BE1003815A4 - DIDEOXYDIDEHYDROCARBOCYLIC NUCLEOSIDES AND PHARMACEUTICAL COMPOSITION CONTAINING THEM. - Google Patents

Abstract

The invention relates to new compounds of formula (see fig.) In which X represents H, NRR1, SR, OR or a halogen; Z represents H, OR2 or NRR1; R, R1, R2 represent H, a C1 to C4 alkyl or aryl group, and their pharmaceutically acceptable derivatives. It also relates to pharmaceutical formulations containing in particular compounds of the above formula. The compounds of the invention are endowed with antiviral and antitumor activity.

Description

"Dideoxydidehydrocarbocyclic nucleosides and pharmaceutical composition containing them"

The present invention relates to analogs of the type of dideoxydidehydrocarbocyclic nucleosides. It relates more particularly to analogs of the type of carbocyclic nucleosides of 2 ', 3’-2-dideoxy-1,3'-didehy-dropurin and their use in therapy, in particular as antiviral agents.

Due to the similarity between viral and host cell functions, it is difficult to selectively attack a virus while leaving the host cells intact. There are therefore relatively few agents effective against viruses themselves, and it is difficult to find antiviral agents with a suitable therapeutic index, that is to say agents which produce a significant antiviral effect at a dose rate. for which the agent has an acceptable profile of toxicity or side effects.

A group of viruses that have become of major importance in recent times include the retroviruses responsible for acquired immunodeficiency syndrome (AIDS) in humans. These viruses have already been designated according to various terminologies, but they now correspond to the general name of human immunodeficiency virus (HIV); two of these viruses, HIV-I and HIV-II, have been reproducibly isolated from patients with AIDS and related conditions such as the AIDS-related complex (ARC) and persistent generalized lymphadenopathy.

Although a number of nucleosides have been taught as substances useful in the treatment * of conditions linked to HIV virus infections, only zidovudine (AZT, Retrovir) has received regulatory approval for the treatment of such conditions . However, it is known that zidovudine produces serious side effects, resulting in the suppression of bone marrow, which leads to a decrease in the number of leukocytes accompanied by pronounced anemia, and it is necessary to find effective agents that are less cytotoxic.

The Applicant has just found a new class of analogs of the nucleoside type endowed with antiviral activity. Consequently, the invention proposes, according to a first aspect, a compound of formula (I)

wherein X is hydrogen, NRR1, SR, OR or halogen; Z is hydrogen, an OR2 or NRR1 group; R, R1 and R2 can be the same or different and are chosen from hydrogen, C1 to C4 alkyl groups and aryl groups? and pharmaceutically acceptable derivatives of this compound.

Those skilled in the art will recognize that the compounds of formula (I) are compounds and further that the cyclopentene ring of the compounds of formula (I) contains two centers of chirality (designated in formula (I ) by the sign *) and that they can therefore exist in the form of two optical isomers (that is to say enantiomers) and in the form of their mixtures, including racemic mixtures. All these isomers and their mixtures, including racemic mixtures, come within the scope of the invention. Thus, in the compounds of formula (I), the center of chirality to which the base is attached to the R configuration and the center of chirality to which the CH2OH group is attached to the S configuration (D isomer below) or else the center of chirality to which the base is attached to the S configuration and the center of chirality to which the CH2OH group is attached to the R configuration (L isomer below). The compounds are advantageously in the form of a racemic mixture or mainly in the form of the pure D isomer. The D isomers can be represented by the formula (la)

in which X and Z are as defined for formula (I). References made below to compounds of formula (I) include compounds of formula (la).

Those skilled in the art will also appreciate the fact that some of the compounds of formula (I) can exist in several tautomeric forms and that all of these tautomers fall within the scope of the invention.

The term halogen used in this memo denotes fluorine, chlorine, bromine and iodine? when X is a halogen, it is preferably chlorine.

The expression C1-C4 alkyl used herein refers to a straight chain or branched chain alkyl group, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl and tert-butyl . The C1 to C4 alkyl group is advantageously a methyl group.

The term aryl used herein refers to any monocyclic or polycyclic aromatic group and includes unsubstituted and substituted aryl groups (such as phenyl, tolyl, xylyl, anisyl) and unsubstituted and substituted aralkyl groups including ar groups ( C1-4alkyl) such as phen- (C1-4alkyl), for example benzyl or phenethyl.

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

In a first appreciated class of compounds of formula (I), X is an OR group, in particular an OH group.

In another preferred class of compounds of formula (I), X is a group NRR1, in particular NH2, or a hydrogen atom.

Particularly preferred compounds of formula (I) are those in which Z is an NH2 group and X represents H, NH2 or in particular an OH group. It is in particular these compounds which have particularly appreciable therapeutic indices as antiviral agents.

The expression “pharmaceutically acceptable derivative” designates any salt, ester or salt of such a pharmaceutically acceptable ester, of a compound of formula (I) or any other compound which, by administration to the patient, is capable of providing (directly or indirectly) a compound of formula (I) or a metabolite or a residue endowed with antiviral activity of this compound.

Preferred esters of the compounds of formula (I) include esters of carboxylic acids in which the non-carbonyl portion of the ester group is chosen from hydrogen, straight chain or branched chain alkyl groups (for example methyl, ethyl, n -propyl, tert-butyl, n-butyl), alkoxyalkyl groups (for example methoxymethyl), aralkyl (for example benzyl), aryloxyalkyl (for example phenoxymethyl), aryl (for example phenyl optionally substituted by a halogen, an alkyl radical in to C4 or alkoxy to C4); sulfonic esters such as alkyl- or aralkylsulfonyl (for example methanesulfonyl)? amino acid esters (for example L-valyle or L-isoleucyle) and monophos-phoric, diphosphoric or triphosphoric esters.

With regard to the esters defined above, unless otherwise specified, any alkyl group present advantageously contains 1 to 18 carbon atoms, in particular 1 to 4 carbon atoms. Any aryl group present in such esters advantageously comprises a phenyl group.

Pharmaceutically acceptable salts of the compounds of formula (I) include those which are derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic acids. , benzoic, maloni-que, naphthalene-2-sulfonic and benzenesulfonic. Other acids such as oxalic acid, although not pharmaceutically acceptable in themselves, may be useful in the preparation of salts which can be used as intermediate compounds for obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from suitable bases include salts of alkali metals, eg sodium, alkaline earth metals (eg magnesium), ammonium and NR4 + (where R is a C 2 to C 4 alkyl radical).

When reference is made below to a compound according to the invention, this reference includes both the compounds of formula (I) and their pharmaceutically acceptable derivatives.

Representative compounds of formula (I) include the following: (la, 4a) -4- (6-chloro-9H-purine-9-yl) -2-cyclopen-tenylcarbinol? (1α, 4α) -4- (6-hydroxy-9H-purine-9-yl) - 2-cyclopentenylcarbinol; (1α, 4α) -4- (6 -amino-9H-pure ine-9 -y 1) -2 -cyclopen-tenylcarbinol; (1α, 4α) -4- (6-mercapto-9H-purine-9-yl) -2-cyclopentenylcarbinol; (la, 4a) -4- (2-amino-6-chloro-9H-purine-9-yl) -2-cyclopentenylcarbinol; (Ια, 4a) -4- (2-amino-6-hydroxy-9H-purine-9-yl) -2-cyclopentenylcarbinol? (1α, 4α) -4- (2,6-diamino-9H-purine-9-yl) -2-cyclopentenylcarbinol; as a racemic mixture or as an individual enantiomer.

The compounds of the invention themselves have antiviral activity and / or can be metabolized into such compounds. In particular, these compounds are effective in inhibiting the replication of retroviruses, including human retroviruses such as the human immunodeficiency viruses (HIV), agents responsible for AIDS.

Other compounds of the invention have anticancer activity, in particular those in which X is hydrogen.

According to another aspect of the invention, there is therefore provided a compound of formula (I) or a pharmaceutically acceptable derivative of this compound, intended for use as an active therapeutic agent, in particular as an antiviral agent, for example in the treatment of retrovirus infections, or as an anticancer agent.

In another aspect, or alternatively, there is provided a method of treating a viral infection, particularly an infection caused by a retrovirus such as HIV, in a mammal including humans, which comprises administering a effective amount of an antiviral compound of formula (I) or a pharmaceutically acceptable derivative of such a compound.

It is also proposed according to another aspect or as a variant the use of a compound of formula (I) or of a pharmaceutically acceptable derivative of this compound for the preparation of a medicament intended for the treatment of a viral infection or its use as an anticancer agent.

The compounds of the invention endowed with antiviral activity are also useful in the treatment of AIDS-related conditions such as the AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), neurological states associated with AIDS (such as dementia or tropical paraparesis), positive for HIV antibodies and positive for HIV viruses, Kaposi's sarcoma and thrombocytopenic purpura.

The antiviral compounds of the invention are also useful in preventing the progression of clinical disease in subjects who are positive for anti-HIV antibodies or HIV antigens and in prophylaxis following exposure to HIV viruses.

The antiviral compounds of formula (I) or their pharmaceutically acceptable derivatives can also be used in the prevention of viral contamination of physiological fluids such as blood or sperm in vitro.

Some of the compounds of formula (I) are also useful as intermediates in the preparation of other compounds of the invention.

Those skilled in the art will understand that when treatment is referred to herein, it covers prophylaxis as well as the curative treatment of established infections or symptoms.

It should also be noted that the amount of a compound of the invention which must be used in a treatment varies not only according to the particular compound which is chosen, but also with the route of administration, the nature of the condition being treated and the age and condition of the patient, and that it is ultimately at the discretion of the attending physician or veterinarian. In general, however, a suitable dose is in the range of about 1 to about 750 mg / kg, for example a range of about 10 to about 750 mg / kg of body weight, such as a range of 3 to about 120 mg per kilogram of patient's body weight per day, preferably in the range of 6 to 90 mg / kg / day, especially in the range of 15 to 60 mg / kg / day.

The desired dose can advantageously be presented in a single dose or in divided doses administered at appropriate intervals, for example two, three, four or more than four dose fractions per day.

The compound is advantageously administered in a unit dosage form, containing for example 10 to 1500 mg, better still 20 to 1000 mg, in particular 50 to 700 mg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered so as to achieve maximum concentrations of the active compound in the plasma of from about 1 to about 75 μΜ, more preferably from about 2 to 50 μΜ, especially from about 3 to about 30 μΜ. This can be achieved for example by intravenous injection of a 0.1-5% solution of the active ingredient, optionally in a physiological salt solution, or by oral administration in the form of a bowl containing approximately 1 to about 100 mg / kg of active ingredient. Suitable blood levels can be maintained by continuous infusion to provide about 0.01 to about 5.0 mg / kg / hour or by intermittent infusions providing about 0.4 to about 15 mg / kg of active ingredient.

Although it is possible that a compound of the invention, for use in therapy, can be administered as a crude chemical compound, it is preferable that the active ingredient be presented as a pharmaceutical formulation.

The invention therefore further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable derivative of this compound 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 must be compatible with the other ingredients of the formulation and must not harm the recipient.

Pharmaceutical formulations include formulations which are suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (intramuscular and intravenous) administration or in a form which is suitable for administration by inhalation or insufflation . In appropriate cases, the formulations can be conveniently presented in physically separate dosage units and can be prepared by any of the methods well known in the pharmacy field. All methods include the step of bringing the active compound into association with liquid carriers or finely divided solid supports or both and then, if necessary, forming the product into the desired formulation.

Pharmaceutical formulations which are suitable for oral administration can advantageously be presented in physically separate units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution, a suspension, or in the form of an emulsion. The active ingredient can also be presented in the form of a bowl, an electuary or a paste. Tablets and capsules for oral administration may contain conventional excipients such as binders, fillers, lubricants, disintegrants or wetting agents. The tablets can be coated according to methods well known in the art. Oral liquid preparations can be, for example, in the form of suspensions, solutions, emulsions in water or in oil, syrups or elixirs, or they can be presented in the form of a dry product to be mixed with water or other suitable vehicle before use. Such liquid preparations can contain conventional additives such as suspending agents, emulsifiers, non-aqueous vehicles (which may include edible oils) or preservatives.

The compounds according to the invention can also be formulated for parenteral administration (for example by injection, in the form of a bowl or by continuous infusion) and they can be presented in unit dosage form in ampoules, in syringes previously loaded or in containers containing multiple doses, with the addition of a preservative. The compositions can affect forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending agents, stabilizing agents and / or dispersing agents. Alternatively, the active ingredient may be in the form of powder, obtained by aseptic isolation of sterile solid material or by lyophilization from a solution, of powder to be mixed with a suitable vehicle, for example sterile pyrogen-free water, before use.

For local administration on the epidermis, the compounds according to the invention can be formulated as ointments, creams or lotions, or as a transdermal adhesive dressing. Ointments and creams can, for example, be formulated with an aqueous or oily base added with suitable thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base and they also generally contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents.

Formulations suitable for local administration in the mouth include tablets containing the active ingredient in a flavored base, usually sucrose and gum arabic or gum tragacanth; lozenges comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and gum arabic; and mouthwash compositions comprising the active ingredient in a suitable liquid carrier.

Pharmaceutical formulations which are suitable for rectal administration the support of which is a solid material are very advantageously presented as suppositories containing a unit dose. Suitable carriers include cocoa butter and other materials commonly used in the art, and suppositories can be conveniently formed by adding the active compound to one or more softened or melted carriers, followed by cooling and of forming in molds.

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

For intranasal administration, the compounds of the invention can be used as a sprayable liquid composition or in the form of drops.

Drops can be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents or suspending agents. Sprayable liquid compositions are conveniently delivered using pressure vessels.

For administration by inhalation, the compounds according to the invention are conveniently delivered by an insufflator, a nebulizer or a pressurized container or by other practical means making it possible to deliver a spray jet in aerosol. Pressure vessels may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the metered unit can be determined using a valve designed to deliver a measured quantity.

Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example of a powder mixture of the compound and of a suitable powder base such as than lactose or starch. The powder composition can be presented in unit dosage form for example in capsules or cartridges or for example in gelatin envelopes or in the form of blisters, of which the powder can be administered using an inhaler or 'an insufflator.

When desired, the formulations described above can be used in a form suitable for allowing sustained release of the active ingredient.

The pharmaceutical compositions in accordance with the invention may also contain other active ingredients such as antimicrobial agents or preservatives.

The compounds of the invention can also be used in combination with other therapeutic agents, for example other anti-infectious agents. In particular, the compounds of the invention can be used in conjunction with known antiviral agents.

According to another of its aspects, the invention therefore provides an association formed of a compound of formula (I) or of a physiologically acceptable derivative of this compound with another agent endowed with therapeutic activity, in particular an antiviral agent.

The combinations referred to above can advantageously be presented, for their use, in the form of a pharmaceutical formulation and, consequently, pharmaceutical formulations comprising a combination as defined above together with a support. another pharmacologically acceptable aspect is another aspect of the invention.

Advantageous therapeutic agents for use in these combinations include acyclic nucleosides such as aciclovir, interferons such as α-interferon, renal excretion inhibitors such as probenicid, nucleoside transport inhibitors such as dipyridamole, 2 ', 3' -dideoxynucleosides such as 2 ', 3'-dideoxycytidine, 2', 3 '-dideoxyadenosine, 2', 3 '-dideoxyinosine, 2', 3 '-dideoxythymidine and 2 ', 3' -dideoxy-2 ', 3 1 -didehydrothymidine and immunomodulators such as interleukin II (IL2) and granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin and ampligen .

The individual components of these combinations can be administered successively or simultaneously in separate or combined pharmaceutical formulations.

When the compound of formula (I) or a pharmaceutically acceptable derivative of this compound is used in combination with a second therapeutic agent active against the same virus, the dose of each compound may be different from that used when using the compound alone. Appropriate doses are readily appreciated by those skilled in the art.

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

Methods which are suitable for preparing the compounds of formula (I) and their pharmaceutically acceptable derivatives are described below; groups X and Z

are as defined above, unless otherwise specified. It should be noted that the following reactions may require the use of starting materials, or may be conveniently applied to starting materials which carry protected functional groups, and removal of the protecting groups may therefore be necessary as an intermediate step. or final step to obtain the desired compound. The protection and elimination of the protection of functional groups can be carried out by conventional means. Thus, for example, amino groups can be protected by a group chosen from aralkyl (for example benzyl), acyl or aryl (for example 2,4-dinitrophenyl) radicals; the subsequent removal of the protective group being carried out at the appropriate time by hydrolysis or hydrogenolysis, as appropriate, under normal conditions. Hydroxyl groups can be protected by the use of any conventional group protecting a hydroxyl group, as described for example in "Protective Groups in Organic Chemistry", published under the direction of J.F.W. McOmie (Plenum Press, 1973) or "Protective Groups in Organic Synthesis" by Theodora W. Greene (John Wiley and Sons, 1981). Examples of groups suitable for the protection of hydroxyl groups include groups chosen from alkyl (for example methyl, tert-butyl or methoxymethyl), aralkyl (for example benzyl, diphenylmethyl or triphenylmethyl) radicals, heterocyclic groups such as tetrahy -dropyrannyl, acyl groups (for example acetyl or benzoyl) and silyl groups such as trialkylsilyl groups (for example tert-butyldimethylsilyl). Groups protecting hydroxyl functions can be removed by conventional techniques. Thus, for example, the alkyl, silyl, acyl and heterocyclic groups can be removed by solvolysis, for example by hydrolysis under acidic or basic conditions. Aralkyl groups such as triphenylmethyl can likewise be removed by solvolysis, for example by hydrolysis under acidic conditions. Aralkyl groups such as benzyl can be cleaved by hydrogenolysis in the presence of a catalyst based on a noble metal such as palladium fixed 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 their pharmaceutically acceptable derivatives can be prepared by reaction of a compound of formula (II)

(in which X and Z are substituents having the definition given for formula (I) or are protected forms thereof and the hydroxyl group in the cyclopentenylcarbinol group may be in a protected form) or of a pharmaceutically acceptable derivative of this compound with a reagent chosen between formic acid and its reactive derivatives, the reaction being followed, when necessary, by the elimination of the unwanted groups introduced by said reagent and / or the elimination of any protective groups present.

Examples of suitable formic acid derivatives which can be used in process (A) above include orthoformates (e.g. triethyl orthoformate), dialkoxymethyl acetates (e.g. diethoxymethyl acetate), acid dithioformic, formamide, s-triazine or formamidine acetate.

Unwanted groups introduced by formic acid or by a reactive derivative of this acid can advantageously be eliminated by mild hydrolysis, for example by using an inorganic acid such as aqueous hydrochloric acid.

When a trialkyl orthoformate such as triethyl orthoformate is used, it also advantageously constitutes the solvent for the reaction. Other solvents which can be used include amides (for example dimethylformamide or dimethylacetamide), chlorinated hydrocarbons (for example dichloromethane), ethers (for example tetrahydrofuran) or nitriles (for example acetonitrile).

In some cases (for example when using a trialkyl orthoformate such as triethyl orthoformate), the reaction can advantageously be carried out in the presence of a catalyst such as a strong acid (for example concentrated hydrochloric acid, nitric acid or sulfuric acid). The reaction can be carried out at a temperature in the range from -25 e to +150 eC, for example from 0 to 100 "C and preferably at room temperature.

In another process (B), compounds of formula (I) and their pharmaceutically acceptable derivatives or a protected form of these compounds are exposed to an interconversion reaction in which the substituent X initially present is replaced by a substituent X different and / or the group Z initially present is replaced by a different group Z, the operation being followed, if necessary, by the elimination of any protective groups present.

In one embodiment of process (B), compounds of formula (I) in which X represents an NRRR group (where R and R1 are as defined above) can be prepared by amination of a compound correspondent of formula (I) in which X represents a halogen atom (for example chlorine). Amination can be carried out by reaction with an HNRR1 reagent (where R and R1 are as defined above), advantageously in a solvent such as an alcohol (for example methanol). The reaction can be carried out at any suitable temperature and advantageously at an elevated temperature, for example at reflux or alternatively, when using liquid ammonia, in a sealed tube at a temperature of about 50 to 80 ' vs. Conditions suitable for the transformation of halides into secondary and tertiary amines have also been described by I.T. Harrison et al in Compendium of Oraanic Svnthetic Methods. Wiley-Inter-science, New York (1971), pages 250-252.

In another embodiment of process (B), compounds of formula (I) in which X represents an OR group (where R is as defined above) can be prepared by displacement of the atom halogen (for example chlorine) with an appropriate RO "anion. When R represents a hydrogen atom, the displacement reaction can be carried out by hydrolysis which can be carried out in water or in a mixture of water and a water-miscible solvent such as an alcohol (for example methanol or ethanol), an ether (for example dioxane or tetrahydrofuran), a ketone (for example acetone), an amide ( for example dimethylformamide) or a sulfoxide (for example dimethylsulfoxide), advantageously in the presence of an acid or a base. Suitable acids include organic acids such as p-toluenesulionic acid or inorganic acids such as hydrochloric acid, nitric acid or sulfuric acid. suitable bases include inorganic bases such as hydroxides or carbonates of alkali metals (eg sodium or potassium hydroxide or carbonate). An aqueous acid or an aqueous base can also be used as the reaction solvent. The hydrolysis can advantageously be carried out at a temperature in the range from -10e to +150 * 0, for example at reflux. When R represents a C 1 to C 4 alkyl or aryl group, the RO anion is advantageously formed from a corresponding alcohol ROH using an inorganic base such as an alkali metal (for example metallic sodium) or a hydride of alkali metal (e.g. sodium hydride). The reaction with the anion formed in situ can conveniently be carried out at room temperature.

In another embodiment of process (B), compounds of formula (I) in which X represents an SH group can be prepared by reaction of the halogenated compound of formula (I) with thiourea in a suitable solvent such as an alcohol (for example n-propanol) at an elevated temperature (for example at reflux), the reaction being followed by an alkaline hydrolysis. Suitable bases which can be used include alkali metal hydroxides (eg sodium hydroxide). The reaction can advantageously be carried out in accordance with the method of G.G. Urquart et al., Org. Syn. Coll. Flight. 3, 363 (1953), for example by refluxing the intermediate product with an aqueous NaOH solution 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 reduction of the halogenated compound of formula (I) using a reducing system which does not does not affect the rest of the molecule. Suitable reducing agents which can be used to drive the desired dehalogenation reaction include the metallic zinc / water system with which the method described by J.R. Marshall et al in J. Chem. Soc., 1004 (1951). Alternatively, the reaction can be carried out by photolysis in a suitable solvent such as tetrahydro-furan containing 10% triethylamine and, advantageously, in a Rayonet photochemical reactor (2537A) in accordance with the process described by V. Nair et al. in J. Ora. Chem. 52. 1344 (1987).

According to yet another embodiment of method (B), compounds of formula (I) in which X represents a halogen atom can be prepared from a different halogenated compound of formula (I) by methods halide exchange classics. Alternatively, when X is chlorine, this substituent can be replaced by other halogen atoms using various p- (halogeno) benzene-diazonium chlorides according to well known methods.

Compounds of formula (I) in which X represents an SR group where R is a C 1 -C 4 alkyl or aryl group can be prepared from the corresponding thiols using standard procedures for alkylation or arylation, as described, for example, in U.S. Patent No. 4,383,114.

Compounds of formula (I) in which Z represents a hydroxyl group can be conveniently prepared from a corresponding compound of formula (I) in which Z represents NH2 by reaction with nitrous acid, using for example the procedure used by J. Davoll in J. Amer. Chem. Soc. 73. 3174 (1951).

Many of the reactions described above have been widely described in connection with the synthesis of nucleosi-purine derivatives, for example in Nucleoside Analogs - Chemistry. Bioloov and Medical Applications, published under the supervision of R.T. Walker et al., Plenum Press, New York (1979), pages 193-223, the subject of which is incorporated here for documentary purposes.

Pharmaceutically acceptable salts of the compounds of the invention can be prepared as described in United States Patent No. 4,383,114 incorporated herein for reference. Thus, for example, when it is desired to prepare an acid addition salt of a compound of formula (I), the product of any of the above processes can be converted into a salt by treatment of the resulting free base with suitable acid, using conventional methods. Pharmaceutically acceptable acid addition salts can be prepared by reaction of 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 (for example methanol, ethanol or isopropanol). Inorganic basic salts can be prepared by reacting the free base with a suitable base such as an alcoholate (eg sodium methylate), optionally in the presence of a solvent such as an alcohol (eg 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 into a phosphoric ester or another pharmaceutically acceptable ester by reaction with a phosphorylating agent such as POCI3 or with a suitable esterifying agent such as a halide or an acid anhydride, according to the case.

An ester or a salt of a compound of formula (I) can be converted into the corresponding compound, for example by hydrolysis.

The compounds of formula (II) and their salts are new compounds and constitute another feature of the present invention.

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

by reaction with an excess of a pyrimidine of formula (III)

(in which Y is a halogen atom such as chlorine and Z is hydrogen or a hydroxyl group) in the presence of an amino base such as triethylamine and in an alcoholic solvent (for example n-butanol), advantageously at reflux.

Compounds of formula (II) in which Z represents NH2 can be prepared using the compound of formula 2a by reaction with an excess of a pyrimidine of formula (IV)

(in which Y is as defined in formula (III) above under conditions similar to those which have just been described above for the preparation of compounds of formula (II) in which Z represents hydrogen or a hydroxyl group to form a compound of formula (V)

which can be diazotized using a diazonium salt ArN2 + E ~ (where Ar represents an aromatic group, for example p-chlorophenyl, and E “represents an anion, for example a halide anion such as chloride) in a solvent such as l water, an organic acid such as acetic acid or their mixture, advantageously at a temperature of the order of room temperature to form a compound of formula (VI)

(in which Ar has the definition which has just been given thereof) 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, for example acetic acid. It should be noted that the choice of reducing agent depends on the nature of group X.

Compound 2a can be prepared from la-acetylamino-3a-acetoxy-methylcyclopent-2-ene (la), a precursor endowed with flexibility of use, by hydrolysis in the presence of a soft base such as a metal hydroxide alkaline earth.

A particularly convenient synthesis of compounds of formula (I) via 6-chlorinated compounds of formula (II) is illustrated below.

Compound 2a and the compounds of formulas (V) and (VI) are new intermediate compounds and constitute other particularities of the present invention. Compound 1a is a known compound described in U.S. Patent No. 4,138,562.

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

The splitting of the final product or of an intermediate compound or of the corresponding starting material can be carried out by any suitable process known in practice: see for example "Stereochemistry of Carbon Compounds", EL Eliel (McGraw Hill, 1962) and " Tables of Resolving Agents ", SH Wilen.

A suitable method for obtaining compounds of formula (I) of chiral purity is the enzymatic transformation of a racemic mixture of the compound or of a precursor of the compound. By such a process, compounds (+) and (-) of formula (I) can be obtained in the optically pure form. Suitable enzymes include deaminases such as adenosine deaminase.

Other details of the invention emerge from the examples detailed below in which the elementary analyzes were carried out by the M-H-W Laboratories of Phoenix, AZ. The melting points were determined on a Mel-Temp device and were corrected. The nuclear magnetic resonance spectra were recorded in DMSO-Dg on Jeol FX 90QFT or Nicollet NT300 spectrometers. The chemical derivatives are expressed in ppm compared to the tetramethylsilane used as a reference substance. The infrared spectra were determined on KBr pellets with a Nicollet 50XC FT-IR spectrometer and the ultraviolet spectra were determined on a Beckmann DU-8 spectrophotometer. Trap spectra were recorded using an MS-30 mass spectrometer from AEI Scientific Apparatus Limited. Thin layer chromatography (TLC) was carried out on 0.25 mm layers of Merck silica gel (particles 37 to 62 mm). All chemicals and solvents are of analytical quality unless otherwise specified. The expression "active ingredient" used in the Examples designates a compound of formula (I) or a pharmaceutically acceptable derivative of this compound.

Example 1 f ±) - (1α.4ο: ^ -4-Γ f5-Amino-6-chloro-4-pvrimidinvHamino1-2-cyclopenténvlcarbinol (3a)

A mixture of lcr-acetylamino-3a-acetoxymethyl-cyclopent-2-ene (la) (3.0 g, 15 mmol) and aqueous barium hydroxide (0.5 N, 300 ml) was heated at reflux for a night. After cooling, it was neutralized with dry ice. The precipitate was separated by filtration and the aqueous solution was concentrated to dryness. The residue was extracted with absolute ethanol and reconcentrated to give compound 2a as a colorless syrup, 1.6 g (14 mmol).

5-amino-4,6-dichloropyrimidine (4.59 g, 28 mmol), triethylamine (4.2 g, 42 mmol) and n-butanol (50 ml) were added to this syrup and refluxed the mixture for 24 hours. The volatile solvents were removed, the residue was absorbed on silica gel (7 g), conditioned in a flash chromatography column (4.0 x 12 cm) and eluted with a mixture of chloroform and methanol (20: l) giving 2.69 g (74%) of the compound melting it at 130-132 "C. An analytical sample was obtained by recrystallization from ethyl acetate (EtOAc), melting point 134-135" C, mass spectrum (30 ev, 200 “C): m / e 240 and 242 (M + and M + +2) 209 (M * -31), 144 (B +)? infrared spectrum: 3600-2600 (OH), 1620, 1580 (C = C, C = N)? analysis (C10H13C1N40) C, H, N. Example 2 (i) - (la. 4oi ^ -4- Γ (2-Amino-6-chloro-4-pvrimidinvlï aminol-2-cyclopenténvlcarbinol (4a)

To 14 ml of crude product 2a (Example 1) were added 2-amino-4,6-dichloropyrimidine (3.74 g, 22.8 mmol), triethylamine (15 ml) and n-butanol ( 75 ml) and the mixture was heated at reflux for 48 hours. The volatile solvents were removed, the residue was treated with methanol to separate the undissolved by-product (double pyrimidine nucleoside). The methanolic solution was absorbed on silica gel (8 g), conditioned in a column (4.0 x 14 cm) and eluted with a mixture of chloroform and methanol (40: 1) giving 1.52 g ( 42%) of raw product 4a. The product was recrystallized from ethyl acetate to give compound 4a? melting point 132-134eC, mass spectrum (30 ev, 200'C): m / e 240 and 242 (M + and Μ4 "+2), 209 (M * -31), 144 (B +); infrared spectrum: 3600-3000 (NH2, OH), 1620, 1580 (C = C, C = N); anal. (C10H13C1N4) C, H, N.

Example 3 (± ^ - (1α.4αϊ-4- (Γ (2-Amino-6-chloro-5- (4-chlorophénvlÎazol-4-pvrimidinvl-amino) -2-cvclopenténvlcarbinol (5aï

A cold solution of diazonium salt was prepared from p-chloraniline (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 compound 4a (2.40 g, 10 mmol), acetic acid (50 ml), water (50 ml) and sodium acetate trihydrate (20 g). The reaction mixture was stirred overnight at room temperature. The

yellow precipitate was filtered and washed in cold water until neutral, then it was air dried in the hood giving 3.60 g (94%) of compound 5â melting at 229 “C

(decomposition). The analytical sample was obtained from a mixture of acetone and methanol (1: 2), melting point 241-243ec (decomposition). Mass spectrum (30 ev, 260 ° C) î m / e 378 and 380 (M * and M + +2), 282 (B +); infrared spectrum: 3600-3000 (NH2, OH), 1620, 1580 (C = C, C = N); analysis (C16H16C12N60) C, H, N.

Example 4 (t) - (la.4a) -4-Γ (2,5-Diamino-6-chloro-4-pyrimidinvl ^ aminol-2-cvclopenténvlcarbinol (6a)

A mixture of compound 5a (379 mg, 1 mmol), zinc powder (0.65 g, 10 mmol), acetic acid (0.32 ml), water (15 ml) and ethanol ( 15 ml) was heated at reflux under nitrogen for 3 hours. The zinc was removed and the solvents were evaporated. The residue was absorbed on silica gel (2 g), packaged in a

column (2.0 x 18 cm) and eluted with a CHCl3-MeOH mixture

(15: 1). We got a pink syrup. Further purification in a mixture of methanol and ether gave compound 6a as pink crystals, 170 mg (66%), melting point 168-170eC, mass spectrum (30 ev, 220aC): m / e 255 and 257 (M + and M + +2) 224 (M + -31) 159

(B +); infrared spectrum: 3600-3000 (NH2, OH) 1620, 1580 (C = C, C = N); anal. (C10H14C1N5) C, H, N

Example 5 (±) - (la. 4a) -4- (6-Chloro-9H-purine-9-Yl) -2-cyclopenténvl-carbinol (7a)

A mixture of compound 3a (1.30 g, 5.4 mmol), triethyl orthoformate (30 ml) and hydrochloric acid (12N, 0.50 ml) was stirred overnight at temperature ambient. The solvent was evaporated at 35 ° C under vacuum. An aqueous solution of hydrochloric acid (0.5 N, 30 ml) was added to the residue and the mixture was stirred for 1 hour, neutralized to pH 7-8 with 1 N sodium hydroxide and was fixed by absorption on silica gel (8 g), conditioned in a column (4.0 x 8 cm) and eluted with a mixture of chloroform and methanol (20 : 1), which gave white crystals of compound 7a, 1.12 g (82%). The crude product was recrystallized from ethyl acetate giving compound 7a melting at 108-110eC, mass spectrum (30 ev, 200 * C): m / e 250 and 252 (M + and M + + 2) , 219 (M + -31), 154 (B +); infrared spectrum: 3600-2800 (OH), 1600 (OC, ON)? anal. (C1; 1Hi; iC1N40) C, H, N.

Example 6 (i) -fl0i.4a) -4- (6-Hvdroxv-9H-purine-9-vl> -2-cvclopenténvl-carbinol f8a) ün mixture of compound 7a (251 mg, 1 mmol) and hydroxide of aqueous sodium (0.2 N, 10 ml) was heated at reflux for 3 hours. After cooling, the pH of the reaction mixture was adjusted to 5-6 with acetic acid. The reaction mixture was absorbed on silica gel (2 g), conditioned in a column (2.0 x 11 cm) and eluted with a mixture of CHCl3 and MeOH (10: 1), giving 105 mg (45 %) of compound 8a. The crude white product was recrystallized from a mixture of water and methanol (3: 1), giving compound 8a melting at 248-250 * C (decomposition), mass spectrum (30 ev, 300 “C) : m / e 232 (M +), 214 (M + -18), 136 (B +)? infrared spectrum: 3600-2600 (OH), 1680, 1600 (C = 0, OC, ON)? anal. (^ n% 2 ^ 4®2) C, H, N.

Τ? Γοτηρ1 7 (±) - (Ια.4α) -4- (6-Amino-9H-purine-9-vl) -2-cvclopenténvl-carbinol (9a)

Liquid ammonia was transferred to a bomb containing a solution of compound 7a (250 mg, 1 mmol) in methanol (5 ml) at -80 ° c. The bomb was closed and heated at 60 ° C for 24 hours. Ammonia and methanol were evaporated and the residue was recrystallized from water to give slightly dirty white crystals of compound 9a, 187 mg (81%), melting point 198-200 eC. Mass spectrum (30 ev, 210 "C); m / e 231 (M +), 213 (M + -18), 135 (B +); infrared spectrum: 3600-2600 (NH2, OH), 1700, 1600 (C = C, C = N); anal. (C ^ H ^ CsO) C, H, N.

Example 8 (±) - (la. 4a) -4- (6-Mercapto-9H-purine-9-vl) -2-cvclopenténvl-carbinol (10a)

A mixture of compound 2a (125 mg, 0.5 mmol), thiourea (40 mg, 0.64 mmol) and n-propanol (5 ml) was heated at reflux for 2 hours. After cooling, the precipitate was isolated by filtration, washed with n-propanol and dissolved in sodium hydroxide (1 N, 5 ml). The pH of the solution was adjusted to 5 with acetic acid. The crude compound 10a (90 mg, 73%) was isolated again, melting point 260-262eC (decomposition), and it was recrystallized from N, N-dimethylfor-mamide to give compound 10a. melting point 263-265 ° C (decomposition). Mass spectrum (30 ev, 290eC): m / e 248 (M *), 230 (M + -18), 152 (B +); infrared spectrum: 3600-3200 (OH), 3100, 2400 (SH), 1600 (C = C, C = N); anal.

(C11H12N40S> c 'h> n *

Tgygmple Q

(±) - (los. 4ο: ΐ -4- (2 -Amino-6-chloro-9H-Purine-9 -vl ^ -2-cvclopen-ténvl-carbinol (13a)

A mixture of compound 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. Diluted hydrochloric acid (0.5 N, 40 ml) was added and the mixture was kept in reaction for 1 hour at room temperature. The mixture was neutralized to pH 8 with 1 N sodium hydroxide and absorbed on silica gel (7.5 g) conditioned in a column (4.0 x 10 cm) and it was eluted with a mixture of chloroform and methanol (20: 1) to give slightly dirty white crystals of compound 13a. 1.18 g (80%). The crude product was recrystallized from ethanol to give compound 13a, melting point 145-147 "C. Mass spectrum (30 ev, 220 * C): m / e 265 and 267 (M + and M + +2 ), 235 (11+ -30), 169 (B +); infrared spectrum: 3600-2600 (NH2, OH), 1620-1580 (C = C, C = N); anal. (CxiH12N50C1.3 / 4 H20) C, H, N.

Example 10 (±) - (1α.4α) -4- (2-Amino-6-hvdroxv-9H-purine-9-vl ^ -2-cvclopenténvlcarbinol (14a)

A mixture of compound 13a (266 mg, 1 mmol) and aqueous sodium hydroxide (0.33 N) was heated at reflux for 5 hours, absorbed on silica gel (2g), conditioned in a column (2 , 0 x 7.5 cm) and eluted with a mixture of chloroform and methanol (5: 1). The crude product was recrystallized from a mixture of methanol and water (1: 4) to give white crystals of compound 14a. 152 mg (61%), melting point 254-256 "C (decomposition). Mass spectrum (30 ev, 200" C): m / e 247 (M +), 217 (M + -30), 151 (B +) ; infrared spectrum: 3600-2600 (NH2, OH), 1700, 1600 (C = 0, C = C, C = N); anal.

(CiiH13N502.3 / 4 H20) C, H, N.

Example 11 (i) - (la.4a ^ -4- (2.6-Diamino-9H-purine-9-vl) -2-cvclopenténvl-carbinol (15a ^

Liquid ammonia was transferred to a solution of compound 13a (265 mg, 1 mmol) in methanol (10 ml) at -80 ° C in a bomb. The bomb was closed and heated to 75 ° C for 48 hours. The ammonia and methanol were evaporated. The residue was absorbed on silica gel (2 g), conditioned in a column (2.0 x 10 cm) and was eluted with a mixture of chloroform and methanol (15: 1). The crude product was recrystallized from ethanol to give 196 mg (80%) of compound 15a, melting at 152-155 ° C. Mass spectrum (30 ev, 200 "C): m / e 246 (M +), 229 (M + -17), 216 (M + -30), 150 (B +); infrared spectrum: 3600-3000 (NH2, OH) , 1700, 1650, 1600 (C = 0, C = C, C = N)? Anal. (C11H14N60) C, H, N.

Example 12 (IS.4R) -4- (2.6-Diamino-9H-purine-9-vl) -2-cvclopenténvl-carbinol [(IS, 4R) -4- (2,6-Diamino-9H-purine-9 -yl) -2-cyclopentene-methanol] (a) Intermediate Compound 1: Du (1R, 2S, 3R, 5R) -3- [6-Amino-9H-purine-9-yl] -5- [((l , l-dimethylethyl) dimethylsilyloxy) -methyl] -1,2-cyclopentanediol (-) Aristeromycin1 (12.505 g), tert-butyldimethylsilyl chloride (7.8 g) and imidazole (12.96 g) in anhydrous dimethylfor-mamide (85 ml) were stirred at room temperature for 2.5 hours. The resulting solution was diluted with ethyl acetate (500 ml), then washed with water (3 x 100 ml) and a salt solution (50 ml) before a white solid material separates by crystallization. This solid material was collected by filtration, washed with ethyl acetate and then dried under vacuum to give the title product (3.92 g)? proton magnetic resonance (DMSO-dg) 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 (Ui) * 2.09 (1H), 1.79 (1H), 0.89 (9H), 0.07 (6H).

1 Journal of the American Chemical Society 1983, vol. 105, 4049-4055.

(b) Intermediate compound 2 î (4R, 3aS, 6R, 6aR) -4- [6-Amino-9H-purine-9-yl] -6- [((1,1-dimethylethyl) dimethylsilyloxy) -methyl] - 3a, 5,6,6a-tetrahydro-4H-cyclopenta-l, 3-dioxole-2-thione

A stirred suspension of Intermediate Compound 1 (3.45 g) in anhydrous dimethylformamide (56 ml) was treated with 1,1'-thiocarbonyldiimidazole (3.3 g) to give a yellow solution. After 15.5 hours at room temperature, the resulting solution was combined with the solution from a previous test (on a 6% scale) and the solvent was removed by evaporation. The residual oil was diluted with ethyl acetate (100 ml) then washed with water (2 x 20 ml) and a salt solution (2 x 20 ml), dried (MgS04) and evaporated to giving a yellow solid. This solid was washed with diethyl ether (25 ml) then collected by filtration, further washed with ether (25 ml) and dried in vacuo giving the title product as a solid of pale cream color (3.61 g); Amax (ethanol) 240.0 nm (E? "* 459); proton magnetic resonance (DMSO-dg) 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 ).

(c) Intermediate compound 3: (l'R, 4'S) -9- [4 - (((1,1-

Dimethylethyl) dimethylsilyloxy) methyl) -2-cyclopentene-1-yl] -9H-purine-6-amine

A solution of Intermediate Compound 2 (3/57 g) in anhydrous tetrahydrofuran (25 ml) was treated with a solution of 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (4.94 g) in anhydrous tetrahydrofuran (10 ml) then stirred at room temperature for 8.75 hours. The solvent was removed by evaporation. The residual oil was combined with that which came from a previous test (on a 40% scale) then it was subjected to chromatography on a silica column (200 g, Merck 7734), eluted with chloroform then with mixtures of chloroform and ethanol to give a white solid. This solid was washed with diethyl ether (25 ml) and then collected by filtration. The solid was further washed with ether (10 ml) and then dried under vacuum to give the title product (1.47 g); Xmax (ethanol) 261.4 nm (E ^ * 443); proton magnetic resonance (DMSO-d6), 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) Intermediate compound 4: 1-oxide of (1'R, 4'S) -9- [4- ((((1,1-dimethylethyl) dimethylsilyloxy) methyl) -2-cyclopen-tene-1-yl] -9H -purine-6-amine

A solution of Intermediate Compound 3 (1.37 g) in chloroform (30 ml) was treated with m-chloroperoxybenzoic acid (1.29 g) at 80-90% and then stirred at room temperature for 3 hours . The solvent was removed by evaporation and the residual gum was dissolved in ethyl acetate (10 ml). A white solid separated by crystallization. This solid and the material collected by evaporation of the filtrate were dissolved in chloroform (100 ml), then the solution was washed with a saturated aqueous solution of sodium bicarbonate (3 x 10 ml) and a salt solution (2 x 10 ml). The aqueous wash liquors were reextracted with chloroform (50 ml). The combined organic solutions were dried (MgSO 4) and then evaporated until a solid material was obtained. This solid material was washed with diethyl ether (25 ml) and then collected by filtration. The white solid was further washed with ether (10 ml) and then dried under vacuum to give the title product (1.16 g) / * ^ max (ethanol) 235.4 nm (E * 1324), 263.2 nm (E * ^ 248), 300.2 nm (E * * m 75); proton magnetic resonance (CDC13) 8.72 (1H), 8.02 (1H), 7.16 (2H), 6.21 (1H), 5.87 (1H), 5.72 (1H), 3 , 68 (2H), 3.04 (1H), 2.82 (1H), 1.74 (1H), 0.89 (9H), 0.06 (6H).

(e) Intermediate Compound 5: (1'R, 4'S) -7- [4 - (((1,1-dimethylethyl) dimethylsilyloxy) methyl) -2-cyclopentene-1-yl] -2-imino-1 hydrobromide , 2-dihydro [1,2,4] oxadiazolo- [3,2-i] -9H-purine. An ice-cold stirred suspension of Intermediate Compound 4 (1.08 g) in methanol (20 ml) was treated with a solution of cyanogen bromide (0.34 g) in methanol (20 ml) added in 5 minutes. After 15 minutes, the suspension was allowed to warm to room temperature to give a solution. After 90 minutes, the solvent was removed by evaporation. The residue was washed with diethyl ether (25 ml) and then collected by filtration. The solid material was further washed with ether (25 ml) and then dried under vacuum, giving the title product (1.37 g): Amax (ethanol) 228.2 nm (E * 530), 285.2 nm (E * 445); proton magnetic resonance (CDC13) 10.20 (1H), 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).

(f) Intermediate compound 6: (l'R, 4'S) -9- [4 - (((1,1-

Dimethylethyl) dimethylsilyloxy) methyl) -2-cyclopentene-1-yl] -6-cyanimino-1,6-dihydro-1-methoxy-9H-purine

A solution of Intermediate Compound 5 (1.36 g) in dimethylformamide (10 ml) was stirred at room temperature and then treated with triethylamine (1.2 ml). After 40 minutes, 11iodomethane (0.54 ml) was added to give a yellow solution.

After 3.75 hours, 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 a salt solution (20 ml), dried (MgSC> 4) and evaporated until a solid material was obtained. This solid material was washed with diethyl ether (25 ml) and then collected by filtration. This white solid was further washed with ether (10 ml) and then dried under vacuum to give the title product (0.865 g); Amax (ethanol) 227.2 nm (E * * 449), 287.0 nm (E *% 544); resonance '1 cm' 1 cm magnetic protons 8.23 (1H), 7.96 (1H), 6.24 (1H), 5.85 (1H), 5.65 (1H), 4.21 (3H ), 3.66 (2H), 3.04 (1H), 2.77 (1H), 1.68 (1H), 0.88 (9H), 0.05 (6H).

(9) Intermediate compound 7: (l'R, 4'S) -9- [4 - (((1,1-

Dimethylethyl) dimethylsilyloxy) methyl) -2-cyclopentene-1-yl] -6-methoxyamino-9H-purine-2-amine

A solution of Intermediate Compound 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. Heating was stopped after 9 hours and the solution was kept at room temperature overnight. The solvent was removed by evaporation. The residual oil was combined with that which came from a previous test (on a 4% scale) then the mixture was subjected to chromatography on a silica column (40 g, Merck 9385), eluted with chloroform then mixtures of chloroform and ethanol, which gave a foam. This foam was triturated with diethyl ether (10 ml) and the resulting solid was collected by filtration. The solid material was further washed with ether (5 ml) and then dried under vacuum to give the title product (594 mg); Xmax (ethanol) 282f2 nm (E * ^ 409)? proton magnetic resonance (DMSO-dg) 9.76 (1H), 7.32 (1H), 6.53 (2H), 6.08 (1H), 5.88 (1H), 5.26 (1H) , 3.72 (3H), 3.61 (2H), 2.90 (1H), 2.50 (1H), 1.52 (1H), 0.83 (9H), 0.02 (6H).

(h) Intermediate compound 8: (lS, 4R) -4- [2-Amino-6-methoxyamino-9H-purine-9-yl] -2-cyclopentene-methanol

A solution of Intermediate Compound 7 (356 mg) in tetrahydrofuran (35 ml) was stirred at room temperature and then treated with tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 1.4 ml). After 90 minutes, the reaction was stopped with water (1 ml) and then the solvents were removed by evaporation. The residual oil was subjected to chromatography on a silica column (20 g, Merck 7734), eluted with chloroform and then with mixtures of chloroform and ethanol, and the title product was thus obtained in the form of '' a solid substance (243 mg); \ 1%

Amax (buffer at pH 6) 280.2 nm (E ^ cm 534); proton magnetic resonance (DMSO-dg) 9.75 (1H), 7.39 (1H), 6.52 (2H), 6.10 (1H), 5.84 (1H), 5.27 (1H) , 4.73 (1H), 3.40 (2H), 2.83 (1H), 2.55 (1H), 1.52 (1H).

fis. 4R) -4-Γ2.6-Diamino-9H-purine-9-vl1-2-cvclopentènecar-binol

An ice-stirred solution of Intermediate Compound 8 (210 mg) in water (10 ml) and tetrahydrofuran (50 ml) was treated with aluminum amalgam [prepared from aluminum (237 mg) and 0.5% aqueous solution of mercuric chloride], added in small amounts over 15 minutes. After 40 minutes, the mixture was allowed to stir to warm to room temperature. After 15 hours, the resulting mixture was filtered through Kieselguhr to remove insoluble matter. These materials were washed with a mixture of water and tetrahydrofuran (1: 5, 60 ml). The combined filtrates were evaporated. The residue was subjected to silica column chromatography (10 g, Merck 9385), eluted with mixtures of chloroform and ethanol, to give the title product in the form of a foam (159 mg) ; [a] D -81 * (ç 1.04, methanol); Amax (pH 6 buffer) 255.0 nm (E. 302), 280.8 nm 1%. 1,010 (E- 381), proton magnetic resonance (DMSO-d6) 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 (1H), 1.60 (1H).

Example 13 (IS. 4R) -4- (2-Amino-6-hvdroxy-9H-purine-9-vl) -2-cvclopen-tenvlcarbinol (1'R, 41 S) -2-Amino-1,9- dihydro-9- [4-hydroxymethyl-2- cyclopentene-1-yl] -6H-purine-6-one

A cloudy solution of the title compound of Example 12 (144 mg) in a 0.1 M buffer at pH 6 (10 ml) (prepared from 28.4 g of disodium orthophosphate in 2 liters of water, adjusted to orthophosphoric acid) was treated with an adenosine deaminase solution (0.5 ml, 778 units) in a 50% mixture of glycerol and 0.01 M potassium phosphate, pH 6.0 , then stirred and heated to 37 °. After 18.5 hours, the resulting suspension was refrigerated. The collected solid was recrystallized from water to give the title product as a white solid (86 mg); [α] ο -49e (ç, 0.5, dimethylsulfoxide); \ max 1% (buffer at pH 6) 252.6 nm (E ^ cm 531), proton magnetic resonance (DMS0-d6) 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 fia, 4a) -4-f2-amino-6-hvdroxv-9H-purine-9-vl) -2-cvclopenténvlcarbinol (a) (1S. 4R) -4- (2-Amino-6- hydroxv-9H-Purine-9-vlï -2-cyclopentenylcarbinol The diamino analog (100 mg) (Example 11) was dissolved in 3 ml of 0.05 M K2PO4 buffer (pH 7.4) at warm temperature (50 ° C) The solution was allowed to cool to room temperature and 40 units of adenosine deaminase (Sigma, Type VI, calf intestinal mucosa) were added.

After three days of incubation at room temperature, a precipitate formed which was collected by filtration; yield 18.2 mg. The filtrate was concentrated to a volume of 1.5 ml and refrigerated for 2 days. An additional amount of solid material was obtained by filtration in an amount of 26.8 mg. The two solid fractions were recrystallized from water giving the title product in the pure / melting state at 269-24 2720C, [a] £ -62.1e (ç 0.3, MeOH).

(b) (IR. 4SÏ -4- (2-Amino-6-hvdroxv-9H-Purine-9-vlï-2-cvclopenténvlcarbinol

The filtrates of the preparation of the 1S, 4R isomer (Example 14a) were combined and evaporated to dryness. The unchanged diamine starting material was separated on a flash column packed with silica gel, using a 10% mixture of methanol and chloroform. The diamine compound was dissolved in 0.05 M K2PO4 buffer pH 7.4 (15 ml) and 800 units of adenosine deaminase were added. The solution was incubated for 96 hours at 37 ° C. Thin layer chromatography indicated that some unreacted product remained. The solution was heated in boiling water for 3 minutes and filtered to remove the denatured protein. Another 800 units of adenosine deaminase were added and the process was repeated. The protein-free solution was evaporated to dryness and the product was crystallized from water. The title product in the form of a white solid was collected by filtration in water, melting point 265-270 *. +61.1 (s 0.3,

MeOH).

Example 15 (±) - (lai.4ot) -4- (2-Amino-6-hvdroxv-9H-pur ine-9-vl ^ -2-cvclopenténvlacétoxvcarbinol

Acetic anhydride (0.06 ml, 0.6 mmol) was added 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). The mixture was stirred at room temperature for 3 hours. Methanol (1 ml) was added to stop the reaction. The solution was concentrated and absorbed on silica gel (1.5 g) conditioned on a column (2.0 x 12 cm) and elution was carried out with a mixture of chloroform and methanol ( 20: 1). The product fractions were collected and concentrated to give a white solid. The solid product was washed with a mixture of methanol and ethyl acetate: yield 123 mg (85%). Further purification in methanol gave the title product as needle crystals melting at 237-239’C. Anal. (C13H15N503) C, H, N.

Example 16 (1S.4R) -4) r2-Amino-9H-purine-9-vl1-2-cvclopenténvlcarbinol An ice-cold stirred solution of (lS, 4R) -4- [2-amino-6 -methoxyamino-9H-purine-9-yl] -2-cyclopentene-methanol (Intermediate Compound 8, Example 12) (1.202 g) in tetrahydrofuran (250 ml) and water (50 ml) was treated with aluminum amalgam (prepared from aluminum (1.761 g) and 0.5% aqueous solution of mercuric chloride) added in small portions over 1 hour and 47 minutes. After 35 minutes, the mixture was allowed to stir to warm to room temperature. After 16 hours and 50 minutes, further aluminum amalgam (prepared from 235 mg of aluminum) was added over 14 minutes. After another 4 hours and 10 minutes, the resulting mixture was filtered through Kieselguhr to remove insoluble matter. The latter were washed with a mixture of tetrahydrofuran and water (5: 1, 300 ml). The combined filtrates were evaporated leaving a yellow foam. The foam was subjected to column chromatography on silica (33.8 g, Merck 7734) prepared in chloroform and eluted with mixtures of chloroform and ethanol, which gave several fractions (578 mg, 420 mg and 40 mg). The two largest fractions were crystallized separately from isopropanol. The filtrates were combined with the smallest fraction of the column and the mixture was subjected to preparative thin layer chromatography (Merck 5717) developed three times in a mixture of chloroform and methanol at 10: 1. The plates were eluted with ethyl acetate and with a mixture of ethyl acetate and ethanol (1: 1), to give a brown solid (45 mg). The solid was subjected to silica column chromatography (2.7 g, Merck 7734), prepared in chloroform and eluted with mixtures of chloroform, methanol and triethylamine to give a gum (17 mg). After unsuccessful crystallization from isopropanol and charcoal treatment with methanol, an aqueous solution of the collected material was lyophilized to give the title compound (15 mg). Proton magnetic resonance (DMSO-dg) 1.62 (1H), 2.63 (1H), 2.89 (1H), 3.45 (2H), 4.73 (1H), 5.48 (1H) , 5.91 (1H), 6.14 (1H), 6.50 (2H), 7.98 (1H), 8.57 (1H). Mass spectrum, [MH] + 232.

Example 17

Formulations for tablets A. The following formulation is prepared by wet granulation of the ingredients with a solution of povidone in water, drying and sieving, then addition of magnesium stearate and compression.

ai / tablet (a) Active ingredient 250 (b) Lactose BP 210 (c) Povidone BP 15 (d) Sodium salt of starch glycolate 20 (e) Magnesium stearate 5,500 B. The following formulation is prepared by compression direct; lactose is of the direct compression type.

ma / tablet

Active ingredient 250

Lactose 145

Avicel 100

5,500 C magnesium stearate. (Release controlled formulation) The formulation is prepared by wet granulation of the ingredients (below) with a solution of povidone in water, drying and sieving followed by the addition of sodium stearate. magnesium and compression.

mq / comorimed (a) Active ingredient 500 (b) Hydroxypropylmethylcellulose (Methocel K4M, superior quality) 112 (c) Lactose B.P. 53 (d) Povidone B.P. 28 (e) Magnesium stearate 7 700

Example 18

Formulation for capsules

A capsule formulation is prepared by mixing the ingredients below and introducing the mixture into a two-part hard gelatin capsule.

mq / capsule

Active ingredient 125

Lactose 72.5

Avicel 50

Magnesium stearate 2.5 250

Example 19

Injection formulation Active ingredient 0.200 g

0.1 M sodium hydroxide solution, sufficient quantity to adjust the pH to approximately 11 Sterilized water, sufficient quantity for 10 ml

The active ingredient is suspended in a small amount of water (which can be heated) and the pH is adjusted to about 11 with a solution of sodium hydroxide. The volume of water is then completed and filtered through a quality membrane for sterilization in a sterile 10 ml glass vial which is closed with sterile caps topped with capsules.

Example 20 Suppository mq / suppository

Active ingredient (63 μη) 250

Hard fat, B.P. 1770 2020

One fifth of the hard fat is melted in a container with a steam jacket, at a maximum temperature of 45 ° C. The active ingredient is sieved through a 200 μη sieve and added to the molten base with stirring, using a high shear agitator, until a homogeneous dispersion is obtained. Maintaining the mixture at 458 ° C., the remaining hard fat is added to the suspension and the mixture is stirred in order to obtain a homogeneous mixture. The entire suspension is passed through a 250 μη stainless steel sieve and, while continuing to stir, it is allowed to cool to 408 C. By operating at a temperature of 38 to 408C, 2.02 g of the mixture are charged in suitable 2 ml plastic molds. The suppositories are allowed to cool to room temperature.

Example 21 - activity anttvtrat.î:

(A) HIV test

The compounds of formula (I) have been subjected to selective tests for determination of anti-HIV activity at the National Cancer Institute, Frederick Cancer Research

Facility, Frederick, Maryland (FCRF). The usual selective study procedures used by the FCRF are indicated below. The protocol is divided into three parts, (I) preparation of infected cells and distribution between test plates, (II) preparation of drug dilution plates and distribution between test plates and (III) method of analysis XTT. See D.A. Scudiero et al., "A New Simplified Tétrazolium Assay for Cell Growth and Drug Sensitivity in Culture", Cancer Res. 48, 4827 (1988).

I. Infection and distribution of ATH8 cells in microtitraae trays

Cells intended to be infected (normal lymphoblastic cell line which expresses CD4) are placed in 50 ml conical centrifuge tubes and treated for 1 hour with 1-2 Mg / ml of polybrene at 37 ° C. The cells are then collected by centrifugation for 8 minutes at 1200 rpm. The HIV virus, diluted to one tenth in a medium (RMP1-1640, 10% human serum or 15% fetal calf serum (FCS) added with IL-2 and antibiotic) is added in order to obtain a ME of 0.001. Only medium is added to the control cells not containing the virus. If an infectious virus titer of 10-4 is accepted, an MOI of 0.001 represents 8 infectious viral particles per 10,000 cells. About 500,000 cells per tube were exposed to 400 μΐ of the virus dilution. The resulting mixture is kept in incubation for 1 hour at 37 ° C in a mixture of air and CO2. Infected or uninfected cells are diluted so that there is 1 x 10-4 (with human serum) or 2 x 10 “4 (with fetal calf serum) cell for 100 μΐ.

The infected or uninfected cells (100 μΐ) are distributed between appropriate cells of a microtiter plate comprising 96 cells, with a bottom in ü. Each compound dilution is tested in duplicate with infected cells. Uninfected cells are examined to assess drug sensitivity in a single cell for each dilution of the compound. Infected and uninfected drug-free control cells are studied in triplicate. The cells B2 to 62 serve as controls containing the reagents and only receive the medium. The plates are incubated at 37 ° C in a mixture of air and carbon dioxide until the time of addition of the drug.

XI. Dilution and addition of the drug

Dilution plates (microtiter plates with 96 flat-bottomed cells) are treated overnight with a phosphate buffered salt solution (PBS) or a medium containing at least 1% FCS or 1% human serum (depending on the medium used in the test), from the day before the test. This "blocking" method is used to limit the adsorption of medication by the microtiter plate during the dilution process. The cells are completely filled with blocking solution and left to stand at room temperature in a humidified chamber, under a hood.

The dilution process is started by first diluting the test compound to 1:20. Blocked dilution plates are prepared by blowing away the blocking solution and drying by absorption on a sterile gauze pad. All the cells of each plate are then filled with 225 μΐ of the appropriate medium, using a Cetus liquid handling system. 25 μΐ of each compound diluted 1:20 is then added by hand in row A of a blocked and loaded dilution plate. Four compounds are added per dilution plate, which is sufficient to feed two test plates. The four compounds are then diluted serially by a factor of 10 from row A to row H using a Cetus liquid handling system. The starting dilution of each compound in row À is, at this point, equal to 1: 200. The dilution plates are kept on ice until ready to use.

Using a 6-channel multichannel pipetting apparatus, 100 μΐ of each drug dilution is transferred to the test plate which already contains 100 μΐ of medium supplemented with cells. The final dilution in the test plate begins at 1: 400 (cells B4 to G4). This dilution (up to 0.25% DMSO) prevents the DMSO used as a vehicle from interfering with cell growth. Infected or uninfected cells devoid of drug (cells B3 to G3) and controls containing the reagents (B2 to G2) receive the medium alone. The two final compounds are then transferred from cells H7 to H12 on a second test plate, according to the same procedure. The test plates are incubated at 37 ° C. in a mixture of air and carbon dioxide for 7 to 14 days or until the controls containing the virus are lysed, by macroscopic examination.

III. Quantitative expression of viral pathogenicity and activity of the medinaTnftnt A. Reagents 1. 2,3-bis [2-methoxy-4-nitro-5-sulfophenyl] -5- [(phenylamino) carbonyl] hydroxide solution ^ H-tetrazolium. (XTT) - 1 mg / ml solution in medium without FCS. Store at 4eC. Prepare every week.

2. Stock solution of phenazine methosulfonate (PMS) - It can be prepared and kept frozen at -20 ° C until it is used. It should be prepared in phosphate buffered saline at a concentration of 15.3 mg / ml.

B. Tetrazolium test in microculture fMTAI 1. Preparation of the XTT-PMS solution - The XTT-PMS solution is prepared immediately before its addition to the cells of the culture dish. The PMS stock solution is diluted 1: 100 (0.153 mg / ml). Diluted PMS is added to each milliliter of XTT necessary to reach a final PMS concentration of 0.02 mM. An aliquot of 50 μΐ of the XTT-PMS mixture is added to each of the appropriate cells and the plate is incubated for 4 hours at 37 ° C. The plate covers are removed and replaced by adhesive plugs (Dynatech cat 001-010-3501). The closed plate is shaken on a mixer for microculture plates and the absorption is determined at 450 nm.

IV. Results

The results which were obtained following the tests are represented as a percentage of test cells relative to the uninfected cells (%) for infected and uninfected cells, as a function of the increase in concentration of the compound of the Example 10.

The results represented graphically in the single figure allow the calculation of an effective concentration (EC50) compared to infected cells of approximately 0.15 fig / ml, of an inhibitory concentration (IC50) compared to normal cells d '' approximately 100 Mg / ml and a therapeutic index (IT50) of approximately 667. A test carried out previously at the Southern Research Institute gave an IT5Q of approximately 200 when MT-2 cells were cultured in the presence of H9 / HTLV-IIIB.

The inhibitory concentrations vis-à-vis the HIV virus, determined as described above, are reproduced in Table 1 for the compounds of Examples 7, 9, 10, 11 and 14 (b).

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

(B) Activity against cat leukemia virus

A selective study of antiviral activity against the FeLV-FAIDS virus was carried out in 96-cell plates (Corning) using 81C indicator cells in Dulbecco medium modified according to Iscove, supplemented with 10% fetal bovine serum ( FBS) heat inactivated. Twenty hours before the test, the plates were inoculated with 81C cells at a rate of 5 × 10 · * cells per cell. On the day of the test, the cells were pretreated for 30 minutes at 37 ° C. with DEAE-dextran (25 μg / ml) in 0.1 ml of balanced solution of Hanks salts. This solution was eliminated, then an amount of 0.1 ml of growth medium containing 32 TCID50 of FeLV-FAIDS or 0.1 ml of growth medium alone was added to each cell. The virus was allowed an absorption time of 1 hour and then 0.1 ml of test compound or positive control compound (2 ', 3'-dideoxycytidine; ddC) or growth medium was added. The plates were incubated at 37 ° C. The cells were added with fresh growth medium containing the compound on the fourth day after infection. The culture medium was completely changed and replaced with fresh medium containing the compound on the seventh day after infection. On the tenth day after infection, the cells were fixed with formalin, stained with 0.1% Coomassie R-250 bright blue and examined under a microscope to determine the cytopathic effect and cytotoxicity of the drug.

The compound of Example 10 exhibited an ED50 dose of 1/9 Mg / ml.

(C) Activity against mouse AIDS virus

Falcon 6-cell tissue culture plates were seeded with 1.75 x 105 cells per cell in a total volume of 2.5 ml of EMEM containing 5% heat-inactivated FBS. Twenty hours after cell seeding, the medium was separated by decantation and 2.5 ml of DEAE-dextran (25 µg / ml in phosphate buffered salt solution) was added to each cell. The cultures were incubated at 37 ° C for 1 hour, after which the DEAE-dextran cell was separated by decantation and the cell layers were rinsed once with 2.5 ml PBS. Controls formed from normal cells were prepared with 2.5 ml of medium alone (without virus or drug). Control cultures containing the drug received 2.5 ml of medium containing the drug but not containing virus. Control cultures infected with the virus were given 0.5 ml of the appropriate dilution of CAS-BR-M stock solution to produce countable plates, 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 were tested in a series of 10 base semi-log dilutions. Three concentrations of the ddC positive control drug were tested. Each trial included three cells for each concentration of test compound and six virus-infected cultures and six cell control cultures. On the third day after inoculation of the virus, the toxicity of the drug to SC-1 cells was determined by microscopic examination of a colored control culture in duplicate containing the cells and the drug. The test cultures and remaining control cultures were irradiated with an ultraviolet lamp for 20 seconds and XC cells were added to each culture (5 × 10 5 cells / cell in 2.5 ml of EMEM medium containing 10% of Heat-inactivated FBS). On the third day after irradiation with ultraviolet rays, the cultures were fixed with formalin and stained with crystal violet. The plates were counted using a dissecting microscope.

Antiviral activity in reducing CAS-BR-M plaques was expressed in terms of reduction in the average number of plaques counted in virus-infected cultures treated with the drug compared to the average number of plaques counted in cultures untreated controls, infected with virus (percent compared to controls). The compound of Example 10 had an ED50 dose of 1.1 µg / nl.

(D) Activity against the SAIDS simian retrovirus (SRV-2)

A selective antiviral study against the SAIDS virus (D / Washington) was carried out according to a syncytial inhibition test involving Raji cells. The drug was diluted in complete iscove medium and then 100 ml of each dilution was added to the appropriate wells of a 96-well plate. Raji cells in the active growth phase, in an amount of 5 × 10 3 cells in 50 μΐ of complete iscove medium, were then added to each alveolus. This operation was followed by the addition of 50 μΐ of clarified supernatant liquor originating from a co-culture of SRV-2 / Raji cells. DdC was included in this trial as a positive control drug. Plates were incubated at 37 ° C in a humidified atmosphere containing 5% CO 2. Syncytial cells were counted on the seventh day after infection. The toxicity of the drug was evaluated by comparing the numbers of viable cells in the uninfected sample treated with the drug with the viability of the untreated and uninfected control. The compound of Example 10 exhibited an ED50 value of 2.8 Mg / ml.

(E) Activity against the Visna Maedi virus The antiviral activity against the WLC-1 strain of the Visna Maedi virus (VMV) was determined by measuring the reduction in the specific immunohistochemical staining of the virus. Monolayers of sheep choroid plexus cells were infected with the VMV virus and were coated with serial dilutions of the test compounds. After incubation for five days, the monolayers were further incubated with virus-specific antisera conjugated to horseradish peroxidase (HRP). Subsequent incubation of the monolayers with a chromogenic HRP substrate colors areas of virus replication. These discrete foci were counted and the concentration of test compound necessary to reduce the number of foci to 50% of that of the controls not treated with the drug was calculated.

The compound of Example 13 had an ED50 value of 0.2 μg / ml.

Example 22

CYTOTOXIC ACTIVITY

The compounds of Examples 5, 7 and 8 showed cytotoxic activity when tested against a culture of leukemia cells from P388 mice, as described by R.G. Alonquist and R. Vince in J. Med. Chem. 16, 1396 (1973). The values of DE5q (g / ml) obtained were as follows:

Example 5 12

Example 7 40

Example 8 3

Claims (17)

1. Compound of formula (I)

wherein X is hydrogen, NRR ^ ·, SRf OR or halogen; Z is hydrogen, an OR2 or NRR1 group? R, R1 and R2 may be the same or different and are chosen from hydrogen, C1 to C4 alkyl and aryl and its pharmaceutically acceptable derivatives. 2. Compound according to claim 1, characterized in that Z represents H, OH or NH2 in formula (I). 3. Compound according to claim 1 or 2, characterized in that Z represents NH2 · 4. Compound according to any one of claims 1 to 3, characterized in that X represents hydrogen, a chloro radical, an NH2, SH or OH group. 5. Compound according to any one of claims 1 to 4, characterized in that X represents OH. 6. Compound according to any one of claims 1 to 4, characterized in that X represents H or NH2. 7. Le (la, 4a) -4- (6-chloro-9H-purine-9-yl) -2-cyclopentenylcarbinol; (Ια, 4α) -4- (6-hydroxy-9H-purine-9-yl) -2-cyclopentenylcarbinol; (la, 4a) -4- (6-amino-9H-purine-9-yl) -2-cyclopentenylcarbinol? (la, 4a) -4- (6-mercapto-9H-purine-9-yl) -2-cyclopentenylcarbinol; (Ια, 4a) -4- (2,6-diamino-9H-purine-9-yl) -2-cyclopentenylcarbinol; (la, 4a) -4- (2-amino-6-chloro-9H-purine-9-yl) -2-cyclopentenylcarbinol or le (Ια, 4a) -4- (2-amino-9H-purine- 9-yl) -2-cyclopentenylcarbinol according to claim 1. 8. The (la, 4a) -4- (2-amino-6-hydroxy-9H-purine-9-yl) -2-cyclopentenylcarbinol according to claim 1. 9. Compound according to any one of claims 1 to 8, characterized in that it is mainly in the form of a racemic mixture. 10. Compound according to any one of claims 1 to 8, characterized in that it essentially consists of an optical isomer. 11. Compound according to any one of claims 1 to 8, characterized in that it is mainly composed of the D isomer. 12. Compound of formula (I) according to any one of claims 1 to 11 or a pharmacologically acceptable derivative of this compound, intended for use as an active therapeutic agent. 13. Compound of formula (I) as defined in any one of claims 1 to 11 or a pharmaceutically acceptable derivative of this compound, intended for use in the preparation of a medicament for the treatment of a viral infection. 14. Pharmaceutical formulation, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable derivative of this compound in association with an appropriate pharmaceutically acceptable carrier. 15. Pharmaceutical formulation, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt of this compound in association with an appropriate pharmaceutically acceptable carrier. 16. Pharmaceutical formulation according to claim 13, characterized in that it further comprises another therapeutic agent. 17. Compound of formula (II)

wherein X represents hydrogen, a group NRR ^ -, SR, OR, a halogen or their protected forms; Y represents OH or one of its protected forms; Z represents hydrogen, an OR2 group, NRR · * · or one of their protected forms? R, R1 and R2 may be the same or different and are selected from hydrogen and C1-4alkyl and aryl groups, or their pharmaceutically acceptable derivatives.