HK1073841B - Crystalline sodium salt of telmisartan and the use of the same as an angiotensin antagonist - Google Patents

Description

crystalline sodium salt of telmisartan and use thereof as angiotensin antagonist

Technical Field

The invention relates to a crystal sodium salt (Telmisartan for short) of 4' - [ 2-n-propyl-4-methyl-6- (1-methylbenzimidazole-2-yl) benzimidazole 1-ylmethyl ] biphenyl-2-carboxylic acid, a preparation method thereof and application thereof in preparing medicaments.

Background

The compound telmisartan (telmisartan) is described in european patent EP502314B1 and has the following chemical formula:

telmisartan, and physiologically acceptable salts thereof, has valuable pharmacological properties. Telmisartan is an angiotensin antagonist, particularly angiotensin II-antagonist, among which it is useful, due to its pharmacological properties, for example in the treatment of hypertension and cardiac insufficiency, in the treatment of ischemic peripheral blood flow disorders, myocardial ischemia (angina pectoris), in the prevention of the progression of cardiac insufficiency after myocardial infarction, in the treatment of diabetic neuropathy, glaucoma, gastrointestinal diseases and bladder diseases. Other possible medical applications are found in the content of EP502314B1 cited herein.

Telmisartan is available under the trade nameAnd (4) obtaining the product. Starting from the free acid of telmisartan, its commercial formulation is manufactured in a complex spray-drying process. Because of their solubility in free acids, it is difficult to prepare alternatives in a less complex process.

The object of the present invention is to make telmisartan by presenting the active substance in a less complex manner. It must be noted that: the manufacture of compositions comprising pharmaceutically active substances is generally based on various parameters relating to the properties of the active ingredient. Examples of such parameters are, without being limited thereby, the stability of the action of the starting materials under different environmental conditions, the stability during the manufacture of the pharmaceutical formulation and the stability of the final composition of the pharmaceutical formulation. The pharmaceutically active substances used for the preparation of the above pharmaceutical compositions should be purified as much as possible, and the stability in long-term storage must be ensured under various environmental conditions. This is absolutely necessary in order to prevent the pharmaceutical compositions used from containing, in addition to the intrinsic active substance, also their decomposition products. In this case, the active substance content in the manufactured preparation may be less than the specified content.

On the other hand, in solid dosage products it is important that the active substance has the most stable possible crystalline form for pharmaceutical quality. Otherwise, the form of the active substance may change in specific cases under the conditions of manufacture of the formulation. Such variations may in turn affect the reproducibility of the manufacturing process and result in final formulations that do not meet the high quality requirements of pharmaceutical composition formulations. To this end, one should generally remember: any change in the solid state of a pharmaceutical composition that improves its physical and chemical stability, results in a significant benefit for the same drug in a less stable form.

It is therefore an object of the present invention to provide a new stable form of telmisartan which meets the above-mentioned stringent requirements imposed on pharmaceutically active substances.

Detailed description of the invention

Surprisingly, it has been found that telmisartan can be of the formula1In the form of the sodium salt of (a) to obtain the crystal form thereof

By appropriately selecting the production conditions, polymorphic crystalline sodium salts meeting the above requirements can be selectively obtained.

A crystalline sodium salt of telmisartan, characterized by a melting point T ═ 245 + -5 ℃ (measured with a DSC differential scanning calorimeter; heating rate: 10K/min).

The invention therefore relates to crystals of the sodium salt of telmisartan, characterised by a melting point T ═ 245 ± 5 ℃ (determined by DSC). The above values were obtained using a DSC821 manufactured by Messrs Mettler-Toledo.

The crystalline sodium salt of telmisartan of the present invention was studied more closely by spectroscopy. The X-ray powder diffraction pattern obtained is shown in FIG. 1.

The data obtained from the spectral analysis are summarized in table 1 below:

TABLE 1

In the above table, "2 Θ [ ° C [ ° [ ]]The "values represent diffraction angles in degrees,the value represents the value determined inThe represented cell pitch.

According to the data obtained from table 1, the present invention relates to crystalline telmisartan sodium salt characterized by: in the X-ray powder diffraction pattern, it has characteristic valuesAnd

using a detector equipped with SSD (═ site sensitivity) (Cuk)_α-the radiation is emitted from the radiation source,30kV, 40mA), the X-ray powder diffractogram was recorded within the scope of the invention.

The present invention also relates to the crystalline telmisartan sodium salt of the present invention in the form of its solvate and its hydrate, preferably in the form of its hydrate, most preferably in the form of its hemihydrate.

In another aspect, the present invention relates to a process for the manufacture of crystalline telmisartan sodium salt according to the present invention. The starting material for the preparation of crystalline telmisartan sodium salt according to the present invention may be the free acid of telmisartan, which may be prepared by methods known in the art (e.g. according to EP502314 Al).

The crystalline sodium salt of the present invention is prepared by dissolving the free acid of telmisartan in a suitable solvent, preferably an organic aprotic solvent, most preferably an organic, aprotic and non-polar solvent. According to the invention, the solvents used are preferably toluene, chloroform, dichloromethane, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl-tert-butyl ether, acetone, methyl isobutyl ketone, benzene or acetonitrile, toluene, benzene and methyl isobutyl ketone being particularly preferred. According to the invention, toluene is the most important solvent.

The above solvent is preferably used in an amount of 0.5 to 5ml, more preferably 1 to 3ml, most preferably 1.5 to 2.5ml per gram of telmisartan (free acid).

The appropriate sodium salt is then added as a base to the solution or suspension. Suitable sodium salts for use in the scope of the invention include sodium hydroxide, sodium hydride, sodium carbonate, sodium bicarbonate or sodium alkoxide. Sodium alkoxide means the sodium salt formed with a lower alcohol, preferably with an alcohol selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol, isobutanol, n-butanol and tert-pentanol. According to the invention, sodium salts selected from sodium hydroxide, sodium hydride, sodium ethoxide and sodium methoxide; of these, sodium hydroxide and sodium methoxide are particularly important according to the invention. The above sodium salt may be added as a solid to the reaction mixture. However, in the case of sodium hydroxide, it is preferably added in the form of an aqueous solution. In particular, concentrated aqueous solutions of sodium hydroxide are preferably used. For example, a sodium hydroxide solution having a concentration of about 45% by weight may be used.

The amount of sodium salt used will, of course, depend on the amount of telmisartan free acid used. According to the present invention, at least 1 mole of the sodium salt must be added per mole of telmisartan. According to the invention, an excess of sodium salt may also be added. Preferably 1 to 2.5, more preferably 1 to 2, most preferably 1 to 1.5 moles of the sodium salt are added per mole of the free acid telmisartan used.

If sodium hydroxide is used as the sodium salt, it is advantageous according to a preferred embodiment of the process of the invention to add it as an aqueous solution, if appropriate with the addition of an organic solvent which can be mixed with water. These solvents are preferably selected from the group consisting of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, tert-butanol, 2-butanol, ethylene glycol, ethyl diglycol, 1, 3-butanediol, 1, 4-butanediol, tert-amyl alcohol, acetonitrile, nitromethane, formamide, dimethylformamide, N-methylpyrrolidinone, dimethyl sulfoxide, dimethylacetamide, nitroethane and methoxy-2-propanol, of which the abovementioned alcohols are of particular importance. In the context of the process according to the invention, particular preference is given to using methanol or ethanol, most preferably ethanol. According to the present invention, the solvent used per mole of telmisartan used is preferably 50 to 500ml, more preferably 100 to 400ml, most preferably 200 to 350 ml.

The reaction mixture can then be heated to accelerate the progress of the reaction. The reaction mixture is preferably heated to a temperature greater than 40 c, most preferably greater than 60 c, with thorough mixing. The maximum temperature that can be selected will of course depend on the boiling point of the solvent used. According to the invention, if the preferred solvents described herein above are used, the mixture is preferably heated to above 70 ℃. The heating time is generally 15 minutes to 2 hours, preferably 20 minutes to 1 hour. The resulting solution is then filtered and any solids remaining on the filter are washed with one or more of the solvents described above.

The filtrate obtained in the above process is added slowly, preferably dropwise, to the organic solvent which has been heated to a temperature of more than 40 c, preferably more than 60 c, most preferably to its boiling point. The solvent used is preferably an organic aprotic solvent, more preferably an organic, aprotic and apolar solvent. The solvents which can be used according to the invention are most preferably toluene, chloroform, dichloromethane, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl-tert-butyl ether, acetone, methyl isobutyl ketone, benzene or acetonitrile, of which toluene, benzene and methyl isobutyl ketone are particularly preferred. The solvent toluene is particularly important according to the invention. Meanwhile, in a preferred embodiment of the present invention, since the filtrate is added to a hot solvent, a part of the solvent is distilled off (optionally azeotropically). After all the filtrate is added, more solvent (e.g., about one-third to two-thirds of the total amount of solvent added at this stage) is optionally removed by distillation.

The concentrated solution thus obtained is cooled, preferably to room temperature, whereupon the sodium salt of telmisartan crystallizes out. After completion of the crystallization, the crystals are isolated, optionally washed with the above-mentioned organic solvents and finally dried.

In another specific embodiment of the present invention, according to the present inventionThe crystalline telmisartan sodium salt may be represented by the formula2The acid addition salt of (a) is prepared,

wherein H-X represents an acid selected from one of hydrochloric acid, hydrobromic acid, toluenesulfonic acid or methanesulfonic acid. In-situ type2Of the above acid addition salts, H-X represents a salt of hydrochloric acid is particularly important. The acid addition salt is hereinafter referred to as telmisartan hydrochloride.

Formula (II)2The compounds of (A) can also be prepared from 4' - [ [ 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl ] as known in the prior art]-methyl radical]Biphenyl-2-carboxylic acid tert-butyl ester (tert-butyl ester of telmisartan) was prepared by saponification in acetic acid in the presence of acid H — X.

To be composed of2Starting with an acid addition salt of (a) to prepare a compound of formula (b) according to the invention1The crystalline telmisartan sodium salt of (1), according to the present invention, the following procedure can be used.

Formula (II)2Is dissolved in a suitable solvent and combined with a suitable sodium salt.

The solvent may be water and/or a suitable alcohol such as methanol, ethanol or isopropanol, mixed with an aprotic organic solvent selected from toluene, chloroform, dichloromethane, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl-tert-butyl ether, acetone, methyl isobutyl ketone, benzene or acetonitrile. As the solvent, particularly preferably used is water mixed with ethanol or isopropanol mixed with an aprotic organic solvent selected from toluene, benzene and methyl isobutyl ketone, most preferably toluene. Mixtures of water, isopropanol and toluene have proven particularly suitable for this synthesis step.

The amount of solvent or solvent mixture used depends on the acid addition salt used2The amount of (c). Preferably per mole of compound used2About 0.3-3.5L, preferably about 1-2.5L, more preferably about 1.5-2L of the above-mentioned are usedA solvent or a mixture of solvents. If the solvent used is a preferred solvent mixture according to the invention which, in addition to water and aprotic organic solvent, also comprises an alcohol as third solvent component, the volume ratio of water to aprotic organic solvent according to the invention is preferably between 1:5 and 1:50, and the ratio of water to alcohol used is in the range from 2:1 to 1: 40. Preferably, the ratio of water to aprotic organic solvent in the solvent mixture is in the range of 1:10 to 1:30, more preferably between 1:15 and 1:25, and the ratio of water to alcohol used is between 1:1 and 1:20, preferably from 1:5 to 1: 15.

Preferably for each mole2The above solvent or solvent mixture contains about 10 to 100ml of water, preferably about 30 to 80ml of water, most preferably about 40 to 70ml of water. Preferably for each mole2The solvent or solvent mixture used also contains about 100 to 1000ml of alcohol, preferably about 300 to 800ml of alcohol, most preferably about 400 to 700ml of alcohol. Finally, per mole2The solvent or solvent mixture used preferably comprises as third component a solvent, from about 200 to 2000ml of the above-mentioned aprotic organic solvent, preferably from about 600 to 1600ml, most preferably from about 800 to 1400ml of the above-mentioned aprotic organic solvent.

For reaction2To1Suitable sodium salts of (a) include sodium hydroxide, sodium hydride, sodium carbonate, sodium bicarbonate or sodium alkoxide. The sodium alkoxide is a sodium salt formed with a lower alcohol, preferably an alcohol selected from methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol, isobutanol, n-butanol and tert-pentanol. Particularly advantageous sodium salts according to the invention are selected from sodium hydroxide, sodium hydride, sodium ethoxide and sodium methoxide, while sodium ethoxide and sodium methoxide, especially sodium methoxide, of the sodium alkoxide in the reaction step according to the invention are of particular importance. The above sodium salt may be added to the reaction mixture as a solid. However, in the case of sodium methoxide, it is preferably added as a methanol solution. Most preferred is a methanol solution containing sodium methoxide at a concentration of at least 10%, most preferably about 20-40% (w/w). For example, the methanol solution of sodium methoxide used may have a concentration of about 30 wt%.

The amount of sodium salt used naturally depends on the amount of telmisartan free acid used. According to the invention, per mole of the formula used2Telmisartan acid addition salt, at least 2 moles of the sodium salt must be added. According to the invention, an excess of sodium salt can also be added.

If necessary, it is useful to add activated carbon to the above reaction mixture. For example, per mole of the compound used2The activated carbon may be added in an amount of about 5 to 50g, preferably, per mole used2The amount of the additive is about 10-40 g.

After addition of the sodium salt and optional activated carbon, the resulting reaction mixture is heated to a temperature of about 50-100 deg.C, preferably about 60-90 deg.C, most preferably about 70-80 deg.C for a time period of about 10 minutes to 2 hours, preferably about 20-45 minutes. During the heating, part of the solvent, preferably about 10-50%, most preferably about 20-40% of the total solvent amount, will be distilled off.

The remaining suspension is filtered and the residue on the filter is optionally washed with one of the above-mentioned aprotic organic solvents, preferably the aprotic organic solvent used in the reaction.

The filtrate obtained is diluted with a solvent or solvent mixture. The dilution is preferably carried out using a mixture of water and the above-mentioned aprotic organic solvent. Preferably, this time per mole of the compound originally used2About 10 to 100ml of water are used, preferably about 30 to 80ml of water, most preferably about 40 to 70ml of water. Per mole of the compound used2250 to 3000ml of aprotic organic solvent are used, preferably about 800 to 2000ml, most preferably about 1200 to 1800 ml.

After dilution, the resulting mixture was refluxed. Per mole of the compound used2About 1-2 liters, preferably about 1200 to 1800ml of solvent is evaporated. After evaporation of the solvent, telmisartan sodium salt according to the invention1And (4) crystallizing and precipitating. The crystals obtained are isolated, optionally washed with one of the aprotic organic solvents mentioned above and finally dried.

In another aspect of the present invention, crystalline telmisartan sodium salt, optionally in the form of a solvate or in the form of a hydrate thereof, preferably in the form of a hydrate thereof, most preferably in the form of a hemihydrate thereof, is obtainable by the above process.

Due to the formula2As a valuable starting material for the direct synthesis of the telmisartan sodium salt of the present invention1And are of great significance, another aspect of the invention relates to2The compounds themselves are, in particular,

wherein H-X represents an acid selected from one of hydrochloric acid, hydrobromic acid, toluenesulfonic acid or methanesulfonic acid. Wherein H-X represents hydrogen chloride2The compound telmisartan hydrochloride is particularly preferred.

Most preferably, the invention also relates to crystals of the above formula2The compound of (1).

Furthermore, due to the pharmaceutical activity of the crystalline telmisartan sodium salt of the present invention, the present invention also relates to its use as a pharmaceutical composition.

In another aspect, the present invention relates to the use of the crystalline telmisartan sodium salt according to the present invention for the preparation of a pharmaceutical composition, in particular for the preparation of a pharmaceutical composition for the prevention or treatment of a disease, wherein administration of a therapeutically effective dose of one or more angiotensin-II-antagonists provides therapeutic effectiveness, due to the pharmaceutical activity of the crystalline telmisartan sodium salt according to the present invention. Preferably, the present invention relates to the use of crystalline telmisartan sodium salt for the preparation of a pharmaceutical composition for the prevention or treatment of a disease selected from hypertension, cardiac insufficiency, ischemic peripheral circulatory disorder, myocardial ischemia (angina pectoris), progression of cardiac insufficiency after myocardial infarction, diabetic neuropathy, glaucoma, gastrointestinal diseases and bladder diseases, particularly preferably for the prevention or treatment of hypertension.

Thus, in another aspect, the object of the present invention are pharmaceutical formulations characterized in that they comprise crystalline telmisartan sodium salt.

The following synthesis examples, which are presented by way of example to illustrate the process for preparing crystalline telmisartan sodium salt. The possible steps are provided by way of example only, without limiting the content of the invention.

Synthesis example 1: starting from telmisartan, crystalline telmisartan sodium salt is prepared:

the starting material for the preparation of the crystalline telmisartan sodium salt according to the present invention may be the free acid of telmisartan, which may be obtained according to methods known in the art (e.g. according to EP502314 Al).

In a suitable reaction vessel 154.4g of telmisartan are placed in 308.8ml of toluene, the suspension is combined with 27.8g of 44.68% sodium hydroxide solution and 84.9ml of ethanol, heated at 78 ℃ for about 30 minutes and the mixture is filtered. Optionally, if a significant amount of solids remain on the filter, it can be washed with a mixture of 61.8ml of toluene and 15.3ml of ethanol.

463.2ml of toluene were placed in a separate reaction vessel and refluxed. The filtrate obtained in the above-described manner is slowly added dropwise at the boiling temperature and simultaneously distilled off azeotropically. After all addition, the solution obtained by washing the filter was also added and again azeotropically distilled off. The mixture was distilled to 103 ℃ and the suspension was allowed to cool to room temperature. The crystals were filtered off with suction, washed with 154.4ml of toluene and dried in a circulating air drying cabinet at 60 ℃.

Yield: 154.6g (96%) of colorless crystals:

C₃₃H₂₉N₄O₂Na×0，5H₂calculated value of O: C72.51H 5.72N 10.25

Experimental values: C72.57H 5.69N 10.21

Synthesis example 2: preparation of crystalline telmisartan sodium salt starting from telmisartan hydrochloride:

A) preparing telmisartan hydrochloride:

411g of tert-butyl 4' - [ [ 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl ] -methyl ] biphenyl-2-carboxylate were suspended in 822ml of glacial acetic acid and mixed with 213g of concentrated hydrochloric acid (37%). The mixture was heated to reflux and about 640ml of solvent was distilled off. The residue which remains is slowly mixed with about 620ml of water at 50-60 ℃. To this mixture was added 20g of activated carbon (e.g. Norit SX2Ultra) and the resulting mixture was stirred at constant temperature for about 10 minutes. After filtration, the residue was washed 3 times with 25ml of glacial acetic acid and about 620ml of water. The resulting filtrate was heated to about 50-60 c and about 2 liters of water was added. After stirring at about 23 ℃ for about 12 hours, the crystals formed are filtered off with suction and washed 2 times with about 500ml of water and 1 time with about 900ml of acetone and then dried at about 60 ℃.

Yield: 367g (92.5%), colorless crystals, melting point: 278 deg.C

B) Preparing crystal telmisartan sodium salt from telmisartan hydrochloride:

55.1g telmisartan hydrochloride is dissolved in 110.2ml toluene, 5.5ml water and 55.1ml isopropanol, the mixture is mixed with 36.9g sodium methoxide (30% in methanol) and 2.75g activated carbon (e.g. Sorit SX2Ultra), then the mixture is heated to about 75 ℃ and about 50ml of the solvent mixture is distilled off over a period of about 30 minutes at constant temperature. The resulting suspension was filtered and the residue was washed with about 20ml of toluene. The filtrate was mixed with about 5ml of water and about 150ml of toluene. The resulting mixture was refluxed. During this period about 150ml of the solvent mixture distilled off azeotropically (at up to 102 ℃). The mixture was allowed to crystallize at 100 ℃ for 1 hour. The crystals are filtered off with suction, washed with about 50ml of toluene and dried at about 60 ℃.

Yield: 53.6g (99%) of colorless crystals;

C₃₃H₂₉N₄O₂Na·0.5H₂calculated value of O: c72.5l H5.72N 10.25

Experimental values: C72.44H 5.68N 10.20

For the preparation of pharmaceutical compositions containing the active substance, in particular for oral administration, most preferably tablets, the processes known in the art can be used.

Suitable tablets may be made, for example, by mixing the active substance with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrating agents, such as corn starch or alginic acid, binding agents, such as starch or gelatin, lubricating agents, such as magnesium stearate or talc, and/or delayed release agents, such as carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablet may also be composed of multiple layers.

The following are some examples of pharmaceutical formulations used in accordance with the present invention. They are purely by way of example and do not therefore limit the subject of the invention.

Tablet 1:

tablet 2:

tablet 3:

Claims (8)

1. Formula (II)1The crystalline telmisartan sodium salt or a hydrate thereof of (1),

the melting point T is 245 +/-5 ℃; has characteristic value in X-ray powder diffraction patternAnd

2. a crystalline telmisartan sodium salt or a hydrate thereof according to claim 1, characterized in that it is present in the form of a hemihydrate.

3. A process for the preparation of crystalline telmisartan sodium salt or hydrate thereof according to claim 1 or 2, characterized in that the free acid of telmisartan is dissolved in a suitable solvent and the solution is then mixed with a suitable sodium salt, wherein at least 1 mole of sodium salt is added per mole of telmisartan, the reaction mixture is heated for 15 minutes to 2 hours, the resulting solution is filtered, the resulting filtrate is slowly added to an organic solvent heated to more than 40 ℃, when the above filtrate is added, part of the solvent is optionally distilled off, the resulting concentrated solution is cooled, and the crystalline telmisartan sodium salt can be isolated, optionally washed with the above organic solvent and dried.

4. A process for the preparation of crystalline telmisartan sodium salt or hydrate thereof according to claim 1 or 2, characterized in that a compound of formula (la) wherein H-X represents an acid selected from hydrochloric acid, hydrobromic acid, toluenesulfonic acid or methanesulfonic acid is added2The acid addition salts are dissolved in a suitable solvent,

and with the appropriate sodium salt, per mole of compound used2At least 2 moles of the sodium salt are used.

5. Use of the crystalline telmisartan sodium salt or hydrate thereof according to one of claims 1 to 2 for the preparation of a pharmaceutical composition.

6. Pharmaceutical formulations, characterized in that they comprise the crystalline telmisartan sodium salt according to one of claims 1 to 2 or a hydrate thereof.

7. Formula (II)2A compound which is a mixture of a compound having a structure,

wherein H-X represents an acid selected from the group consisting of toluenesulfonic acid and methanesulfonic acid.

8. A compound according to claim 7, characterized in that it is present in crystalline form.