CZ406899A3 - Hemisulfate of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol - Google Patents

Abstract

In the present invention, 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 such hemisulfate salt as well as pharmaceutical composition in which the salt is comprised. The invented hemisulfate salt is useful in medicine, particularly in the treatment of viral infections.

Description

(1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol hemisulfate

Technical field

The present invention relates to a novel salt of (1S, 4R) -cis-4- [2-amino-65 (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol or a solvate thereof, pharmaceutical compositions containing of this compound and their use in medicine, particularly in the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection.

(1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol ("the compound") and its antiviral use, in particular against HIV infections, is described in European Patent Specification No. 5,940,519. No. 0434450, which also relates to pharmaceutically acceptable derivatives, in particular the salts, esters and salts of these esters of the compound, and particularly describes the hydrochloride salts of the compound. In addition, PCT patent application no. GB 95/02014 discloses the succinate salt of the above compound.

(1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H20 purin-9-yl] -2-cyclopentene-1-methanol is now in clinical research as a pharmaceutical against HIV. There is a need to prepare this compound in a form that is suitable for ease of isolation in large scale production and for ease of formulation into an acceptable product for human administration. The inventors have found that the production of the free base of the compound provides an amorphous solid that entrains solvents and is therefore unsuitable for large scale purification or formulation without further purification procedures.

While the succinate salt disclosed in patent application PCT / GB95 / 02014 has a manufacturing advantage, for example, easily forms a salt from stoichiometric acid / base ratios and very easily crystallizes from solution, it is not ideal for pharmaceutical formulation, especially tablet production. Specifically, the succinate salt of the compound agglomerates to form a "lumpy" mass that is difficult to pour and is therefore unsuitable for use in commercial tabletting machines, so a further processing step - high energy milling - is required to obtain a uniform particle size. A further complication after formulating the succinate salt of the compound is that it can exist in several crystalline forms, each having slightly different physical properties. The preparation of the succinate salt of the compound requires a great deal of attention to prevent the formation of undesirable forms, since if such forms are formed, they must be converted into the desired form.

SUMMARY OF THE INVENTION

The present inventors have found that the advantages of the hemisulfate salt of the compound over the disclosed hydrochloride salts and the succinate salt reside in the suitability of the hemisulfate salt for large-scale production and especially for use in the manufacture of pharmaceutical compositions. In particular, the hemisulphate salt forms a free-flowing powder which has no undesirable tendency to agglomerate and which is easy to pour and compress and is therefore suitable for use in commercial tabletting machines without the need for grinding. It is believed that this salt exists as a single morphological and crystalline form. The salt is not easily hydrated or solvated (for example on storage). The salt is easy to filter and dry, which facilitates manufacturing. Another advantage is the higher water solubility of hemisulphate compared to succinate, so that hemisulphate is particularly suitable for the production of liquid compositions.

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The inventors have also found that when the hemisulphate salt is prepared by a " salt exchange " By converting the precursor salt of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol, especially the glutarate or succinate salt, an increase in the optical purity against the precursor salt. Thus, further preparation or purification steps can be reduced or eliminated to increase the optical purity of the hemisulfate salt produced.

According to a first embodiment of the invention there is provided (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol hemisulphate salt or solvate thereof including hydrate , hereinafter referred to as a compound of the invention.

For the avoidance of doubt, (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9Hpurin-9-yl] -2-cyclopentene-1-methanol hemisulphate salt is a salt formed between (1S, 4R), 4R) 15 cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol and sulfuric acid in a 2: 1 stoichiometric ratio.

The invention further includes the following embodiments:

a) A compound of the invention for use in medicine, particularly in the treatment of viral infections, in particular HIV or HBV infection.

b) A method of treating a viral infection, particularly an HIV or HBV infection in a human, comprising administering to the human an effective amount of a compound of the invention.

c) Use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment of a viral infection, in particular an HIV infection or an infection

HBV.

The compound of the invention is particularly useful for treating HIV infections.

It will be apparent to those skilled in the art that references to treatment also apply to prevention as well as treatment of developed infections or symptoms.

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Examples of clinical conditions caused by HIV infections that can be treated according to the invention include Acquired Immune Deficiency Syndrome (AIDS) or symptoms that often precede AIDS, or related clinical conditions such as AIDS-related complex (AIDS-related) complex, ARC), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thrombocytopenic purpura, AIDS-related neurological conditions such as multiple sclerosis or tropical paraparesis as well as anti-HIV antibodies and HIV-positive conditions including AIDSio asymptomatic patients.

The compounds of the invention may be administered alone or in combination with other therapeutic agents for the treatment of HIV infections, such as Nucleoside Reverse Transcriptase Inhibitors (NRTIs), for example, zidovudine, zalcitabine, lamivudine, didanosine, stavudine, 5-chloro-2. ', 3'dideoxy-3'fluoruridine, adefovir and (2R, 5S) -fluoro-1- [2- (hydroxymethyl) 1,3-oxathiolan-5-yl] cytosine, lovaride, non-NRTIs, for example nevirapine, delavuridine, α-ΑΡΑ, HBY-1293 and efavirenz HIV inhibitors such as saquinavir, indinavir, nelfinavir, ritonavir and VX20 478, other anti-HIV agents such as soluble CD4, immunomodulators such as interleukin II, erythropoietin, tucaresol, and interferons , for example α-interferon. In addition, the compounds of the invention may be administered in combination with other therapeutic agents useful in the treatment of HBV infections such as lamivudine, (2R, 5S-5-fluoro-1- [2- (hydroxymethyl) -1,3-oxathiolane-5- yl] cytosine, immunomodulators, and interferons as mentioned above These combinations may be administered together or sequentially provided that the time between administration of each therapeutic agent does not diminish their additive effect.

While it is possible for the compound of the invention to be administered as a raw chemical, it is preferable to administer the compound of the invention.

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5 of the invention in the form of a pharmaceutical composition which constitutes another embodiment of the invention. The pharmaceutical composition comprises a compound of the invention together with one or more acceptable carriers and optionally other therapeutic agents. The carrier (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The compounds of the invention may be administered by any suitable route for the condition to be treated, by suitable routes including oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) . It will be appreciated that the preferred mode of administration may vary, for example, according to the condition of the recipient.

For each of the above uses and indications, the amount of individual active ingredient required will depend upon a variety of factors including the severity of the condition being treated and the recipient, and the ultimate decision will depend upon the attending physician. In general, however, an effective dose in the range of 1 to 120 mg / kg body weight of the recipient per day, preferably in the range of 3 to 90 mg / kg body weight per day, and most preferably in the range of 5 to 60 mg / day will be suitable for all such uses and indications. kg body weight per day, such as 5 to 20 mg / kg body weight per day. The dose may, if desired, be presented as two, three, four or more subdoses administered at appropriate intervals throughout the day.

Formulations include forms suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any suitable method known in the art of pharmacy.

Such methods include the step of bringing into association the active ingredient with the carrier, which comprises one or more accessory ingredients. Generally

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The compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the article.

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

The tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be made by compressing the active ingredient in a free-flowing form such as a powder or granules, optionally in admixture with a binder (e.g. povidone, gelatin, hydroxypropylmethylcellulose), a glidant, an inert diluent, a disintegrant (e.g. starch glycolate sodium), cross-linked povidone, cross-linked sodium carboxymethylcellulose), with a surfactant or dispersant, in a suitable tabletting machine. Molded tablets may be made by molding in a suitable machine a mixture of the powdered components moistened with a suitable inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient, for example, by adding hydroxypropyl methylcellulose in varying amounts to obtain the desired release profile.

The capsule can be made by filling loose or compressed powder on a suitable filling machine, optionally together with one or more accessory ingredients. Examples of suitable additives include binders such as povidone, gelatin, glidants, inert diluents and disintegrants, as is the case with tablets. The capsules may also be formulated such that 9999 9999 9 9 9999 9999 9999 9999 9999 * 9 «· 9 ·· ··· 98 9 ·

7 contain pellets or discrete subunits to achieve slow or controlled release of said component. These can be obtained by extruding and rounding the wet drug mixture together with an extrusion aid (for example microcrystalline cellulose) and a diluent such as lactose. The rounded particles thus formed can be coated with a semipermeable membrane (eg, ethylcellulose, Eudragit WE30D) to create delayed release properties.

For infections of the eye or other external tissues, such as the mouth and skin, the compositions are preferably used as an ointment or cream for topical use including an active ingredient in an amount of, for example, 0.075 to 20% by weight, preferably 0.2 to 15% by weight and most preferably 0. 5 to 10% by weight. When the active ingredients are in the form of an ointment, the active ingredients may be used together with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be in the form of a cream with an oil-in-water base or a water-in-oil base.

If desired, the aqueous phase of the cream base may contain, for example, at least 40 to 45% by weight of a polyhydroxy alcohol, i.e. an alcohol with two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. Topical compositions may, if desired, contain a compound that enhances absorption or penetration of the active agent through the skin or other affected areas. Examples of such skin penetration enhancers are, for example, dimethylsulfoxide and related analogs.

The oily phase of the emulsions of the invention may be composed of known ingredients in a known manner. Although this phase may contain only an emulsifier (emulsifying agent), it comprises, if desired, a mixture of at least one emulsifier with a fat or an oil or both with a fat and an oil. Preferably a hydrophilic emulsifier is added together with a lipophilic emulsifier which acts as a stabilizer. It is also • fcfc * fcfc fc fcfcfcfc fc fcfcfcfc fc ·· fcfcfc fc fcfcfcfc fcfcfcfc • fcfc · fc ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· fc · fcfc

It is preferable to add both oil and fat. Emulsifier (s) with or without stabilizer (s) together form an emulsifying wax, and this wax together with the oil and / or fat forms the so-called emulsifying ointment base which forms the oil-dispersed phase of the cream compositions.

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

According to the first method (A), the compound of the invention can also be produced by mixing sulfuric acid and (1S, 4R) -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, most preferably in an aqueous organic solvent, preferably at elevated temperature, more preferably at the reflux temperature of the selected solvent system. Upon cooling, crystals of the compound of the invention are formed. The crystallization is preferably carried out by "seeding" the solution with a small amount of a compound of the invention.

Optionally, washing and recrystallization may be used to improve product purity.

In an alternative method (B), a compound of the invention may be formed by mixing (1S, 4R) -cis-4- [2-amino-6 (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol monosulfate (1: 1 salt) and (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol while maintaining a molar ratio of substantially 1 : 1.

A particularly preferred process (C) for producing a compound of the invention comprises converting the salt of (1S, 4R) -cis-4- (2-amino-6- (cyclopropylamino) 9H-purin-9-yl) -2-cyclopentene-1-methanol to the compound according to the invention. Salts suitable for this conversion include salts with dicarboxylic acids such as succinic, glutaric, hemisuberic acid (i.e., 2: 1 salt, base: acid suberic acid). cork), adipic, fumaric, hemisebacic (i.e., 2: 1 salt, base: sebacic acid), and pimelic acid salts. Mixtures of dicarboxylic acid salts may be used. The use of succinate and glutarate salts is preferred. The preparation of the succinate salt is described in PCT / GB95 / 02014. Other (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol salts useful for the conversion to hemisulphate include the benzate and salicylate salts and their salts. mixtures. These salts form a further embodiment of the invention.

In a preferred embodiment of the present invention, the conversion can be accomplished by mixing sulfuric acid and (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol salt. other than hemisulphate in a suitable stoichiometric ratio. For the avoidance of doubt, a stoichiometric ratio (i.e., (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol: acid salt ratio) will be appropriate sulfuric acid will be 2: 1 if the salt is a 1: 1 salt (i.e. the ratio of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9Hpurin-9-yl] -2-cyclopentene- 1-methanol to acid is 1: 1) and 1: 1 when the salt is a 2: 1 (i.e., (1S, 4R) -cis-4- [2-amino-620 (cyclopropylamino) -9H-purine- 9-yl] -2-cyclopentene-1-methanol to the acid is 2: 1). Stirring is preferably carried out in solution, more preferably in an aqueous organic solvent, preferably at elevated temperature, more preferably at the reflux temperature of the selected solvent system. Hemisulfate crystals are formed upon cooling the reaction mixture, optionally with seeding as described above. This salt conversion process provides advantages in terms of purity of the compound of the invention so obtained.

A particularly advantageous feature of the process for converting the aforementioned salts to hemisulphate is that the conversion leads to an increase in optical purity, i.

The amount of undesired isomer (1R, 4S) thus contained in the compound of the invention thus formed is less than originally in the starting salt.

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Suitable solvents for use in the process of the invention include alcohols such as ethanol or propan-2-ol. These solvents can be used alone or in a mixture, optionally in the presence of another organic solvent such as acetone, or in the presence of water to form an aqueous organic solvent mixture.

The compound (1S, 4R) -cis-4 - = [2-amino-6- (cyclopropylamino) -9Hpurin-9-yl] -2-cyclopentene-1-methanol can be synthesized in accordance with European Patent Specification No. 5,960,049. No. 0434450 or alternatively PCT application no. PCT / GB9500225, incorporated herein by reference.

The succinate salt of (1S, 4R) -cis-4- [2-amino-6 (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol can be synthesized according to patent application PCT / GB95 / 02014 , which is also incorporated by reference.

The invention is further described in the following examples, which are illustrative and not intended to limit the invention in any way.

In the following examples, IMS means industrial methylated alcohols (denatured ethanol) and IPA means propan 2-ol.

DETAILED DESCRIPTION OF THE INVENTION

Intermediate 1

Preparation of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -225 cyclopentene-1-methanol

(1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol hydrochloride salt (EP0434450, 80 g) was heated to reflux. in industrial denatured alcohol (800 ml) with cyclopropylamine (110 ml) for 5 hours. The mixture was fcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcf Cool to 70-75 ° C and add aqueous sodium hydroxide solution (10 M, 55 mL, 2 molar equivalents) dropwise. The resulting suspension was cooled to 20-25 ° C and filtered, and the separated solid was washed with IMS (2 x 60 mL). The combined filtrates and washings were mixed with activated carbon (8 g) and a Harborlite J2 filtration aid (4 g) and heated to 40-50 ° C. After about 0.5 h, the mixture was cooled to 15-20 ° C and the solids were removed by filtration, washed with IMS (2 x 160 mL and 1 x 80 mL), and the combined filtrates and washings were concentrated by distillation under reduced pressure to a residue. volume approximately 240 ml. IMS (560 mL) was added and the mixture was concentrated under reduced pressure to a residual volume of approximately 240 mL. The dilution and concentration was repeated and the obtained concentrate was diluted with IMS (240 mL) and heated to give a completely dissolved solution which was divided into four equal portions.

One portion was concentrated by distillation under reduced pressure to a residual volume of approximately 60 ml. Acetone (140 mL) was added and the mixture was concentrated again to approximately 60 mL. This dilution and repeated concentration was performed two more times to give a liquid volume of approximately 80 ml. The resulting suspension was cooled to 0-5 ° C and the product was filtered, washed with cold (9-5 ° C) acetone (2 x 40 mL) and dried in vacuo to give the title compound as an orange solid (16.8 g). , 90%); ¹ H-NMR (D ₂ O) δ: 7.71 (s, 1, CH of purine), 6.22 (m, 1 = CH), 5.93 (m, 1, = CH), 5.37 ( m, 1,

NCH), 3.61 (m, 2, OCH ₂ ), 3.04 (br m, 1, cyclopropyl CH), 2.82 (br m, 1, CH), 2.80-2.70 (m, 1, CH), 1.58 to 1.50 (m, 1, CH), 0.90-.060 (m, 4, 2 * _CH2 of cyclopropyl).

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Preparation of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol hemisulphate salt

A stirred mixture of water (25 mL) and IPA (100 mL) was heated to 45-55 ° C and the (1S, 4R) -cis-4- [2-amino-6 (cyclopropylamino) -9H-purine-, succinate salt was added. 9-yl] -2-cyclopentene-1-methanol (WO 96/06844, 50 g), and the mixture was washed with IPA (12.5 mL). The mixture was heated at reflux for 0.5 h to obtain a clear solution and then cooled to 65-75 ° C and a solution of concentrated sulfuric acid (6.07 g) in water (12.5 mL) was added. A mixture of IPA (37.5 mL) and water (12.5 mL) was added and the solution was cooled to 45-55 ° C and then seeded with (1S, 4R) -cis-4 [2-amino-6] hemisulfate salt. - (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol. After stirring in this temperature range of about 1 hour to allow crystallization, additional IPA (300 mL) was added, maintaining the temperature of the mixture at 45-55 ° C. The suspension was cooled to 0 to 5 ° C over 2 hours and the product was filtered, washed with IPA (2 x 75 mL) and dried under vacuum at 40 to 45 ° C to give the title compound as a pale yellow-brown powder (34.3). g, 90%); mp 224-225 ° C (dec.); ¹ H-NMR (DMSO-d 6) δ: 1076 (br m, 1, NH purine), 8.53 (vbr m, 1, NH), 7.80 (s, 1, CH purine), 6.67 ( br m, 1, NH ₂ ), 6.13 (m, 1, = CH), 5.87 (m, 1, = CH), 5.40 (m, 1, NCH), 3.45 (d, J = 5.8 Hz, 2, OCH ₂ ), 2.96 (br m, 1, cyclopropyl CH), 2.87 (m, 1, CH), 2.67 - 2.2.57 (m, 1 , CH), 1.65 - 1.55 (m, 1, CH), 0.84 - 0.64 (m, 4, 2 x

_CH2 of cyclopropyl).

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- 13 Example Β

Preparation of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl-2-cyclopentene-1-methanol hemisulphate salt

Mixed salt suspension of (1S, 4R) -cis-4- [2-amino-5 - (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol succinate salt (WO 96/06844, 1000 g) in industrial denatured alcohol (IMS) (7000 mL) was heated at reflux for about 0.5 hours to obtain a clear solution. The solution was cooled to about 70 ° C and concentrated sulfuric acid (121 g) in IMS (1000 mL) was added. After seeding with (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol hemisulfate salt, the mixture was stirred at about 70 ° C for allowing the product to crystallize. After about 0.5 hours, the mixture was cooled to 20-30 ° C over about 2 hours. The mixture was filtered, the cake was washed with IMS (2 x

2000 mL) and dried under vacuum at 40-45 ° C to give the title compound as a light tan powder (764 g, 92%), the spectra were identical to the product of Example A.

Example C

Preparation of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-in-2-cyclopentene-1-methanol hemisulphate salt

Suspension of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol succinate salt (10 g) in industrial denatured alcohol (IMS) (30 mL) and water (5 mL) was heated at reflux for about 0.5 h to obtain a clear solution. The solution was cooled to 55-65 ° C and concentrated sulfuric acid (1.21 g) dissolved in water (2.5 mL) was added, followed by a mixture of IMS (7.5 mL) and water (2.5 mL). The solution was further cooled to 45-55 ° C and acetone (80 mL) was added to the mixture over a period of about 0.25 hours. The obtained suspension was

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The product was filtered, washed with acetone (2 x 10 mL) and dried under vacuum at 40 to 45 ° C to give the title compound as a pale yellow-brown powder (6.28). g, 82%), which was spectroscopically identical to the product of Example A.

Example D

Preparation of (1S, 4R) -cis-4- (2-amino-6- (cyclopropylamino) -9H-purin-9-1H-2-cyclopentene-1-methanol) (1S, 4R) -cis-4- [2- amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol (intermediate 1) (5.98 g) was suspended in IMS (40 mL) and the suspension was heated to reflux 0.5 The mixture was cooled to 70-75 ° C and a mixture of concentrated sulfuric acid in IMS (10 M,

1.03 mL, 0.5 molar eq) and IMS (10 mL). The acid was washed with additional IMS (10 mL) and the resulting suspension was cooled to 0-5 ° C. The product was isolated by filtration, washed with IMS (2 x 12 mL) and dried under vacuum at 40-45 ° C to give the title compound as a pale yellow solid (6.15 g, 88%), spectra were identical to the product of Example AND.

Example E

(1S, 4R) -cis-4- [2-amino-6- (cycloproplamino) -9H-purin-9-in-2-cyclopentene-1-methanol

Another portion of the IMS solution of intermediate 1 was heated to 75 ° C to ensure complete dissolution. The solution was cooled to 70-75 ° 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 was cooled to 0 to 5 ° C over approximately 2 hours and the product was filtered, washed with IMS (2 x 40 mL) and dried under vacuum at 40 to 45 ° C to 9 ° C.

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99 of the title compound as a yellow-orange solid (17.7 g, 76%), the spectra were identical to those of the product of Example A. 5.0 g of this product was suspended in a mixture of isopropanol (IPA) (40 mL) and water (10 mL) and heated to reflux for approximately

0.5 hours and allowed to cool to 55 to 60 ° C, and then seeded with (1S, 4R) -cis-4- [2-amino-6 (cyclopropylamino) -9H-purin-9-yl] - Of 2-cyclopentene-1-methanol. The suspension was further cooled to 0-5 ° C and the temperature was maintained for about 1 hour. The solid was filtered, washed with IPA (2 x 5 mL) 10 and dried under vacuum at 40-45 ° C to give the title compound as a tan powder (4.4 g, 88%), spectra identical to those of the product of Example A .

Example F

(1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol benzoate salt

(1S, 4R) -cis-4- [2-amino-6-chloro-9H-purin-9-yl] -2-cyclopentene-1-methanol hydrochloride EP 0434450 (70 g) was heated to reflux in IMS (700 ml) with cyclopropylamine (94.5 ml) for about 4 hours. The solution was cooled to 45-50 ° C and Harborlite J2 (3.5 g) and charcoal (7 g) were added. After about 0.5 hours, the mixture was cooled to 20-25 ° C and filtered. The solid was washed with IMS (2 x 140 mL) and the combined filtrates and washings were concentrated by distillation under reduced pressure to a volume of approximately 210 mL. After dilution with IMS (490 mL), the solution was re-concentrated to approximately 210 mL. The dilution and concentration was repeated once more and the final concentrate was divided into seven equal portions.

One portion was diluted with IMS (80 mL) and heated until complete dissolution. Benzoic acid (4.85 g) was added all at once, and the mixture was heated at 70-75 ° C until complete dissolution and then 9999 99 9 · 9 99

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9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

- 16 allowed to cool slowly. At 40-45 ° C, the mixture was seeded with (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol benzoate salt and the mixture was further cooled to 0-5 ° C. The solid was filtered, washed with IMS (2 x 20 mL) and dried under vacuum at 40-45 ° C to give the title compound as a white solid (8.7 g, 64%), mp 156-157 ° C ; ¹ H-NMR (DMSO-d ₆ ) δ: 7.95 (m, 2, CH benzoate), 7.63 (m, 1, CH benzoate), 7.61 (s, 1, CH purine), 7, 50 (m, 2, CH of benzoate), 7.28 (br m, 1, NH), 6.11 (m, 1, = CH), 5.86 (m, 1, 10 = CH), 5.81 (br m, 1, OH), 5.39 (m, 1, NCH), 3.45 (d, J = 6.0 Hz, 2, OCH 2), 3.04 (br m, 1, CH cyclopropyl) 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 * _CH2 of cyclopropyl).

Example G

Preparation of (1S, 4R) -Sis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl-2-cyclopentene-1-methanol-hemisulfate salt

A suspension of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol benzoate salt (5 g) in IPA (25 mL) was heated to 60 to 65 ° C. A solution of concentrated sulfuric acid (0.64 g) in water (1.25 ml) was added and the resulting cloudy suspension was heated to 70-75 ° C. The mixture was cooled to 20-25 ° C and filtered. The solid was washed with IPA (2 x 10 mL) and dried under vacuum at 40-45 ° C to give the title compound as a white solid (3.57 g, 87%), the spectra were identical to those of the product of Example A.

• to • to <

to · this this ·· • to • «this

- 17 • to · to · to · to · to · »

Example H

Preparation of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol glutarate salt

(1S, 4R)-cis-4- [2-Amino-6-chloro-9H-purin-95-yl] -2-cyclopentene-1-methanol hydrochloride (EP 0434450) (25 g) was heated at reflux in IMS (250 mL) with cyclopropylamine (30 mL) for about 4 hours. The solution was cooled to 45-50 ° C, diluted with IMS (75 mL) and mixed with activated carbon (1 g) and a Harborlite J2 filter aid (0.5 mL). G). After about 1 hour, the mixture was cooled to 20-25 ° C and filtered. The solid was washed with IMS (50 mL) and the combined filtrates and washings were diluted with IMS (150 mL) and then concentrated by distillation under reduced pressure to approximately 75 mL. The mixture was diluted with IMS (90 mL) and concentrated again to approximately 75 mL. The dilution and concentration was repeated two more times. The final concentrate was diluted with IMS (75 mL) and heated to 70-75 ° C to obtain a solution. To this solution was added a solution of glutaric acid (13 g) in IMS (75 mL), which had been pre-heated to 70-75 ° C. The mixture was further diluted with IMS (25 mL) and cooled to about 25 ° C over about 2 hours. The mixture was further cooled to 0 to 5 ° C, stirred for about 2 hours and filtered. The product was washed with IMS (2 x 50 mL) and dried under vacuum at 45 ° C to give the title compound as a light brown solid (27.1 g, 78%); mp 184-188 ° C; ¹ H NMR _(DMSO- d 6)?: 7.60 (s, 1, purine CH), 7.27 (br m, 1, NH), 6.10 (m, 1, CH), 5.86 ( m, 1, = CH), 5.82 (br m, 1, OH), 5.39 (m, 1, NCH), 3.44 (d, J = 5.9 Hz, 2, OCH ₂ ), 3.04 (br m, 1H of cyclopropyl), 2.87 (br m, 1H,

CH), 2.65-2.55 (m, 1, CH), 2.24 (t, J = 7.2 Hz, 4.2 x CH ₂ glutarate), 1.70 (m, J = 7, 2 Hz, 2, CH ₂ glutarate), 1.62-1.54 (m, 1 CH), 0.68 0.54 (m, 4.2 x ₂ cyclopropyl CH ₂ ).

·· ···· f « • ·· ·· • ♦ · • • «· • • • 9 • ··· • • • »» • • « « • · • • • • • • 0 ·· «·· ·· ··

Example I

Preparation of (1S, 4R) -cis-4- [2-amino-6 (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol hemisulphate salt

Suspension of (1S, 4R) -cis-4- [2-amino-65 (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol glutarate salt (20 g) in IPA (80 mL) and water (20 mL) was heated to reflux to give a solution. The solution was cooled to approximately 75 ° C and concentrated sulfuric acid (2.4 g) dissolved in water (5 mL) was added. The resulting solution was diluted with a mixture of IPA (16 mL) and water (4 mL) and then IPA (20 mL). The solution was cooled to 50-55 ° C, seeded with (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9Hpurin-9-yl] -2-cyclopentene-1-methanol hemisulphate salt and stirring for approximately 30 min. To the obtained suspension was added IPA (160 mL) over 15 min, then the suspension was cooled to about 25 ° C over 2 hours and then to about 0 to 5 ° C. After stirring for an additional 2 h, the product was filtered, washed with IPA (2 x 40 mL) and dried under vacuum at 45 ° C to give the title compound as a light brown solid (14.98 g, 93%), the spectra were identical to those obtained. spectra of the product of Example A.

Example J

Preparation of (1S, 4R) -cis-4- [2-amino-6 (cyclopropvlamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol hemisulphate salt from succinate salt in the presence of its enantiomer

A mixture of (1S, 4R) -cis-4- [2-amino-625 (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol succinate salt and its enantiomer (134 g) in enantiomeric ratio 97.5: 2.5 by chiral HPLC (eluent 1.0 v / v acetonitrile solution in aqueous 0.05 M potassium phosphate buffer, pH 6.5; ChromTech ChiralAGP column, 100 x 4.0 mm; flow rate 1, 0 ml / min (detection at 220 nm) was suspended in isopropanol (IPA) (302 ml) and water (67 ml).

and heated to reflux to obtain a clear solution. The solution was cooled to 75-80 ° C and a solution of concentrated sulfuric acid (16.26 g) in water (33.5 mL) was added and the solution was clarified by hot filtration followed by washing the filter with IPA / water (3: 1). The filtrates and washings were cooled to 45-50 ° C and seeded with (1S, 4R) -cis-4- [2-amino-6 (cyclopropylamino) -9H-purin-9-yl] - hemisulfate salt - Of 2-cyclopentene-1-methanol. IPA (804 mL) was then added over the temperature range and the resulting suspension was cooled to 0-5 ° C. The suspension was filtered 10 and the product was washed with IPA (2 x 200 mL) and dried under vacuum at 40 ° C to give the title compound as a crystalline solid (75 g, 68%).

Analysis of the product by chiral HPLC (conditions above) showed an enantiomer ratio of 99.2: 0.8.

A series of similar experiments was performed on a 8 g scale using different ratios of enantiomers in the succinate salt feed and the same experimental protocol. The results are summarized in the following table:

Ratio of input enantiomers succinate salts The ratio of enantiomers produced hemisulphate salts 99.5: 0.5 99.9: 0.1 99.0: 1.0 99.7: 0.3 98.0: 2.0 99.5: 0.5 96.0: 4.0 99.0: 1.0

I · · · · · · ···

- 20 Example Κ

Preparation of (1S, 4R) -cis-4- [2-amino-6 (cyclopropylamino) -9H-purin-9-vH-2-cyclopentene-1-methanol hemisulfate salt from glutarate salt in the presence of its enantiomer

A mixture of (1S, 4R) -cis-4- [2-amino-6 (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol glutarate salt and its enantiomer (100 g) in an enantiomeric ratio of 98 6: 1.4 by HPLC (under the same conditions as in Example J above) was suspended in isopropanol (IPA) (400 mL) and water (100 mL) 10 and heated to reflux to obtain a clear solution. The solution was cooled to 70-75 ° C and a solution of concentrated sulfuric acid (12.01 g) in water (25 mL) was added, followed by the addition of IPA / water (4: 1, 100 mL) followed by IPA (100 mL). ). The solution was cooled to 50-55 ° C and seeded with (1S, 4R) -cis-4- [215 amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol hemisulfate salt. Additional IPA (800 mL) was then added over the same temperature range and the resulting suspension was cooled to 0-5 ° C. The suspension was filtered and the product was washed with IPA (2 x 200 mL) and dried under vacuum at 40-45 ° C to give the title compound as a white crystalline solid (72 g, 90%).

Analysis of the product by chiral HPLC (same conditions as in Example J above) showed an enantiomeric ratio of 99.6: 0.4.

Example L

Preparation of (1S, 4R) -cis-4- (2-amino-6- (cyclopropylamino) 9H-purin-9-yl) -2-cyclopentene-1-methanol (1S, 4R) -cis-4- [2- amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol (intermediate 1) (1.0 g) and salicylic acid (0.428 g) were heated in IMS (approximately 25 mL) to form of a clear solution. This was allowed to cool to approximately 20 ° C and obtained.

- the 21 suspension was filtered and the solid dried under vacuum at about 40 ° C to give the title compound as a white solid (1.163 g, 78%); mp: 195-198 ° C; @ ¹ H-NMR (dmso-d6) .delta .: 7.78 (d of d, J = 7.7 Hz, J = 1.7 Hz, 1H, aromatic CH); 7.66 (s, 1H, CH of purine); 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, .dbd.CH); 6.11 (br m, 1H, OH); 5.87 (m, 1H, .dbd.CH); 5.40 (m, 1 H, NCH); 3.45 (m, 2H, OCH ₂ ); 3.03 (br m, 1H, cyclopropyl CH); 2.87 (m, 1 H, CH); 2.55 - 2.65 (m, 1H, CH); 1.63-1.55 (m, 1H, CH); 0.73 to 0.58 (m, 4, 2 * _CH2 of cyclopropyl io).

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

Example M

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

A stirred suspension of (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -2H-purin-9-yl] -2-cyclopentene-1-methanol (10.00 g) in industrial denatured alcohol ( IMS) (40 mL) was heated to 60 ° C to obtain a clear solution. A solution of concentrated sulfuric acid (6.99 g) in IMS (15 mL) was added dropwise and the mixture was heated under reflux for about 0.25 hours to recover a clear solution. The mixture was cooled to 20-30 ° C over 1 hour, with crystallization upon cooling. This suspension was further cooled to 0-5 ° C over 0.25 hours and stirred for about 1 hour within this temperature range. The product was filtered, washed with IMS (2 x 15 mL) and dried under vacuum at 40-45 ° C to give the title compound as a fine white powder (9.07 g, 67%); ¹ H-NMR (DMSO-d 6) δ: 0.78 (2H, m), 0.93 (2H, m), 1.10 (3H, t, J 7.1 Hz) · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 22 (ethanol), 1.63 (1H, dt, J 13.8, 5.5 Hz), 2.64 (1H, dt, J 13.8, 8.8 Hz), 2.8-3, O (3H wide m), 3.46 (2H, m), 3.74 (2H, q, 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).

Example N

Preparation of (1S, 4R) -cis-4- (2-amino-6 (cycloproplamino) -9H-purin-9-in-2-cyclopentene-1-methanol hemisulphate salt

A stirred suspension of (1S, 4R) -cis-4- [2-amino-6io (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol monosulfate salt (5.00 g) and (1S 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol (3.725 g) in ispropanol (IPA (30 mL) and water (10 mL) The solution was cooled to 50-55 ° C and IPA (40 mL) was added over approximately 0.25 hours while maintaining the temperature in the range of 50-55 ° C. The mixture was cooled to 20-30 ° C over 1 hour, then further cooled to 0-5 ° C over about 0.25 hours, and stirred for about 1 hour over this temperature range. was filtered, washed with IPA (2 x 10 mL) and dried under vacuum at 40-45 ° C to give the title compound as a fine white powder (5.17 g, 59.1%), spectra identical to the product spectra in Example AND.

Example 1

Tablet formulation

The following formulations A, B and C were prepared by wet granulation of the ingredients with a povidone solution followed by the addition of magnesium stearate and compression.

• · · · ·

- 23 Formulation A

mg / tablet mg / tablet and) active substance 250 250 (b) lactose Β. P. 210 26 C) povidon Β. P. 15 Dec 9 (d) sodium starch glycolate 20 May 12 E) magnesium stearate 5 3

500 300

Formulation B

mg / tablet mg / tablet and) active substance 250 250 (b) lactose 110 - C) Avicel PH 101 60 26 (d) povidon Β. P. 15 Dec 9 E) sodium starch glycolate 20 May 12 F) magnesium stearate 5 3 500 300

Formulation C1 (controlled release formulation)

This formulation is prepared by wet granulation of the ingredients below with a solution of povidone followed by the addition of magnesium stearate and compression.

mg / tablet

(a) the active substance

500 · · · · · · · · · · · · · · · · · · ·

(b) hydroxypropylmethylcellulose 112 (Methocel K4M Premium) C) lactose Β. P. 53 (d) povidone P., P.C. 28 E) magnesium stearate 7 700 Capsules are prepared by dispersion active ingredient in

and peanut oil and filling the dispersion into soft elastic gelatin capsules.

Formulation C (controlled release capsules)

The following controlled-release capsules are prepared by extruding components A, B and C using an extruder followed by rounding of the extrudate and drying. The dried pellets are then coated with a controlled release membrane (d) and filled into two-piece hard gelatin capsules.

active substance mg / capsule 250 microcrystalline cellulose 125 lactose BP 125 ethylcellulose 13

513 fc 4 • ···· fcfcfcfc • fcfcfc fcfcfc fcfc ··· fcfc fcfc

- 25 Formulation D (film coated tablet)

The following film-coated tablet is prepared using direct compression. The (1S, 4R) -cis-4- [2-amino-6 (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol hemisulfate salt is sieved and mixed with microcrystalline cellulose and sodium starch glycolate. . Magnesium stearate and colloidal silica are then sieved and mixed with the other ingredients. The mixture is compressed into tablets, which are then film coated in a standard manner.

Tablet core mg / tablet and) hemisulphate salt 351.0 (b) microcrystalline cellulose 414.6 C) sodium starch glycolate 24.0 (d) magnesium stearate 8.0 colloidal silica 2.4 Total tablet core weight 800.0 Tablet coating F) Opadry ™ Yell 24.0 (g) G) purified water USP as required Total tablet weight 824.0

The amount of colloidal silica present in the tablet core can be changed to, for example, 0.8 mg.

ff · ff

Example 2

Formulation in the form of an injection

Active substance 0.200 g

Sterile pyrogen-free phosphate buffer (pH 7.00) to 10 ml

The active ingredient is dissolved in most phosphate buffer (35-40 ° C), then made up to final volume and filtered through a sterile 5 microporous filter into a sterile 10 ml brown glass vial (type 1), which is sealed with a sterile cap and cap.

Example E

Intramuscular injection active substance 0.20 g benzyl alcohol 0.10 g

Glycofurol 75 1.45 g water for injections as necessary into 3.00 ml I 10 The active substance is dissolved in glycofurol. Benzyl alcohol is then added and dissolved and water is added to make up to 3 ml. The mixture is then filtered through a sterile microporous filter and sealed into sterile 3 ml glass ampoules (type 1).

Example 4

Suspension syrup active substance sorbitol solution glycerol dispersible cellulose

0,2500 g

1,5000 g

2,0000 g

0.0750 g • · · ♦ · · ···

- 27 peach benzoate flavor peach 17.42.3169 purified water as needed

0.0050 g

0.0125 ml to 5.0000 ml

Sodium benzoate is dissolved in a portion of the purified water and sorbitol solution is added. The active ingredient is added and dispersed. A thickener (dispersible cellulose) is dispersed in glycerol. The two dispersions are mixed and made up to volume with purified water.

Example 5

Suppositories mg / suppository Active Substance 250 Solid Fat BP (Witepsol H15-Dynamite Nobel) 770

1020

The active ingredient is used in the form of a powder having at least 90% of particles having a diameter of 63 µm or less.

One fifth of Witepsol H15 fat is melted in a steam-heated pan at a maximum of 45 ° C. The active ingredient is sieved through a 200 µm sieve and added to the molten base with stirring using a Silverson stirrer equipped with a cutting head, until a smooth dispersion is obtained. While keeping the mixture at 45 ° C, the remaining suspension is added

Witepsol H15 and mix until homogeneous. The entire suspension is passed through a 250 µm stainless steel screen and allowed to cool to 45 ° C with stirring. At a temperature of 38 ° C to 40 ° C, 2.02 g of the mixture is filled into suitable plastic molds. The suppositories are allowed to cool to room temperature.

- 28 ························ · 944 4 4 9 9 4 4 4 • 4 . 9 4 4 4 4

9444 444 94 994 49

Example 6

Pesary

mg / pessary active substance 250 anhydrous dextrose 380 potato starch 363 magnesium stearate 7

1000

The active ingredient is used in the form of a powder in which at least 90% of the particles have a diameter of 63 µm or less.

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

Example 7

Topical product

Cream active substance 50,00 g glycerol 2,00 g cetostearyl alcohol 6,75 g sodium lauryl sulfate 0.75 g white soft paraffin 2,50 g liquid paraffin 5.00 chlorocresol 0,10 g cleaned water up to 100,00 g

φ • f f f f f f f f f f f f f f f f

The active substance is dissolved in a mixture of purified water and glycerol and heated to 70 ° C. The remaining components are heated to 70 ° C. The two parts are mixed and emulsified. The mixture is cooled and filled into containers.

Represented by:

0 0 ··

0 • ···

• 00 00 ·· 0 0 0 0

0 0 0 0 * 0 0 0 0 0 * 0 0 0 0

000 00 00

Claims (21)

PATENT CLAIMS (1S, 4R) -cis-4- [2-amino-6- (cyclopropyl-5-amino) -9H-purin-9-yl] -2-cyclopentene-1-methanol hemisulfate salt or solvate thereof. A compound according to claim 1 in the form of a hydrate. io A method of treating a viral infection in a human comprising administering to the patient an effective amount of a compound of claim 1 or 2. A compound according to claim 1 or 2 for use in medicine. Use of a compound according to claim 1 or 2 in the manufacture of a pharmaceutical composition for the treatment of a viral infection. Use of a compound according to claim 5, wherein the viral infection is 20 HIV or HBV infection. A process for the production of a compound according to claim 1 or 2, characterized in that: mixing sulfuric acid and (1S, 4R) -cis-4- [2-amino-625 (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol in a stoichiometric ratio of about 1: 2. Ff ff ff ff ff ff ff ff ff · · · · · ··············· - 31 A process for the preparation of a compound according to claim 1 or 2, characterized in that: mixing (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) 9H-purin-9-yl] -2-cyclopentene-1-methanol sulfate as a 1: 1 salt; and 5 (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol in solution at a substantially 1: 1 molar ratio. A process for the preparation of a compound according to claim 1 or 2, characterized in that the sulfuric acid and the salt of (1S, 4R) -cis-4- [2-amino-6 (cyclopropylamino) -9H-purin-9- yl] -2-cyclopentene-1-methanol other than the hemisulphate salt. 15 Dec The method of claim 9, wherein the sulfuric acid and said salt are present in approximately the stoichiometric ratio required to form the compound. A method according to any one of claims 9 or 10, 20, characterized in that the salt with (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol is a salt with a dicarboxylic acid. 12. The method of claim 11, wherein the dicarboxylic acid salt is selected from succinate, glutarate, hemisuberate, adipate, fumarate, hemisebacate, and pimelate salts, and any mixtures thereof. ··. 4 44 4 • 4 44 4 4 4 4 4 4 4 4 4 4 4 4 4 44 44 - 32 • 4 · 4 · 44 4 4 4 4 4 44 44 4 Process according to either of Claims 9 or 10, characterized in that, as (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene salt In methanol, a salt selected from benzoate is used And salicylate salts and any mixtures thereof. The method according to any one of claims 9 to 13, characterized in that the optical purity of the hemisulphate is higher than the optical purity of the starting salt. A pharmaceutical composition comprising a compound of claim 1 or 2 and a pharmaceutically acceptable carrier. A pharmaceutical composition, characterized in that the capsule or liquid composition of claim 15 is in the form of a tablet, 17. A pharmaceutical composition characterized by parenteral administration. according to claim that it is modified 15, for Pharmaceutical composition according to one of Claims 15 to 17, characterized in that it additionally contains one 25 or more therapeutic agents selected from the group of nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, immunomodulators, and interferons. 00 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00 - 33 • 0000 0 0 0 0 · 00 0 0 0 0 000 0 000 0 0 0 0 0 0 * 0 0 * 400 (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol dicarboxylate salt, wherein the dicarboxylic acid is selected from glutarate, hemisuberate , adipate, fumarate, hemisebacate, and pimellate. (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol, glutarate salt. (1S, 4R) -cisio 4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol monosulfate, benzoate or salicylate salt.