MXPA99010373A - Carbocyclic nucleoside hemisulfate and its use in treating viral infections - Google Patents

Abstract

There is described the hemisulfate salt of (1S,4R)-cis-4- [2-amino-6-(cyclopropylamino) -9H-purin-9-yl]-2-cyclopentene-1-methanol or a solvate thereof. Also described are preparative routes and starting compounds for making the hemisulfate salt. The hemisulfate salt is useful in medicine, particularly in the treatment of viral infections.

Description

HEMISULFATO CARBOCICLICO NUCLEOSIDO AND ITS USE IN THE TREATMENT OF VIRAL INFECTIONS.

Field of Invention The present invention relates to a novel salt of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol or of a solvate thereof, to pharmaceutical formulations containing such compound and to its use in medicine, specifically in the treatment of the infection caused by the human immunodeficiency virus (HIV) and the infection by hepatitis (B) virus (HBV).

An-inventions of the invention.

(LS, 4R) -cis-4- [2-amino-6- (cyclopropyl amino) -9H-purin-9-yl] -2-cyclopenten-l-methanol ("the compound") and its use as an anti -viral, especially against HIV infections, is described in European Patent Specification No. 0434450 which also relates to specifically derived pharmaceutically acceptable salts, esters and salts of such esters of the Ref: 032032 compound, and in particular describes hydrochloride salts of the compound. Additionally, PCT Patent Application No. PCT GB95 / 02014 describes the succinate salt of the above compound.

The compound (1 S, R) -cis-4 - [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-l-methanol is currently under clinical investigation as a pharmaceutical agent anti-HIV There is a need for the compound to be prepared in a suitable manner to provide an ease of isolation in large-scale production, and to provide a formulation facility in a product acceptable for administration to humans. It has been found that the manufacture of the free base of the compound produces an amorphous solid which entraps the solvents and is therefore unsuitable for large-scale purification, or for the formulation, without further purification procedures.

Although the succinate salt described in PCT Patent Application No. PCT / GB95 / 02014 has advantages in its preparation, for example, the same Salt forms easily from the techiometric ratios of the acid and base and crystallizes very easily out of the solution, it is not an ideal material for the pharmaceutical formulation, especially for tabletting. In particular, the succinate salt of the compound is agglomerated to form a "lumpy" mass which can not be easily poured and is therefore unsuitable for use in conventional tabletting machines, such that an additional processing step is required. milling that consumes a lot of energy, to give a uniform particle size. An additional complication that arises during the formulation of the succinate salt of the compound is that it can exist in several crystalline forms, each form having slightly different physical properties. The preparation of the succinate salt of the compound requires careful attention to avoid the preparation of undesirable forms, which if formed require them to be reworked into the desired shape.

Description of the invention It has been found that the advantages of the compound hemisulfate salt over the described hydrochloride salts and the succinate salt make the hemisulfate salt particularly suitable and advantageous for the large-scale preparation, and in particular for its use in the preparation of pharmaceutical formulations. Specifically, the hemisulfate salt forms a free-flowing powder, which lacks any undue tendency to agglomerate, and which is easily poured and compacted, and is therefore ideal for use in commercial tabletting machines without the need for grinding. Salt is believed to exist as a unique crystalline and orphic form. The salt is not easily converted into a hydrate or a solvate (for example during storage). The salt is easily filtered and dried, which helps the ease of preparation. An additional advantage is the larger aqueous solubility of the hemisulfate when compared to the succinate, which makes the hemisulfate particularly suitable for the preparation of liquid formulations.

It has also been found that where a hemisulfate salt is prepared by a process of "exchange of a salt", ie by the conversion of a precursor salt of (IS, 4R) -cis-4- [2-amino-6 - (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol, particularly the glutarate or succinate salt, an enrichment in the optical purity can be achieved over that of the precursor salt. Accordingly, the need for any additional purification or preparation steps to improve the optical purity of the hemisulfate salt product can be reduced or eliminated.

According to the first aspect of the invention, the hemisulfate salt of (SS, 4R) -cis- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1 is provided. -me t anol or a solvate thereof, including a hydrate thereof, hereinafter referred to as the compound according to the invention.

For the avoidance of doubt, when the hemisulphate salt of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten 1- is used here methanol means the salt formed between the (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-l-methanol and the sulfuric acid in a stoichiometric ratio of 2: 1.

Additional aspects of the invention include: a) The compound of the invention for use in medicine, particularly in the treatment of viral infections, specifically an infection caused by HIV or HBV. b) A method for the treatment of a viral infection, particularly an infection caused by HIV or HBV in a human being, which comprises administering to the human being an effective amount of the compound according to the invention. c) The use of a compound according to the invention in the manufacture of a medicament for the treatment of a viral infection, particularly an infection caused by an HIV or an HBV infection.

The compound of the invention is particularly useful for the treatment of infections caused by HIV.

It will be appreciated by those skilled in the art that the reference herein to treatment extends to prophylaxis as well as treatment of established infections or symptoms.

Examples of clinical conditions caused by HIV infections which can be treated according to the invention include Acquired Immune Deficiency Syndrome (AIDS) or the symptoms that often precede AIDS, or related clinical conditions such as the complex AIDS-related (ARC), progressive generalized lymphadenopathy (PLG), Kaposi's sarcoma, t-bocitophenic purpura, neurological conditions related to AIDS, such as multiple sclerosis or tropical paraphasis and also the positive conditions of HIV and positive anti-HIV antibodies including AIDS patients.

The compounds of the invention can be administered alone or in combination with other suitable therapeutic agents in the treatment of infections caused by HIV, such as Nucleoside Reverse Transcriptase Inhibitors (NRTIs) for example zidovudine, zalcitabine, lamivudine, didanosine, stavudine, 5-chloro-2 ', 3'-dideoxy-3' -fluorouridine, adefovir 'and (2R, 5S) -5-fluoro-1 [2- (hydroxymethyl) -1, 3- oxathiolan-5-yl] cytosine, lovaride, substances other than NRTIs, for example to neviparin, delavuridine, α-APA, HBY-1293 and HIV protease inhibitors of efavirenz for example saquinavir, indinavir, nelfinavir, ritonavir and VX-478, other anti-HIV agents for example soluble CD4, immune modulators for example interleukin II, eri t ropoye tina, tucaresol, and interferons for example la -interferone. Furthermore, the compound of the invention can be administered in combination with other suitable therapeutic agents in the treatment of infections caused by HBV, for example lamivudine, (2R-5S) -5-fluoro-1- [2- (hydroxymethyl) -1, 3-oxat iolan-5-yl] cytosine, immune modulators, and the interferons that were described above. Such combinations can be administered jointly or sequentially providing this that any period of time between the administration of each therapeutic agent does not diminish its additive affect.

Although it is possible that the compound of the invention is administered as the chemical raw material, it is preferable and advantageous to present the compound of the invention as a pharmaceutical formulation, and represents a further feature of the invention. The pharmaceutical formulation comprises the compound of the invention together with one or more acceptable carrier (s) therefor and optionally other therapeutic agents. The carrier (s) must be "acceptable" in the sense that they are (are) compatible with the other ingredients of the formulation and not deleterious to the recipients thereof.

The compounds according to the invention can be administered by any appropriate route for the condition to be treated, Suitable routes include oral, rectal, nasal, topical (including transdermal, buccal or sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, int, intrathecal, intrathecal and epidural). It will be appreciated that the preferred route may vary, for example, with the condition of the receiver.

For each of the utilities and indications indicated above, the required amount of the individual active ingredient will depend on several factors including the severity of the condition to be treated and the identity of the recipient and ultimately will be at the discretion of the attending physician. Attention. However, in general for each of these utilities and indications, an effective, adequate dose will be in the range of 1 to 120 mg per kilogram of body weight of the receptor per day, preferably in the range of 3 to 90 mg per kilogram. of body weight per day and more preferably in the range of 5 to 60 mg per kilogram of body weight per day such as 5 s 20 mg per kilogram of body weight per day. The dose if desired can be presented as two, three, four or more sub-doses administered • at appropriate intervals throughout the day.

The formulations include those suitable for oral, rectal, nasal, topical administration (including buccal and subligual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, in radiotherapy, intrathecal and epidural). The formulations can be conveniently presented in a unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by intimately and uniformly bringing into association the active ingredient with the liquid carriers or the finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or as granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as a liquid emulsion of oil in water or water in oil. The active ingredient may also be presented as a bolus, or paste, or may be contained within the liposomes.

A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a machine in a free-flowing form such as a powder or granules, optionally mixed with a binder (for example povidone, gelatin, hydroxypropylmethylcellulose), a lubricant, an inert diluent, a disintegrant (eg sodium starch glycolate, cross-linked povidone, sodium carboxymethylcellulose), a surface-active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the compound pulverized moistened with an inert liquid diluent. The tablets may be optionally coated or scored and may be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.

A capsule can be made by filling a loose or compressed powder in an appropriate filling machine, optionally with one or more additives. Examples of suitable additives include binders such as povidone, gelatin, lubricants, inert diluents, disintegrants, for tablets. The capsules can also be formulated to contain discrete pills or subunits, to provide a slow or controlled release of the described ingredient. This can be achieved by extruding and converting into spheres a wet mixture of the drug plus an extrusion acid (e.g. cellulose microcrystalline talin) plus a diluent such as lactose. The spheroids thus produced can be coated with a semipermeable membrane (for example ethyl cellulose, Eudragit E30D) to produce sustained or prolonged release properties.

For infections of the eye or other external tissues, for example, the mouth or the skin, the formulations are preferably applied as an ointment or topical cream containing the active ingredient in an amount of, for example, 0.075 to 20% w / w , preferably 0.2 to 15% w / w and more preferably 0.5 to 10% w / w. When formulated in an ointment, the active ingredients can be used with either a water-miscible or paraffinic ointment base. Alternatively, the active ingredients can be formulated in a cream with a creamy base of oil in water or as in a base of water in oil.

If desired, the aqueous phase of the cream base may include, for example, at least 40-45% w / w of a polyhydric alcohol, ie an alcohol having two or more hydroxyl groups such as propylene glycol, butan 1, 3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures of same. Topical formulations may desirably include a compound which improves the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sui phoxide and related analogs.

The oily phase of the emulsions of this invention can be constituted from known ingredients in a known manner. Although this phase may comprise only one emulsifier (otherwise known as an emulsifier), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both an oil and a fat. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without the stabilizer (s) make up the so-called emulsifying wax, and the wax together with the oil and / or fat make up the so-called ointment base emulsifier which forms the oily dispersed phase of the creamy formulations.

Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, tearyl alcohol, myristyl alcohol, glycerol monostearate and sodium lauryl sulfate.

According to a first process (A), the compounds of the invention can be prepared by the mixture of sulfuric acid and the (ÍS, R) -cis-4 - [2-amino-6- (cyclopropylamino) -9H-purin -9-yl] -2-cyclopentene-1-methanol in a stoichiometric ratio of about 1: 2, preferably in solution, more preferably in an aqueous organic solvent, preferably at an elevated temperature, more preferably at the reflux temperature of the Solvent system chosen. During cooling, the crystals of the compound of the invention are formed. Preferably the reaction is effected by "seeding" the solution with a small amount of the compound of the invention. The optional washing and recrystallization can be used to improve the purity of the product.

According to an alternative process (B), the compound of the invention can be formed by the mixture of (S, 4 R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9 monosulfate. -yl] -2-cyclopenten-l-methanol (1: 1 salt) and (ÍS, 4R) -cis-4 - [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2 -cyclopenten-1-methanol in a molar ratio substantially 1: 1 in solution.

A process (C) particularly advantageous for the preparation of the compound of the invention comprises the conversion of a salt of (SS, 4R) -cis-4- [2-amino-β- (cyclopropylamino) -9H-purin-9-yl ] -2- _ cyclopenten-1-methanol to the compound of the invention. Suitable salts for the conversion include dicarboxylic acid salts such as succinate, glutarate, hemisuberate (ie the salt formed from 2: 1, base: suberic acid), adipate, fumarate, hemisebacate • (i.e. formed from 2: 1, base: sebacic acid), and pimelate salts. Mixtures of the dicarboxylic acid salts can be used.

The use of the succinate and glutarate salts is preferred. The preparation of the succinate salt is described in PCT Application No. PCT / GB95 / 02014. Other salts of (SS, R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol useful for the conversion to the hemisulfate include the salts of benzoate and salicylate and mixtures thereof. Such salts represent a further feature of the invention.

In a preferred aspect of the present invention, the conversion can be effected by the mixture of the sulfuric acid and a salt of (S, 4 R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purine). -yl] -2-cyclopenten-1-me tanol different from the hemisulfate in the appropriate stoichiometric ratio. For the avoidance of doubt, the appropriate stoichiometric ratio (ie, the salt of (SS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten- 1 - methanol: sulfuric acid) will be 2: 1 if the salt is a salt 1: 1 (ie the ratio of (ÍS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin- 9-yl] -2-cyclopentene-1-methanol with respect to the acid is 1: 1) and 1: 1 if the salt is a salt 2: 1 (ie the ratio of (ÍS, R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1 -methanol with respect to the acid is 2: 1). The mixture is preferably carried out in solution, more preferably in an aqueous organic solvent, preferably at an elevated temperature, more preferably at the reflux temperature of the chosen solvent system. The hemisulfate crystals are formed during cooling of the reaction mixture, optionally with seeding, as previously described. This process of salt interconversion provides advantages in terms of the purity of the compound of the invention obtained thereby.

A particularly advantageous feature of the conversion process of the salts mentioned above with respect to the hemisulfate is that the conversion leads to an improvement in optical purity, ie there is a smaller amount of the unwanted (1S, 4R) isomer in the compound of the invention thus produced, than that which existed in the starting salt.

Suitable solvents for use in the processes of the invention include alcohols such as, for example, ethanol or propan-2-ol. Such solvents can be used alone or in admixture, optionally in the presence of an additional organic solvent, such as acetone, or in the presence of water, whereby a mixture of aqueous organic solvents is formed.

The compound of (ÍS, 4R) -cis-4- [2-amino-6- (cyclopro-ylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol can be synthesized in accordance with Number 0434450 of the Patent Specification European or alternatively the Application 'PCT No. PCT / GB95 / O 0225 which are incorporated herein for reference.

The succinate salt of the compound (ÍS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol. it may be synthesized in accordance with PCT Patent Application No. PCT / GB95 / 02014, which is incorporated herein for reference.

The invention is further described in the following examples which are illustrative thereof and not limiting.

When used in the following examples, IMS means industrial methylated alcoholic substances (denatured ethanol) and IPA means propan-2-ol.

Intermediate Compound 1 Preparation of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-p ?? rin-9-yl] -2-cyclopenten-l-methanol The hydrochloride salt of (SS, R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol (EP0434450 (80g) is heated under reflux in industrial methylated alcoholic substances (800 ml) with cyclopropylamine (110 ml) for about 5 hours The mixture is cooled in the range of 70 to 75 ° C and an aqueous solution of sodium hydroxide (10M, 55 ml, 2 equivalents molars) is added dropwise The resulting suspension is cooled in the range of to 25 ° C and filtered, the collected solids are washed with IMS (2x60 ml). The filtrates are combined and the washes are treated with mineral carbon (8g) and the Herborlite filtration aid J2 (4g) then heated in the range of 40 to 50 ° C. After approximately 0.5 hours, the mixture is cooled in the range of 15 to 20 ° C and the solids are removed by filtration, washed with IMS (2x160 ml and 1x80 ml) and the combined filtrates and the washings are concentrated by low distillation reduced to a residual volume of approximately 240 ml. The IMS (560 ml) was added and the mixture is concentrated under reduced pressure to a residual volume of about 240 ml. The dilution and reconcentration are repeated and the resulting concentrate is diluted with IMS (240 ml) and heated until a complete solution is obtained which is divided into four equal portions.

A portion is concentrated by distillation under reduced pressure to a residual volume of about 60 ml. Acetone (140 ml) is added and the mixture reconcentrates to about 60 ml. This dilution and reconcentration is repeated twice to give a fluid volume of approximately 80 ml. The resulting suspension is cooled in the range of 0 to 5 ° C and the product is filtered, washed with cold acetone (0 to 5 ° C) (2 x 40 ml) and dried in vacuo to give the title compound as an orange solid (16.8 g, 90%; H-NMR (D20) d: 7.71 (s, 1, CH purine), 6.22 (m, 1, = CH), 5.93 (m, 1, = CH), 5.37 ( m, 1, NCH), 3.61 (m, 2, OCH2), 3.04 (br m, 1, cyclopropyl CH), 2.82 (br m, 1, CH), 2.80-2.70 (m, 1, CH) , 1.58-1.50 (m, 1, CH), 0.90-0.60 (m, 4, 2 x CH2 of cyclopropyl).

Example A Preparation of the hemisulfate salt of (1S, 4R) cis-4- [2-amino-β- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-l-methanol A stirred mixture of water (25 ml) and IPA (100 ml) is heated in the range of 45 to 55 ° C and the succinate salt of (SS, 4 R) -cis- - [2-amino-6- ( cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol (W096 / 06844 (50 g)), and washed with IPA (12.5 ml). The mixture is heated under reflux for about 0.5 hour to give a clear solution and then cooled in the range of 65 to 75 ° C and a solution of the concentrated sulfuric acid (6.07 g) in water (12.5 ml) is added. A mixture of IPA (37.5 ml) and water (12.5 ml) is added and the solution is cooled in the range of 45 to 55 ° C, after which a seeding of the hemisulphate salt of (IS, R) is added - authentic cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-yl] -2-cyclopenten-1-methanol. After stirring in this temperature range for about 1 hour to allow the crystallization to become established, additional IPA (300 ml) is added, keeping the temperature of the mixture in the range of 45 to 55 ° C. The suspension is cooled in the range of 0 to 5 ° C for about 2 hours, and the product is filtered, washed with IPA '(2x75 ml), and dried in vacuo in the range of 40 to 45 ° C to give the title compound as a fawn-colored powder (34.3 g, 90%); p.f. 224-225 ° C (decomp.) RMN-H1 (DMSO-d6) d: 10.76 (br m, 1, purine NH), 8.53 (vbr m, 1, NH), 7.80 (s, 1, purine CH), 6.67 (br m, 1, NH2), 6.13 (m, 1, = CH), 5.87 (m, 1, = CH), 5.40 (m, 1, NCH), 3.45 (d, J = 5.8Hz, 2 OCH2), 2.96 (br m, 1, cyclopropyl CH), 2.87 (, 1, CH), 2.67-2.57 (m, 1, CH), 1.65-1.55 (m, 1, CH ), 0.84-0.64 (m, 4, 2 x CH2 of cyclopropyl).

E jmplo B Preparation of the hemisulfate salt of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-l-methanol A stirred suspension of the succinate salt of (1S, 4R) -cis-4 - [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol (096/06844 (1000g)) in an industrial methylated alcoholic substance (IMS) (7000 ml) is heated under reflux for about 0.5 hour to obtain a clear solution. The solution is cooled to about 70 ° C and a concentrated sulfuric acid solution (121 g) is added to the solution.

IMS (1000 ml). After seeding with the hemisulfate salt of (SS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopent en-1-methanol authentic, The mixture is stirred at about 70 ° C to allow the product crystallize. After about 0.5 hour, the mixture is cooled in the range of 20 to 30 ° C for about 2 hours. The mixture is filtered, the cake washed with IMS (2 x 200 ml) and dried under vacuum in the range of 40 to 45 ° C to give the title compound as a fawn-colored powder (764 g, 92 ml). %), spectra identical to those of the product of Example A.

Example C Preparation of the hemisulfate salt of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-l-methanol A suspension of the succinate salt of (SS, 4R) -cis-4 - [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol (10 g) in an industrial methylated alcoholic substance (IMS) (30 ml) and water (5 ml) is heated under reflux for about 0.5 hour to give a clear solution.- The solution is cooled in the range of 55 to 65 ° C and a concentrated sulfuric acid solution (1.21 g) (2.5 ml), followed by a mixture of IMS (7.5 ml). The solution is further cooled in the range of 45 to 55 ° C and acetone (80 ml) is added for about 0.25 hours to the mixture within this temperature range. The resulting suspension is cooled in the range of 0 to 5 ° C for about 1 hour. The product is filtered, washed with acetone (2x10 ml) and dried in vacuo in the range of 40 to 45 ° C to give the title compound as a fawn colored powder (6.28 g, 82%) which was identical spectroscopically with the product of Example A.

Example D Preparation of the hemisulfate salt of (1S, 4R) cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-l-methanol The (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol (Intermediate Compound 1) (5.98 g) becomes a suspension in IMS (40 ml) and the suspension is heated under reflux for about 0.5 hour. The mixture is cooled in the range of 70 to 75 ° C and a mixture of a concentrated sulfuric acid solution in IMS (10 M, 1.03 ml, 0.5 molar equivalent) and IMS (10 ml) is added dropwise. The acid is washed with IMS (10 ml) and the resulting suspension is cooled in the range of 0 to 5 ° C. The product is isolated by filtration, washed with IMS (2 x 12 ml) and dried in vacuo in a range of 40 to 45 ° C to give the title compound as a faint yellow solid (6.15 g, 88% ), spectra identical to those of the product of Example A.

Example E Preparation of the hemisulfate salt of (1S, 4R) cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-l-methanol A further portion of the IMS solution of Intermediate Compound 1 was heated in the range of 75 to 80 ° C to ensure a complete solution. This was cooled in the range of 70 to 75 ° C and a solution of concentrated sulfuric acid (3.90 g) in IMS (30 ml) was added dropwise to give an orange colored suspension.

The mixture is cooled in. the range of 0 to 5 ° C for about 2 hours and the product is filtered, washed with IMS (2x40 ml) and dried in vacuo in the range of 40 to 45 ° C to give the title compound as a yellow solid. orange (17.7 g, 76%), spectra identical to those of the product of Example A.

From this product, 5.0 g is converted into a suspension in a mixture of isopropanol (IPA) (40 ml) and water (10 ml) and heated under reflux for about 0.5 hour and then allowed to cool in the range of 55 g. at 60 ° C, after which seedings of the hemisulfate salt of (SS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2- are added. authentic cyclopenten-1-methanol. The suspension is further cooled in the range of 0 to 5 ° C and the temperature is maintained for about 1 hour. The solid is filtered, washed with IPA (2x5 ml) and dried in vacuo in the range of 40 to 45 ° C to give the title compound as a buff powder (4.4 g, 88%), the spectra identical to those of the product of Example A.

Example F Benzoate salt of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-l-methanol The hydrochloride salt of (SS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol EPO434450 (70 g) is heated under reflux in IMS (700 ml) with cyclopropylamine (94.5 ml) for about 4 hours. The solution is heated in the range of 45 to 50 ° C and treated with a Harborlite J2 filter aid (3.5 g) and mineral carbon (7 g.): After about 0.5 hour, the mixture is cooled in the range of 20 g. at 25 ° C and filtered. The solids are washed with IMS (2 x 140 ml) and the filtrates and the combined washings are concentrated by distillation under reduced pressure to a volume of about 210 ml. After dilution with IMS, (490 ml) the solution is recognized up to about 210 ml. The dilution and reconcentration is repeated once and the final concentrate is divided into seven equal portions.

A portion is diluted with IMS (80 ml) and heated until a complete solution is obtained. The benzoic acid is added as a single portion and the mixture is heated in the range of 70 to 75 ° C to give a complete solution, which is then allowed to cool slowly. In the range of 40 to 45 ° C the mixture is seeded with the benzoate salt of (SS, 4R) -cis- 4 - [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2 authentic cyclopenten-1-methanol and the mixture is further cooled in the range of 0 to 5 ° C. The solid is filtered, washed with IMS (2x20 ml) and dried in vacuo in the range of 40 to 45 ° C to give the title compound as a white solid (8.7 g, m.p .: 156-157 ° C NMR-H1 (DMSO-d6) d: 7.95 (, 2, benzoate CH), 7.63 (m, 1, benzoate CH), 7.61 (s, 1, purine CH), 7.50 (m, 2, benzoate CH), 7.28 '(br m, 1, NH), 6.11 (m, 1, = CH), 5.86 (m, 1, = CH), 5.81 (br m, 1, OH), 5.39 (m, 1, NCH), 3.45 (d, J = 6.0 Hz, 2, OCH2), 3.04 (br m, 1, cyclopropyl CH), 2.87 (br m, 1, CH), 2.65-2.55 (m, 1, CH) 1.63-1.53 (m, 1, CH), 0.70-0.54 (m, 4, 2 x CH2 of cyclopropyl).

E jmplo G Preparation of the hemisulfate salt of (1S, 4R) cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-l-methanol A suspension of the benzoate salt of (SS, 4R) -cis- - [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol (5 g) in IPA (25 ml) is heated in the range of 60 to 65 ° C. A solution of the concentrated sulfuric acid (0.64 g) in water (1.25 ml) is added and the resulting cloudy suspension is heated in the range of 70 to 75 ° C. The mixture is heated in the range of 20 to 25 ° C and filtered. The solid is washed with IPA (2 x 10 ml) and dried in vacuo in the range of 40 to 45 ° C to give the title compound as a white solid (3.57 g, 87%), spectrum identical to those of the product of example A.

E jmplo H Preparation of the glutarate salt of (SS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-syclopentene-1-methanol The hydrochloride salt of (SS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol (EPO434450) (25 g) is heat under reflux in IMS (250 ml) with cyclopropylamine (30 ml) for about 4 hours. The solution is cooled in the range of 45 to 50 ° C, diluted with IMS (75 ml) and treated with charcoal (1 g) and Harbolite filter aid J2 (0.5 g). After about 1 hour, the mixture is cooled in the range of 20 to 25 ° C and filtered. The solids are washed with IMS (50 ml) and the filtrates and the combined washings are diluted with IMS (150 ml) and then concentrated by distillation under reduced pressure to about 75 ml. The mixture is diluted with IMS (90 ml) and reconcentrated to about 75 ml. The process of dilution and reconcentration is repeated twice more. The final concentrate is diluted with IMS (75 ml) and heated in the range of 70 to 75 ° C to give a solution. To this is added a solution of glutaric acid (13 g) in IMS (75 ml) which has been preheated in the range of 70 to 75 ° C. The mixture is further diluted with the IMS (25 ml) and cooled to about 25 ° C during approximately 2 hours. The mixture is further cooled in the range of 0 to 5 ° C and stirred for about 2 hours and filtered. The product is washed with IMS (2 x 50 mL) and dried in vacuo at about 45 ° C to provide the title compound as a light brown solid (27.1 g, 78%); p.f. 184-188 ° C RMN-H1 (DMSO-d6) d: 7.60 (s, 1, purine CH), 7.27 (br m, 1, NH), 6.10 (m, 1, = CH), 5.86 (, 1, = CH), 5.82 (br m, 1, OH), 5.39 (, 1, NCH), 3.44 (d, J = 5.9Hz, 2, OCH2), 3.04 (br m, 1, cyclopropyl CH), 2.87 (br m, 1, CH), 2.65-2.55 (m, 1, CH), 2.24 (t, J = 7.2 Hz, 4, glutarate 2 x CH2), 1.70 (m, J = 7.2 Hz, 2, glutathione CH2), 1.62-1.54 (m, 1, CH), 0.68-0.54 (m, 4, 2 x cyclopropyl CH2).

Example I Preparation of the hemisulfate salt of (1S, 4R) cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-l-methanol "A suspension of the glutarate salt of the (ÍS, 4R) -cis- 4- [2-amino-6- (cyclopropylamino) -9H- purin-9-yl] -2-cyclopenten-l-methanol (20 g) in a mixture of IPA (80 ral) and water (29 ml) is heated to reflux to give a solution. The solution is cooled to about 75 ° C and a solution of concentrated sulfuric acid (2.4 g) in water (5 ml) is added. The resulting solution is diluted with a mixture of IPA (16 ml) and water (4 ml) and then with IPA (20 ml). The solution is cooled in the range of 50 to 55 ° C, is seeded with the hemisulfate salt of (SS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl. ] -2-cyclopenten-1-methanol and stirred for about 30 minutes. To the resulting suspension, IPA (160 ml) is added for about 15 minutes then the suspension is cooled to about 25 ° C for almost 2 hours and then in the range of about 0 to 5 ° C. After stirring for a further 2 hours, the product is filtered, washed with I PA (2 x 40 ml) and dried in vacuo to about 45 ° C to give the title compound as a faint brown solid (14.98 g, 93%), spectra identical to those of the product of Example A.

Example J Preparation of the hemisulfate salt of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol from the salt of succinate in the presence of its enantiomer.

A mixture of the succinate salt of (1S, 4R) -cis-4 - [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol and its enantiomer (134 g) what. it has an enantiomeric ratio of 97.5: 2.5 as shown by chiral HPLC (eluent (acetonitrile 1.0 v / v in a potassium phosphate buffer of 0.05 M, pH 6.5; ChormTech Chiral-AGP column, 100 x 4.0 mm; 1.0 ml / minute, detection at 220 nm) is converted to a suspension in isopropanol (IPA) 302 ml) and water (67 ml) and heated to reflux to give a clear solution. The clear solution is cooled in the range of 75 to 80 ° C and a solution of concentrated sulfuric acid (16.26 g) in water (33.5 ml) is added, and the solution and solution is clarified by hot filtration, through of the filter, with a mixture of IPA and water (3: 1, 134 ml). The filtrates and the washes are cooled in the range from 45 to 50 ° C and are seeded with the hemisulphate salt of (SS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten- authentic l-methanol. Additional IPA (804 ml) is added in this temperature range and the resulting suspension is cooled in the range of 0 to 5 ° C. The suspension is filtered and the product washed with IPA (2x 200 ml) and dried in vacuo in the range of 40 to 45 ° C to give the title compound as a white crystalline solid (75 g, The analysis of the product by chiral HPLC (conditions as above) showed that the proportion of the enantiomers will be 99.2: 0.8.

A range of similar experiments was carried out on a scale of 8 g using different ratios or proportions of the enantiomers of the inlet succinate salt with the same experimental protocol. The results are summarized immediately in the form of a table: E jmplo K Preparation of the hemisulfatrous salt of (1S, 4R) - cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-syclopenten-1-methanol from the salt of glutarate in the presence of its enantiomer.

A mixture of the glutarate salt of (1S.4R) -cis-4 - [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopent en-1-methanol and its enantiomer ( 100 g) that has an enantiomeric ratio of 98. 6: 1.4 as shown by chiral HPLC (conditions as in Example J above), becomes a suspension in isopropanol (IPA), (400ml) and water (100ml) and heated to reflux to give a clear solution. The solution is cooled in the range of 70 to 75 ° C and a concentrated sulfuric acid solution is added (12.01 g) in water (25 ml), followed by a mixture of IPA and water (4: 1, 100 ml) and then by IPA (100 ml). The solution is cooled in the range of 50 to 55 ° C and is seeded with the hemisulphate salt of (SS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-me tanol authentic. Additional IPA (800 ml) is added in this temperature range and the resulting suspension is cooled in the range of 0 to 5 ° C the suspension is filtered and the product washed with IPA (2x200 ml) and dried in vacuo in the range of 40 to 45 ° C to give the title compound as a white crystalline solid (72 g, 90%).

Analysis of the product by chiral HPLC (conditions as above in Example J) shows that the proportion of the enantiomers will be 99.6: 0.4.

Example L Preparation of the salicylate salt of (1S, 4R) cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-l-methanol (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopent en-1-methanol (Intermediate 1) (1.0 g) and acid salicylic acid (0.482 g) are heated in IMS (approximately 25 ml) until a clear solution is formed. This is allowed to cool to about 20 ° C and the resulting suspension is filtered and the solid product dried in vacuo at about 40 ° C to give the title compound as a white solid, (1163 g, 78%); p.f .: 195.-198 ° C; NMR-H1 (dmso-d6) d: 7.78 (d of d, J = 7.7 Hz, J = 1.7 Hz, 1H, aromatic CH); 7.66 (s, 1H, purine CH); 7.66 (br m, 1H, NH); 7.43-7.48 (m, 1H, aromatic CH); 6.85-6.92 (m, 2H, 2 x aromatic CH); 6.11 (m, 1H, = CH); 6.11 (br m, 1H, OH); 5.87 (m, 1H, = CH); 5.40 (m, 1H, NCH); 3.45 (m, 2H, OCH2); 3.03 (br m, 1H, cyclopropyl CH); 2.87 (m, 1H, CH); 2.55-2.65 (m, -1H, CH); 1.63-1.55 (m, 1H, CH); 0.73-0.58 (m, 4, 2 x CH2 of cyclopropyl).

The salicylate salt thus formed can be converted to the desired hemisulfate salt by a method analogous to that described in Example G for the conversion of the benzoate salt to the hemisulfate salt.

Example M Preparation of the monosulf to salt of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol A stirred suspension of (ÍS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol (10.00 g) in the methylated alcoholic substances (IMS) (40 ml) is heated at 60 ° C to obtain a clear solution. A solution of the concentrated sulfuric acid (6.99 g) in IMS (15 ml) is added dropwise, and the mixture is heated under reflux for about 0.25 hours to once again obtain a clear solution. This mixture is cooled in the range of 20 to 30 ° C for about one hour, with the crystallization occurring during cooling. This The suspension is further cooled in the range of 0 to 5 ° C for about 0.25 hours, and is stirred for about 1 hour within this temperature range. The product is filtered, washed with IMS (2 x 15 ml), and dried in vacuo in the range of 40 to 45 ° C to give the title compound as a fine white powder (9.07 g, 67.5%); NMR-H1 (DMSO-d6) d: 0.78 (2H, m), 0.93 (2H, m), 1.10 (3H, t, J 7.1 Hz) (ethanol), 1.63 (1H, dt, J 13.8, 5.5 Hz) , 2.64 (1H, dt, J 13.8, 8.8 Hz), 2.8 3.0 (3H m amp.), 3.46 (2H, m), 3.74 (2H, c, J 7.1 Hz) (ethanol), 5.42 (1H, m) , 5.88 (1H, m), 6.17 (1H, m), 5.4-7.8 (broad, interchangeable), 8.0 (1H, s).

E ng N Preparation of the hemisulfate salt of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-l-methanol A stirred suspension of the monosulfate salt of (SS, 4R) -cis- - [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopen en-1-methanol (5.00 g), and (ÍS, 4R) -cis-4 - [2-amino-6- (cyclopropylamino) -9H- purin-9-yl] -2-cyclopenten-l-methanol (3725 g) in isopropanol (IPA) (30 ml) and water (10 ml) is heated under reflux for approximately 0.25 hours, to obtain a clear solution. The solution is cooled to the range of about 50 to 55 ° C, and IPA (40 ml) is added for about 0.25 hours maintaining the temperature in the range of 50 to 55 ° C. The crystallization occurred during the addition. The mixture is cooled in the range of 20 to 30 ° C for about one hour, then further cooled to the range of 0 to 5 ° C for about 0.25 hours, and stirred for about 1 hour within this temperature range. The product is filtered, washed with IPA (2 x 10 ml), and dried in vacuo in the range of 40 to 45 ° C to give the title compound as a fine white powder (5.17 g, 59.1%), spectra. to those of the product of Example A.

E xemployment 1: Tablet Formulations The following formulations A, B and C are prepared for the wet granulation of the ingredients with a povidone solution, followed by the addition of magnesium stearate and compression.

Formulation A mg / t ablet to mg / tablet (a) Active ingredient 250 250 (b) Lactose B. P. 210 26 (c) Povidone B. P. 15 9 (d) Starch glycolate and 20 12 sodium (e) Magnesium stearate 500 300 Formulation B mg / tablet g / table a (a) Active Ingredient 250 250 (b) Lactose 150 (c) Avicel PH 101 60 26 (d) Povidone B.P. 15 9 (e) Starch glycolate and 20 12 sodium (f) Magnesium stearate 500 300 Cl Formulation (Release Formulation Controlled The formulation is prepared by wet granulation of the ingredients (below) with a solution of providone followed by the addition of magnesium stearate and compression. mg / tablet (a) Active ingredient 500 (b) Hydroxypropylmethylcellulose (Methocel 112 K4M Premium) (c) Lactose B.P. 53 (d) Povidone B.P.C. 28 (e) Magnesium stearate 7 700 The capsules were prepared by dispersing the active ingredient in the peanut lecithin and filling the dispersion in soft, elastic gelatin capsules.

Formulation C (Controlled Release Capsules) The following formulation of the controlled release capsule is prepared by extruding the ingredients a, b, and c using an extruder, followed by the conversion into spheres of the extruded and dried material. The dried microspheres are then coated with a membrane to control the release (d) and filled into a hard, two-piece gelatin capsule. mg / capsules (a) Active Ingredients 250 (b) Cellulose Microcris talin 125 (c) Lactose BP 125 (d) Ethyl cellulose 13 513 Formulation D (tablet coated with a film The next tablet coated with a film is prepared using a direct compression process. The hemisulfate salt of (ÍS, 4R) -cis- 4- [2-amino-6- (cyclopropylamino) -9H-purin-9-y1] -2-cyclopenten-1-me tanol is screened and combined with microcrystalline cellulose and sodium starch glycolate. Magnesium stearate and colloidal silicon dioxide are screened and then combined with the other ingredients. The mixture is compressed into tablets which are then coated using a standard film coating technology. mg / table Core of the Tablet (a) Hemisulfate salt 351.0 (b) Microcrystalline Cellulose 414.6 (c) Sodium and Starch Glycolate 24.0 (d) Magnesium Stearate 8.0 (e) Colloidal Silicon Dioxide 2.4 Weight of Total Core Tablet 800.0 Tablet Coating (f) Yellow Opadry ™ 24.0 (g) (g) Purified Water USP c. s. Total weight of Table 824.0 The amount of the colloidal silicon dioxide present in the core of the tablet can be varied, for example, to 0.8 mg.

Example 2: Injectable Formulation Active Ingredient 0.200 Sterile, pyrogen-free phosphate buffer (pH 7.0) up to 10 ml The active ingredient is dissolved in the majority of the phosphate buffer (35-40 ° C), then brought to the final volume and filtered through a sterile micropore filter in a sterile 10 ml amber glass vial ( type 1) and sealed with sterile closures and overlaps.

Example E: Intramuscular injection cular Active Ingredient 0.20 g Benzyl Alcohol 0.10 g Glycofurol 75 1.45 g Water for Injection c.s up to 3.00 ml The active ingredient dissolves in glycofurol. The benzyl alcohol is then added and dissolved and water is added to 3 ml. The mixture is then filtered through a sterile micropore filter in 3 ml glass ampoules (type 1).

Example 4: Syrup suspension Active Ingredient 0.2500 g Sorbitol solution 1.5000 g Glycerol 2,000 g Dispersable Cellulose 0.0750 g Sodium Benzoate 0.0050 g Flavor, Peach 17.42.3169 0.0125 ml Purified water c.s. Up to 5.0000 ml The sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution is added. The active ingredient is dispersed in the agent thickness (dispersible cellulose). The two dispersions are mixed and compound up to the volume required with the purified water. • Example 5 Suppositions mg / suppository Active Ingredient 250 Hard Fat, BP (Witepsol H15 Dynamit Nobel) 770 1020 The active ingredient is used as a powder where at least 90% of the particles are of a diameter of 63 μm or less.

One fifth of the Witepsol H15 melted in a trough with a steam jacket at a maximum of 45 ° C. The active ingredient is sieved through a 200 μm sieve and added to the molten base with mixing, using a silverson device equipped with a cutting head, until a smooth or smooth dispersion is achieved. Maintaining the mixture at 45 ° C, the remaining Witepson H15 is added to the suspension and stirred to ensure a homogeneous mixture. The complete suspension is passed through a 250 μm stainless steel mesh and, with continuous agitation, allowed to cool to 45 ° C. At a temperature of 38 ° C to 40 ° C, 2.02 g of the mixture are filled in suitable plastic molds. The suppositories are allowed to cool to room temperature.

Example 6 Pessaries mg / pessary Active Ingredients 250 Detroxa Anhidra 380 Potato Seed 363 Magnesium Stratum 7 1000 The active ingredient is used as a powder in which at least 90% of the particles have a diameter of 63 μm or less.

The above ingredients are mixed directly and the pessaries are prepared by direct compression of the resulting mixture.

E xemployment 7: Topical Formulation Active Compound Cream 5.00 g Glicerol 2.00 g Alcohol tearílic ce tos 6.75 g Sodium Sulfate and Lauryl 0.75 g Soft white paraffin 2.50 g Liquid paraffin 5.00 g Cloroceresol 0.10 g Purified water up to 100.00 g The active compound is dissolved in a mixture of purified water and glycerol and heated to 70 ° C. The remaining ingredients are heated to 70 ° C. The two parts are added together and converted into an emulsion. It is cooled and filled in the containers.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, it is claimed as property-contained in the following.

Claims (21)

Claims

1. The hemislulfate salt of (SS, 4R) -cis-4 [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol or a solvate thereof.

2. The compound according to claim 1, characterized in that it is in the form of a hydrate.

3. A method for the treatment of a viral infection in a human host, characterized in that it comprises administering to the host an effective amount of a compound according to claim 1 or claim 2.

4. A compound according to claim 1 or claim 2, characterized in that it is used in medicine.

5. The use of a compound according to claim 1 or claim 2, in the manufacture of a medicament for the treatment of a viral infection. 5

6. The use of a compound according to claim 5, wherein the viral infection is an infection caused by HIV or by HBV infection.

7. A process for the preparation of the compound claimed in claim 1 or claim 2, characterized in that it comprises: the mixture of sulfuric acid and (1S, 4R) -cis-4 - [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol in a skethometric ratio of approximately 1: 2

8. A process for the preparation of the compound according to claim 1 or claim 2, characterized in that it comprises: the mixture of the sulfate of (SS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol (salt 1: 1) and of the (SS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9'-yl] -2- cyclopenten-1-methanol in a molar ratio substantially 1: 1 in the solution.

9. A process for the preparation of the compound according to the rei indication 1 or the rei indication 2, characterized in that it comprises the mixture of sulfuric acid and a salt of (1S, 4R) -cis-4 - [2-amino-6- ( cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-me tanol different from the hemisulfate salt.

10. A process according to claim 9, characterized in that the sulfuric acid and the salt are present in approximately the proportion or stoichiometric ratio required to form the compound.

11. A process according to any of claims 9 or 10 characterized in that the salt of (ÍS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten - 1-methanol is a salt with a dicarboxylic acid.

12. A process according to claim 11, characterized in that the salt with a dicarboxylic acid is selected from the group consisting of the salts of succinate, glutarate, hemisuberate, adi, fumarate, hemisebacate and pimelate and any mixtures thereof.

13. A process according to any of claims 9 or 10, characterized in that the salt of (ÍS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2 - Cyclopentene-1-methanol is selected from the group consisting of the benzoate and salicylate salts and any mixtures thereof.

14. A process according to any of the rei indications 9 to 13, characterized in that the optical purity of the hemisulfate is greater than that of the starting salt.

15. A pharmaceutical formulation, characterized in that it comprises a compound according to claim 1 or claim 2 and a pharmaceutically acceptable carrier thereof.

16. A pharmaceutical formulation according to claim 15, characterized in that it is in the form of a tablet, capsule, or liquid formulation.

17. A pharmaceutical formulation according to claim 15, characterized in that it is adapted for parenteral administration.

18. A pharmaceutical formulation according to any of claims 15 to 17, characterized in that it further comprises one or more therapeutic agents selected from the group consisting of nucleoside reverse transcriptase inhibitors, inhibitors of reverse transcriptase other than nucleosides, protease inhibitors, immune modulators and inter-ferons.

19. A dicarboxylate salt of (SS, R) -cis-4- [2-a ino-β- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol, characterized in that the dicarboxylate is selected of the group that consists of glutarate, hemisulberate, adipate, fumarate, hemisebacate and pimelate.

20. The glutarate salt of (SS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2- -cyclopenten-1-methanol.

21. The monosulfate, benzoate or salicylate salt of (SS, R) -cis-4 - [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-me tanol.