Salt of succinic acid 4-[2-amino-6-(cyclopropylamino)-n - purine-9-yl]-2-cyclopenten-1-methanol as antiviral agent

 

(57) Abstract:

The present invention relates to salts of succinic acid (1S,4R)-CIS-[2-amino-6-(cyclopropylamino)-N-purine-9-yl] -2-CEC-apenten-1-methanol or its MES, to pharmaceutical compositions containing such a compound and to the use of the compounds or pharmaceutical compositions in medical therapy or in the treatment or prophylaxis of viral infection, especially infection with the human immunodeficiency virus (HIV) and hepatitis b virus (HBV). 3 S. and 4 C.p. f-crystals, 1 table.

The present invention relates to a new salt of (1S,4R) 4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl] -2-cyclopenten-1-methanol, exhibiting antiviral activity, in particular anti-HIV activity, the method of production of such salts and pharmaceutical compositions containing such salt and having antiviral activity, in particular anti-HIV activity.

The compound (1S,4R) 4-[2-amino-6-(cyclopropylamino)-9H - purine-9-yl] -2-cyclopenten-1-methanol and its antiviral use, particularly HIV infections, described in the European patent N 0434450, which also mentioned pharmaceutically acceptable derivatives, especially salts, esters, and salts of these esters of this a connection is well known to specialists, and salt accession acids to the specified connection is described in EP 0434450. It is difficult to predict the physical characteristics of any particular salt compounds; at the same time, a small but important differences in physical properties can mean big savings in the production and preparation of pharmaceutical product containing the compound.

The compound (1S,4R) 4-[2-amino-6-(cyclopropylamino)-9H - purine-9-yl] -2-cyclopenten-1-methanol is currently undergoing clinical trials as an anti-HIV pharmaceutical agent. There is a need for this connection in the form convenient for easy selection in large-scale production and for easy processing in an acceptable product for administration to humans. We found that the receipt of this connection in the form of free base yields a resin which absorbs the solvent and therefore not suitable for large-scale purification or for the manufacture of a composition without additional purification.

The present invention is to obtain formed by the joining of the acid salt of (1S,4R) 4-[2-amino-6-(cyclopropylamino)- 9H-purine-9-yl]-2-cyclopenten-1-methanol, which can easily and reproducibly be obtained from equimolar stable, easily allocated, for example, fast and efficient filtration and pharmaceutically acceptable. The present invention is obtaining a pharmaceutical composition containing such a salt, and the development of a method of producing such salts.

According to the first aspect of the present invention proposed salt of succinic acid (1S,4R) 4-[2-amino-6-(cyclopropylamino)-9H - purine-9-yl]-2-cyclopenten-1-methanol, hereafter referred to as the connection according to the invention.

We have found that the advantages of a salt of succinic acid of the above compounds over a known salts of hydrochloric acid to make a salt of succinic acid is particularly suitable and advantageous to obtain on a large scale and use in obtaining pharmaceutical preparations for administration to humans. The advantages of a salt of succinic acid are to obtain it with high yield in the production on an industrial scale.

Further aspects of the invention include:

a) Compound according to the invention, showing antiviral activity, in particular anti-HIV activity.

b) the Compound according to the invention for obtaining a pharmaceutical composition suitable for the treatment or prevention of virusneutralizing)-9H-purine-9-yl]- 2-cyclopenten-1-methanol in a suitable solvent with succinic acid in water at the temperature of reflux distilled and allow the solution to cool to ambient temperature, followed by collecting precipitated crystals and possible recrystallization from a suitable solvent.

g) the Pharmaceutical composition having antiviral activity, in particular anti-HIV activity, including the active ingredient, and at least one pharmaceutically acceptable carrier and as the active ingredient it contains a compound according to the invention. The pharmaceutical composition is presented in the form of tablets or capsules. The pharmaceutical composition is suitable for parenteral administration.

The connection according to the invention is particularly useful for the prevention or treatment of HIV infections.

Examples of clinical conditions caused by HIV infections that can be treated in accordance with this invention, include Acquired Immunodeficiency Syndrome (AIDS) or symptoms that often precede AIDS, or related clinical conditions such as AIDS-dependent complex (sacs), progressive generalized lymphadenopathy (PGL), sarcoma of Canossa, thrombocytopenic purpura, AIDS-related neurological conditions such as multiple sclerosis or tropical prepares, as well as anti-AIDS antibody-positive and HIV-positive status, including AIDS asymptomatic patients.

As an additional aspect, d is S, 4R) 4-[2-amino-6-cyclopropylamino)-9H - purine-9-yl]-2-cyclopenten-1-methanol and succinic acid in water, preferably in equimolar amounts in a suitable solvent such as aqueous ethanol or isopropanol. Such solutions conveniently be obtained by boiling under reflux. During cooling to room temperature from the specified solution with a high output falls crystals of the compounds according to the invention. To increase the purity of the product, if required, can be applied, if desired, washing and recrystallization. The connection according to the invention, being in crystalline form, is the possibility for large-scale production through fast and efficient filtering.

Connection in accordance with the invention can be introduced individually or in combination with other therapeutic agents suitable for the treatment of HIV infections, such as nucleoside inhibitors of reverse transcriptase (NRTIs) such as zidovudine, zalcitabine, lamivudine, didanosine, stavudine, 5-chloro-2',3'-dideoxy-3'-tarorigin and (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine, not-NOT s, for example nevirapine and inhibitors-APA, HIV protease such as saquinavir or YX-478, or anti-HIV agents, for example rasterfarian. In addition, the connection according to the invention can be introduced in combination with other therapeutic agents suitable for the treatment of HBV infections, such as lamivudine, (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3 - oxathiolan-5-yl]cytosine, immune modulators and interferon, as described previously. Such combinations can be entered together or alternately provided that any period between the introduction of each therapeutic agent does not diminish their additive action.

While it is possible to enter one compound according to the invention, it is preferable and advantageous to provide a connection according to the invention in the form of a pharmaceutical composition, which represents a further aspect of the present invention. The pharmaceutical composition includes the compound of the invention together with one or more acceptable carriers for him and optionally other therapeutic agents. The carrier (s) may be "acceptable" in the sense of compatibility with other ingredients of the composition and is not harmful to the recipient.

Compounds according to the invention can be introduced by any route appropriate to the condition that should be treated, and appropriate ways include oral, rectal, natalin the first, intramuscular, intravenous, intradermal, intrathecal and epidural). It will be shown that the preferred path may vary, for example, depending on the condition of the recipient.

For each of the above applications and indications of the number of required individual active ingredient will depend on a number of factors, including the severity of the condition to be treated and the identity of the recipient and will ultimately be at the discretion of the attending physician. Usually, however, each of these applications and indications, a suitable effective dose will be in the range from 3 to 120 mg per kilogram of body weight of the recipient per day, preferably in the range from 6 to 90 mg per kilogram of body weight per day and most preferably in the range from 15 to 60 mg per kilogram of body weight per day. This dose may, if desired, be presented as two, three, four or more subdot, administered at appropriate intervals throughout the day.

The formulations include those suitable for oral, rectal, nasal, local (including bucally and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal ü obtained by any of the methods well known pharmacy. Such methods include the stage of linking the active ingredient with the carrier that contains one or more additional ingredients. Typically, the compositions are prepared on a uniform and homogeneous mixture of the active ingredient with liquid carriers or finely powdered solid carriers or both and then, if necessary, shaping the product.

The compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, pills or tablets, each contains a certain amount of the active ingredient; as a powder or granules; as solution or suspension in an aqueous liquid or non-aqueous liquid; or in the form of a liquid emulsion oil-in-water or liquid emulsion, water-in-oil. The active ingredient may also be presented in the form of pills or paste or can be inside liposomes.

The tablet can be manufactured by extrusion or molding, optionally with one or more additional ingredients. Molded tablets may be made by molding in a suitable machine the active ingredient in free-flowing form such as powder hilzoy), the lubricant, inert diluent, disintegrant (for example, sodium glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets can be produced by forming on the appropriate machine powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or uncoated and may be formed so as to provide slow or controlled release its active ingredient, using, for example, hypromellose in different ratios to obtain the desired release profile.

The capsule can be made by filling in loose or pressed powder or appropriate machine optionally one or more additives. Examples of suitable additives include binders such as povidone, gelatin, lubricant, inert diluents, disintegrant as for tablets. You can also make the capsules so that they contain pills or discrete subagency to obtain slow or controlled release of the main ingredient. This can be achieved ex the example, microcrystalline cellulose) plus diluent, such as lactose. Thus obtained spherical particles can be coated with a semi-permeable membrane (e.g., ethylcellulose, Eudragit WE30D) to get the properties of slow release.

When infection of the eye or other external tissues, for example mouth and skin, the formulations are preferably applied in the form of ointment or cream for topical use containing the active ingredient in amounts of, for example, of 0.075 to 20% by weight, preferably from 0.2 to 15% by weight and most preferably from 0.5 to 10% by weight. When cooking in the form of an ointment, the active ingredients can be used with either paraffin or miscible with water ointment base. Alternatively, the active ingredients can be prepared in the form of cream and cream-based oil-in-water or basis as water-in-oil.

If desired, the aqueous phase of the cream base may include, for example, at least 40-45% by weight of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. Local compositions can optionally include a compound that enhances silicula dermal penetration include dimethyl sulfoxide and related analogues.

The oil phase of the emulsions in accordance with this invention may be constituted from known ingredients in a known manner. While this phase may include merely an emulsifier (otherwise known as emulgent), it is desirable to include a mixture of at least one emulsifier with a fat or oil or grease, and oil. Preferably hydrophilic emulsifier include together with a lipophilic emulsifier, which acts as a stabilizer. Preferably also include as oil and grease. Together, the emulsifier (emulsifying agents) together with or without stabilizer (stabilizer) forms a so-called emulsifiable wax, and the wax together with the oil and/or fat to form a so-called basis emulsifiable ointment base which forms the oily dispersed phase of the cream formulations.

Emulsifiers and emulsion stabilizers suitable for use in the composition of the present invention include tween 60, Span 80, cetosteatil alcohol, ministerului alcohol, glycerylmonostearate and sodium lauryl sulfate.

The compound (1S,4R) 4-[2-amino-6-(cyclopropylamino)-9H-yl]- 2-cyclopenten-1-methanol can be synthesized in accordance with EP 0434450 or, alternatively, the PCT application N GB/9500225, which included the.

An example of a

Obtaining a salt of succinic acid (1S,4R) 4-[2-amino-6- (cyclopropylamino)-9H-purine-9-yl]-2-cyclopenten-1-methanol.

A solution of (1S,4R) 4-[2-amino-6-(cyclopropylamino)-9H-purine - 9-yl]-2-cyclopenten-1-methanol (30,93 g is 0.102 mol) in absolute ethanol (96 ml) was added to a solution of succinic acid (Aldrich, 99%, 12,15 g is 0.102 mol) in water (130 ml). The mixture is brought to the boil under reflux, and the resulting solution was treated with charcoal (0.4 g) and filtered through a layer of celite. While slowly cooling the solution to ambient temperature formed pale yellow crystals (38.0 g). This solid was recrystallize from water (500 ml) to obtain succinate (1S,4R) 4-[2-amino-6-(cyclopropylamino)- 9H-purine-9-yl]-2-cyclopenten-1-methanol as a white powder (34,9 g, 80%), so pl. 168-169oC.

1H-NMR (DMSO-d6) : 12,70-11,70 (brm, 2, 2 carboxyl H), a 7.62 (s, 1, purine CH), 7,30 (d, J = 4,1 Hz), 6,10 (m, 1, =CH), 5,90-of 5.75 (m, 3, =CH and NH2), of 5.40 (m, 1, NCH), 5,20-4,50 (dr m, 1, OH), of 3.46 (d, J = 5,9 Hz, 2, OCH2), 3,10 (br m, 1, CH cyclopropyl), 2,85 (br m, 1, CH), 2,70-of 2.50 (m, 1, CH), 2.40 a (s, 4, 2 CH2succinate), 1.70 to 1,50 (m, 1, CH), 0.75 to 0.50 in (m, 4, 2 CH2cyclopropyl).

Analysis. Calculated for C14H18N6O C4H6O4050H2O: C 52,29; H 6,09; N 20,33. Found: C 52,33; H 6,09; N 20, the urin-9-yl]-2 - cyclopenten-1-methanol.

To a suspension of chloropurine (96 kg 1 weight. part) IMSG (10 vol., 7,94 weight. parts), mixed with 15-20oC add cyclopropylamine (1,375 about., 1.13 weight. parts, 6.0 EQ.). The resulting solution is heated at the temperature of reflux distilled and maintain this temperature for four hours until, until the formation of (1S,4R)-CIS-4-[2-amino-6-(cyclopropylamino)- 9H-purine-9-yl] -2-cyclopenten-1-methanol. The mixture was then again cooled to 20oC and add IMSG (5,99 about., 4.76 weight. parts), then add coal (0.104 g weight. parts) and harborlite (0.05 weight. parts). This mixture is heated to 45-50oC and kept at this temperature for 90 minutes.

The reaction mixture is slightly cooled to 40-45oC and lighten passing through a filter press to remove coal and harborlite. If necessary, this whitening can be completed in parts. The filter cake was washed with warm (40-45oC) IMSG (2x2,0., 1,59 weight. parts, 1x1,0., 0,794 weight. parts).

The filtrate and washing was concentrated in vacuo to about 3 vol., add IMSG (pre-heated to 40-45oC, 3,5 about., 2,78 weight. parts) and this portion is re-concentrated in vacuo to about 3 rpm. This portion was diluted with IMSG (pre-heated to 40-45oC, 3,spending heated to 45-55oC and add an aqueous solution of succinic acid (0,469 weight. parts, 1.2 EQ.) in water (8 vol.), pre-heated to 60-65oC, maintaining the temperature of the reaction mixture above the 50oC. the Temperature of the reaction mixture is brought to 65-70oC for complete dissolution, and then slowly cooled down to 50-52oC and add the appropriate seed crystal (0.001 weight. parts). The solution was stirred at 48-52oC as long, until crystallization. The resulting suspension is cooled to 20-25oC for at least 90 minutes, then to 0-5oC for at least 30 minutes and maintained at 0-5oC for at least one hour before collecting the product by filtration.

The resulting pellet washed twice with a mixture of water:IMSG (2x1,6 weight. parts/about water: 2x0,4 vol., 0,32 weight. parts IMSG). The product is dried in vacuum at temperatures up to 45oC.

Output: 105,6 kg, 110% wt./wt., 82.2% of the].

Example: data on the toxicity of salts of succinic acid (1S,4R)-CIS-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl]-2 - cyclopenten-1-methanol.

Studies of short-term toxic effects of single doses of salt of succinic acid (1S,4R)-CIS-4-[2-amino-6-(cyclopropylamino)- mportant granulation of the ingredients with a solution of povidone were obtained the following compounds A, B and C, after which was added magnesium stearate and extruded.

Composition A, mg/tablet:

(a) Active ingredient 250; 250

(b) Lactose C. R. - 210; 26

(c) Povidone C. R. - 15; 9

(d) sodium starch Glycolate - 20; 12

(e) magnesium Stearate - 5; 3

Total: - 500; 300

Composition B, mg/tablet:

(a) Active ingredient 250; 250

(b) Lactose - 150; -

(c) Avicel PH 101 - 60; 26

(d) Povidone C. R. - 15; 9

(e) sodium Glycolate - 20; 12

(f) magnesium Stearate - 5; 3

Total: - 500; 300

Composition C (controlled release)

The composition obtained by wet granulation of the ingredients (see below) with a solution of povidone, after which was added magnesium stearate and extruded.

Composition (mg/tablet:

(a) Active ingredient: 500

(b) Hypromellose (Methocel K4M Premium) - 112

(c) Lactose C. R. - 53

(d) Povidone C. R. C. - 28

(e) magnesium Stearate - 7

Total: - 700

Capsules are produced by dispersing the active ingredient in the lecithin and peanut oil and filling this dispersion of soft gelatin capsules.

Composition C (Capsules controlled release)

The following composition for capsules controlled release prepared by extrusion ingret controlling the release of the membrane (d) and fill them two-part hard gelatin capsule.

Composition mg/capsule

(a) Active ingredient 250

(b) Microcrystalline cellulose - 125

(c) Lactose C. R. - 125

(d) Ethylcellulose - 13

Total: - 513

Example D: composition for injection

Active ingredient - 0,200 g

Sterile, free from pyrogen phosphate buffer (pH 7.0) Up to 10 ml

The active ingredient is dissolved in most parts of phosphate buffer (35-40oC), then brought to volume and filtered through a sterile micropore filter into a sterile amber glass vial of 10 ml, and sterile carefully closed or sealed.

Example E: intramuscular injection

Active ingredient - 0.20 g

Benzyl alcohol 0.10 g

Glucotrol 75 - 1.45 g

Water for injection Up to 3.00 ml

The active ingredient is dissolved in glucotrole. Then add benzyl alcohol and dissolve, and add water to 3 ml of the mixture is Then filtered through a sterile Millipore filter and sealed in sterile glass vessel with a volume of 3 ml (type 1).

Example F: syrupy suspension

Active ingredient - 0,2500 g

The solution of sorbitol - 1,5000 g

Glycerin - 2,0000 g

Capable of dispersing the cellulose - 0,0750 g

Sodium benzoate - 0,0050

Kosovali and add a solution of sorbitol. Add and dispersed active ingredient. Glycerol is dispersed thickening agent (capable of dispersing the cellulose). Both dispersions are mixed and brought to the desired volume of purified water.

Example G: suppository, mg/suppository

Active ingredient (631m) - 250

Hard fat, BP (Witepsol H-15 - Dynamit NoBel) - 1770

Total: - 2020

The active ingredient used in the form of a powder in which at least 90% of the particles have a diameter of 0.63 µm or less. One-fifth of the Witepsol H15 is melted in a Cup with steam-heated walls at 45oC maximum. The active ingredient is sifted through a 200 μm sieve and added to the molten base with mixing, using a Silverson mixer fitted with a cutting head, until you obtain a homogeneous dispersion. Maintaining the mixture at 45oC, is added to the suspension, the remaining Witepsol H15, and stirred to ensure homogeneous mixing. The entire suspension is passed through a stainless steel sieve 2501m and with constant stirring, allowed to cool down to 40oC. At a temperature of from 38oC to 40oC 2,02 g of the mixture are placed in appropriate plastic casting. The suppositories allowed to cool to room temperature.

Example H: Pessaries, mg/pessary is Agnes - 7

Total: - 1000

The above ingredients are mixed directly, and prepare pessaries direct pressing of the resulting mixture.

Example I: the Local drug - cream

Active connection - 5,00 g

Glycerin - 2,00 g

Cetosteatil alcohol to 6.75 g

Sodium dodecyl sulfate - 0.75 g

White soft paraffin - 2.50 g

Liquid paraffin - 5,00 g

Chlorocresol - 0.10 g

Purified water To 100.00 g

The active compound is dissolved in a mixture of purified water and glycerin and heated to 70oC. Heat the remaining ingredients together in the 70oC. Connect the two parts together and emuleret. Cool and fill the containers.

1. Salt of succinic acid (1S, 4R)4-[2-amino-6-(cyclopropylamino)-N-purine-9-yl]-2-cyclopenten-1-methanol.

2. Connection on p. 1, showing antiviral activity, in particular anti-HIV activity.

3. Connection on p. 1 to obtain a pharmaceutical composition suitable for the treatment or prophylaxis of viral infections.

4. A method of obtaining a connection on p. 1, characterized in that mix (1S, 4R)4-[2-amino-6-(cyclopropylamino)-N-purine-9-yl]-2-cyclopenten-1-methanol in a suitable solvent with succinic acid in Bodom loose crystals and possible recrystallization from a suitable solvent.

5. Pharmaceutical composition having antiviral activity, in particular anti-HIV activity, including an active ingredient and at least one pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains a connection on p. 1.

6. The pharmaceutical composition according to p. 5 in the form of tablets or capsules.

7. The pharmaceutical composition according to p. 5, suitable for parenteral administration.

 

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