in chloroform and eluted with chloroform-methanol-triethylamine mixture to give a gum (17 mg). Following unsuccessful crystallization from isopropanoi and charcoal treatment in methanol, an aqueous solution of the recovered material was freeze-dried to give the title compound (15 mg).

1H NMR (DMSO-de) 1.62 (1H), 2.63 (IH), 2.89 (IH), 3.45 (2H), 4.73 (1H), 5.48 (1H), 5.91 (1H), 6.14 (1H), 6.50 (2H), 7.98 (1H), 8.57 (IH);

MS [MH] * 232.

Example 17

Tablet formulations

A. The following formulation is prepared by wet granulation of the ingredients with a solution of Povi-done in water, drying and sieving and subsequent addition of magnesium stearate and pressing.

mg / tablet

(a)

Active ingredient

250

(b)

Lactose B.P.

210

(c)

Povidone B.P.

15

m

Sodium starch glycolate

20th

(e)

Magnesium stearate

5

500

B. The following formulation is made by direct compression; the lactose is of the direct compression type.

mg / tablet

Active ingredient

250

Lactose

145

Avicel

100

Magnesium stearate

5

500

18th

CH679152 A5

C. (controlled release formulation). The formulation is prepared by wet granulation of the ingredients (below) with a solution of povidone in water, drying and sieving, followed by addition of magnesium stearate and pressing.

5

mg / tablet

(a)

Active ingredient

500

(b)

Hydroxypropylmethylcellulose (Methocel K4M Premium)

112

(c)

Lactose B.P.

53

(d)

Povidone B.P.

28

(e)

Magnesium stearate

7

700

Example 18

20th

Capsule formulation

A capsule formulation is made by mixing the following ingredients and filling into a two-part hard gelatin capsule.

25th

mg / capsule

Active ingredient

125

Lactose

72.5

Avicel

50

Magnesium stearate

2.5

250

35

Example 19

Profitable wording

40 active ingredient 0.200 g

Sodium hydroxide solution, 0.1 M make up to pH of about 11, sterile water make up to 10 ml. The active ingredient is suspended in some of the water (which may be warmed) and the pH adjusted to about 11 with a solution of sodium hydroxide. The mixture is then brought to volume and filtered through a membrane filter with sterilization purity into a sterile 10 ml glass bottle 45 and provided with sterile closures and seals.

Example 20

50 suppository mg / suppository

Active ingredient (63 (im)

250

Hard fat, BP

1770

2020

55

A fifth of the hard fat is melted in a steam-coated crucible at a maximum of 45 ° C. The active ingredient is sprinkled through a 200 micron sieve and added to the melted base with mixing using a high performance shear stirrer until a smooth dispersion is achieved. While maintaining the mixture at 45 ° C, the remaining hard fat is added to the suspension and stirred so that a homogeneous mixture is achieved. The entire suspension is passed through a 250 µm stainless steel screen and allowed to cool to 40 ° C with continued stirring. At a temperature of 38 to 40 ° C, 2.02 g of the mixture are filled into suitable 2 ml plastic molds. The suppositories are allowed to cool to room temperature.

19th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH679152A5

Example 21 - Antiviral Activity (A) Anti-HIV Test

Compounds of formula (I) were tested for anti-HIV activity at the National Cancer Institute, Frederick Cancer Research Facility, Frederick, Maryland (FCRF). The following are the common screening methods used in FCRF. The protocol consists of three areas, (I) preparation of the infected cells and distribution on test plates, (II) production of the drug dilution plates and distribution on the test plates and (III) XTT test methods; forg. THERE. Scudiero et al., "A New Simplified Tetrazolium Assay for Cell Growth and Drug Sensitivity in Culture," Cancer Res., 48, 4827 (1988).

I. Infection and distribution of ATH8 cells on microtiter plates

The cells to be infected (a normal lamphoblastoid cell line which expresses CD4) are placed in 50 ml conical centrifuge glasses and treated with 1 to 2 ng / ml polybrene at 37 ° C. for 1 hour. The cells are then pelleted at 1200 rpm for 8 min. HIV virus diluted 1:10 in media (RMP1-1640.10% human serum or 15% fetal calf serum (FCS), with IL-2 and antibiotics) is added to achieve an MOI of 0.001. Medium alone is added to virus-free control cells. Assuming an infection virus titer of 10-4, an MOI of 0.001 represents 8 infectious virus particles / 10,000 cells. About 500,000 cells / glass are exposed to the 400 ni of virus dilution. The resulting mixture is incubated at 37 ° C in air CÖz for 1 h. The infected or uninfected cells are diluted to give 1 x 10-4 (with human serum) or 2 x 10-4 (with fetal calf serum) cells / 100 nl.

Infected or uninfected cells (100 jil) are distributed into suitable wells of a microtiter plate with 96 wells and U-bottom. Each dilution of a compound is tested twice on infected cells. Uninfected cells are tested for drug sensitivity in a single well for each dilution of a compound. Drug-free control cells, infected and non-infected, run in triplicate. Wells B2 to G2 served as reagent controls and only received medium. The plates are incubated at 37 ° C in air CO2 until the drug is added.

II. Drug dilution and addition

Dilution plates (96-well flat bottom, microtiter plates) are treated overnight with phosphate-buffered saline (PBS) or media containing at least 1% FCS or 1% human serum (depending on the medium used in the test) starting the day before The examination. This "blocking method" is used to limit the adsorption of the drug to the microtiter plate during the dilution process. The wells are completely filled with the blocking solution and left at room temperature in a humid chamber under an extractor hood.

The dilution procedure is started by first diluting the test compound 1:20. Blocked dilution plates are made by tipping the blocking solution and dry-erasing on sterile gauze. All wells of each plate are then filled with 225 fit of the appropriate medium using a Cetus liquid treatment system. 25 ml of each 1:20 diluted compound is then added manually to Row A of a blocked and filled dilution plate. Four compounds, sufficient to fill two test plates, are added per dilution plate. The four compounds are then serially diluted 10-fold from row A to row H using the Cetus liquid handling system. The starting dilution of each compound in row A is 1: 200 at this point. The dilution plates are kept on ice until needed.

Using a multi-channel pipettor with 6 micro tips, 100 nl of each drug dilution is transferred to the test plate, which already contains 100 nl medium plus cells. The final dilution in the test plate starts at 1: 400 (wells B4 to G4). This dilution (to 0.25% DMSO) prevents the DMSO carrier from disrupting cell growth. Drug-free, infected or non-infected cells (wells B3 to G3) and reagent controls (B2 to G2) receive the medium alone. The last 2 connections are then transferred from wells H7 to H12 to a second test plate following the same procedure. The test plates are incubated at 37 ° C in air COa for 7 to 14 days or until the virus control samples are lysed, which is determined macroscopically

III. Quantitative determination of viral cvtopathicity and drug activity A. Materials

1. A solution of 2,3-bis- [2-methoxy-4-nitro-5-sulfophenyl] -5 - [(phenylamino) carbunyl] -2H-tetrazolium hydroxide. (XTT) - 1 mg / ml solution in media without FCS. Storage at 4 ° C. Prepare weekly.

20th

5

10th

15

20th

25th

30th

35

40

45

50

55

CH679152 A5

2. Phenazine Methosulfonate (PMS) Stock Solution - This can be made and kept frozen at -20 ° C until use. It should be made in PBS at a concentration of 15.3 mg / ml.

B. Microculture Tetrazolium Examination (MTAY

1. Preparation of XTT-PMS solution - The XTT-PMS is prepared immediately before it is added to the wells of the culture dishes. The PMS stock solution is diluted 1: 100 (0.153 mg / ml). Diluted PMS is added to each ml of XTT needed to give a final PMS concentration of 0.02 mM. A 50 nl aliquot of the XTT-PMS mixture is added to each of the appropriate wells and the plate is incubated for 4 hours at 37 ° C. The plate covers are removed and replaced with adhesive plate closures (Dynatech cat 001-010-3501). The sealed plate is shaken on a microculture plate mixer and the absorption is determined at 450 nm.

IV. Results

The data obtained was plotted as a percentage of test cells versus uninfected cells (%) for both infected and uninfected cells as a function of increasing test compound concentration. Such curves allow the calculation of an effective concentration (ECso) with respect to infected cells, an inhibitory concentration (IC50) with respect to normal cells and a therapeutic index (TI50).

The inhibitory concentrations against HIV determined as described above for the compounds of Examples?, 9, 10, 11 and 14 (b) are shown in Table 1.

Table 1

Connect

example

Cell line

ED50

iDso

Tlso

9a

7

MT-2

2.3

50

April 21

13a

9

MT-2

0.41

6.97

17.3

14a

10th

MT-2

0.15

100

667

15a

11

MT-2

2.9

> 125

> 42.7

(-) 14a

14 (b)

CEM

0.66

189

284

The compounds of Examples 5 and 8 also showed antiviral activity in this screening.

A previous experiment conducted at the Southern Research Institute gave an extra 200 Tlso for the compound of Example 10 when MT-2 cells were grown with H9 / HILV-IIIB.

(BY activity against cat leukemia virus

Antiviral screening for activity against FeLV-FAIDS was performed in 96-well plates (Corning) using 81C indicator cells in Iscove's Modified Dulbecco's medium supplemented with 10% heat-inactivated fetal bovine serum (FBS). 20 h before the experiment, the plates were inoculated with the 81C cells at 5 × 103 cells / well. On the day of the experiment, the cells were pretreated for 30 min at 37 ° C with DEAE-dextran (25 ng / ml) in 0.1 ml Hanks balanced salt solution. This was removed and then 0.1 ml of growth medium containing 32 TCID50 from FeLV-FAlDS or 0.1 ml of growth medium alone was added to each well. The virus was allowed to adsorb for 1 h, then 0.1 ml of test or positive control compound (2 ', 3'-dideoxycytidine; ddC) or growth medium was added. The plates were incubated at 37 ° C. The cells were loaded with fresh growth medium containing the compound on the 4th day after infection. The culture medium was completely replaced and replaced with fresh medium containing the compound on day 7 after infection. On day 10 after infection, the cells were fixed with formalin, stained with 0.1% Coomassie Brilliant Blue R-250 and observed microscopically for CPE and drug cytotoxicity.

The compound of Example 10 had an ED50 of 1.9 pg / ml.

(G) activity against mouse AIDS

Falcon 6-well tissue culture plates were inoculated with 1.75 x 105 cells / well in a total volume of 2.5 ml EMEM containing 5% heat-inactivated FBS. The medium was decanted 20 hours after cell inoculation and 2.5 ml of DEAE-dextran (25 ng / ml in phosphate-buffered saline) was added to each well. The cultures were incubated for 1 h at 37 ° C, after which the DEAE

21

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH 679152 A5

Dextran solution was decanted and the cell layers were rinsed once with 2.5 ml PBS. Normal cell controls were again loaded with 2.5 ml of medium alone (no virus or drug). The drug control cultures received 2.5 ml of medium containing the drug but no virus. The virus-infected control cultures received 0.5 ml of the appropriate dilution of the CAS-BR-M stock to produce countable plaques plus 2.0 ml of medium. The test samples received 0.5 ml of the appropriate virus dilution plus 2.0 ml of drug dilution medium. Six concentrations of the test compound diluted in serial half-logio dilutions were tested. Three concentrations of the positive control drug, ddC, were examined. Three wells for each concentration of test compound and 6 virus and 6 cell control cultures were included in each experiment. On the 3rd day after the virus inoculation, the toxicity of the drug to the SC-1 cells was determined by microscopic examination of stained duplicate cells and drug control cultures. The remaining test and control cultures were irradiated with an ultraviolet lamp for 20 sec and XC cells were added to each culture (5 x 105 cells / well in 2.5 ml EMEM containing 10% heat-inactivated FBS). On the 3rd day after UV radiation, the cultures were fixed with formalin and stained with crystal violet. The plaques were counted using a dissecting microscope.

The decrease in antiviral activity in the CAS-BR-M plaque was expressed as a decrease in the mean number of plaques counted in the drug-treated, virus-infected cultures compared to the mean number of plaques in the untreated, virus-infected control cultures were counted (percent of control). The compound of Example 10 had an ED of 1.1 ng / ml.

(D) Activity against monkey retrovirus SAIDS (SRV-2Ì

The antiviral screening against the SAIDS virus (D / Washington) was carried out by a syncytium injection attempt on Raji cells. The drug was diluted in complete Iscove's medium and then 100 | xl of each dilution was added to appropriate wells in a 96-well plate.

Active Raji cells, 5 x 103 cells in 50 p.l complete Iscove's medium, were then added to each well. This was followed by the addition of 50 ml of cleared supernatant from an SRV-2 / Raji cell co-culture. DDC was included as a positive control drug over this trial. The plates were incubated at 37 ° C in a humid atmosphere containing 5% CO2. Syncytia were counted on the 7th day after infection. Drug toxicity was determined by comparing viable cell counts of the uninfected, drug-treated sample to the viability of the uninfected, untreated control. The compound of Example 10 had an ED50 of 2.8ng / ml.

(EÏ activity against Visna Maedi virus

Antiviral activity against Visna Maedi virus (VMV) strain WLC-1 was determined by measuring the reduction in virus-specific, immunohistochemical staining. Monolayers of sheep choroid plexus cells were infected with VMV and coated with serial dilutions of the test compounds. After 5 days of incubation, the monolayers were further incubated with virus-specific antisera conjugated to horseradish peroxidase (HRP). Subsequent incubation of the monolayers with a chromagenic substrate from HRP results in areas of virus replication. These individual foci were counted and the concentration of test compound required to reduce the number of foci to 50% of that of the untreated control samples was calculated. The compound of Example 13 had an ED50 of 0.2jig / mf.

Example 22

Cvtotoxic activity

The compounds of Examples 5, 7 and 8 showed cytotoxic activity when tested against P388 mouse leukemia in a cell culture experiment as described by R.G. Alonquist and R. Vince, J. Med. Chem., 16, 1396 (1973). The ED 50 values obtained (pg / ml) were:

Example 512 Example 7 40 Example 8 3.

22

5

10th

15

20th

25th

30th

35

40

45

50

55

60

CH679152 A5

Claims (1)

Claims 1. Compound of formula (I) in the / v \ i t y A \ A / cd ho-cho / v \ \ J wherein X is hydrogen, NRRi, SR, OR or halogen; Z is hydrogen, OR2 or NRR1; wherein R, R1 and R2 may be the same or different and are selected from hydrogen, C1-4-AI-kyl and aryl; and pharmaceutically acceptable salts, esters or salts of such esters thereof. 2. A compound of formula (I) according to claim 1 and pharmaceutically acceptable salts thereof. 3. A compound according to claim 1 or claim 2, wherein in the compound of formula (I) Z = H, OH or NH2. 4. A compound according to any one of claims 1 to 3, wherein Z = NH2. 5. A compound according to any one of claims 1 to 4, wherein X = hydrogen, chlorine, NH2, SH or OH. 6. A compound according to any one of claims 1 to 5, wherein X = OH. 7. A compound according to any one of claims 1 to 5, wherein X = H or NH2. 8. A compound according to claim 1 selected from (1a, 4a) -4- (6-chloro-9H-purin-9-yl) -2-cyclopentenyl carbinol; (1a, 4a) -4- (6-hydroxy-9H-purin-9-yl) -2-cyclopentenyI-carbinoI; (1a, 4a) -4- (6-amino-9H-purin-9-yi) -2-cyclopentenyI-carbinol; (1a, 4a) -4- (6-mercapto-9H-purin-9-yl) -2-cyclopentenyl-carbinol; (1a, 4a) -4- (2,6-diamino-9H-purin-9-yI) -2-cyclopentenyl-carbinoI; (1a, 4a) -4- (2-amino-6-chloro-9H-purin-9-yl) -2-cyclopentenyi-carbinol; and (1a, 4a) -4- (2-amino-9H-purin-9-yI) -2-cyclopentenyl-carbinoI. 9. (1a, 4a) -4- (2-amino-6-hydroxy-9H-purin-9-yl) -2-cyclopentenyl-carbinol according to claim 1. 10. A compound according to any one of claims 1 to 9 in the form of an essentially racemic mixture. 11. A compound according to any one of claims 1 to 9, which consists essentially of an optical isomer. 12. A compound according to any one of claims 1 to 9, which consists essentially of the D isomer. 13. A compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, a pharmaceutically acceptable ester or a salt of such an ester thereof as an active therapeutic agent. 14. Use of a compound of formula (1) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, a pharmaceutically acceptable ester or a salt of such an ester thereof for the manufacture of a medicament for the treatment of a viral infection or an anti-cancer agent. 15. A pharmaceutical formulation comprising a compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, a pharmaceutically acceptable ester or a salt of such an ester thereof together with a pharmaceutically acceptable carrier therefor. 16. A pharmaceutical formulation according to claim 15 comprising a compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier therefor. 17. Pharmaceutical formulation according to claim 15, which additionally contains a further therapeutic agent. 18. Compound of formula (II) 23 5 10th 15 20th 25th 30th 35 40 45 50 55 60 CH679152 A5 ï a r * ï « / y \ h \ / wherein X represents hydrogen, NRR1, SR, OR, halogen or protected forms thereof; Y represents OH or a protected form thereof; Z represents hydrogen, OR2, NRR1 or protected forms thereof; wöbet R, Ri and R2 may be the same or different and are selected from hydrogen, c1-4-AI-kyl and aryl, and pharmaceutically acceptable salts, esters or salts of such esters thereof for the preparation of compounds of formula (I) according to claim 1 . 19. Compound of formula (V) // \ ï â h / y \ h ho-ch2 \ / \ » I I (v) wherein X has the meanings given in claim 18, for the preparation of compounds of the formula (I) according to claim 1. 20. Compound of formula (VI) // \ / n • h / V'V k '= n-ar ho-ch2 \ / \ m i _ (vi) wherein X has the meanings given in claim 18 and Ar denotes an aromatic group, for the preparation of compounds of the formula (I) according to claim 1. 24th