The physical form of (r)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4 - triftoratsetatov)indole-3-ylmethyl]-n-(2 - methylphenylsulfonyl)benzamide, its preparation, pharmaceutical composition having the properties of leukotriene antagonist

 

(57) Abstract:

The physical form of the compound (R)-3-methoxy-4-[1-methyl-5- (2-methyl-4,4,4-triftoratsetatov) indole-3-ylmethyl] -N- (2-methylphenylsulfonyl) benzamide, essentially free of other physical forms, which is crystalline and has a powder x-rays with characteristic peaks at 2=14,0, 19,4, 22,0, 22,4 and 24.7othe methods for obtaining this form and pharmaceutical compositions containing it. The connection is a means for counteracting the leukotrienes, which can be used for the treatment of diseases such as, for example, asthma. 3 S. p. f-crystals, 1 table. 2 Il.

The invention relates to new pharmaceutical substances,in particular the new physical forms derived carbamoyl, its preparation and pharmaceutical compositions containing it.

In European patent application N 432984 A2 discloses compounds (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-triftoratsetatov)indole - 3-ylmethyl] -N-(2-methyl-phenylsulfonyl)-benzamide (hereinafter will be called a connection), the means of obtaining it, and pharmaceutical compositions containing it. It is reported that this compound is an antagonist pharmacological activity of one or more metabolites atorie called leukotrienes, for example, it can be used for treatment of allergic or inflammatory diseases, endotoxic or traumatic shock.

Examples 2 and 3, presented in European patent application N 432984, describe how to obtain this compound. In the example 2 compound in the form of a white solid substance was obtained by precipitation from aqueous solution of hydrochloric acid. In example 3, the compound in the form of white crystalline solid was obtained by crystallization from a mixture of ethanol and acetone.

The products obtained in the two examples was subjected to x-ray analysis. This analysis showed that both products have different physical forms of connection. In particular, the product of example 2 (hereinafter will be called form A) is amorphous. Its x-ray spectrum has no distinguishable peaks. However, the product of example 3 (hereinafter will be called form B) is crystalline. Its x-ray spectrum has distinct peaks at 2 to 13.4 and 17.6o.

Both these forms were investigated because of their ease of obtaining and suitability for use as pharmaceuticals. It was found that the shape And essentially free of other physical forms, it is difficult polugodii do it from chemically pure source connection. It is found that the form, essentially free of other physical forms, it is easier to get than form A. However, it is revealed that she is morphologically unstable when it is subjected to shear effort, for example, when grinding in a ball mill. Also the form In at 110oC turns into another crystalline form of compound (form C). This form has a melting point of about 142oC, and consider that it is a physical form that becomes the connection, when determining the melting point of the product of example 3. The ease with which interconversion of forms b and C, complicates the analysis of their pharmological purity, which is an important procedure for quality control during the manufacture of the pharmaceutical product.

At present, it was found that this compound may have another shape.

Accordingly, according to the invention, was obtained a new physical form of (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4 - triftoratsetatov)-indole-3-ylmethyl] -N-(2-methyl-phenyl-sulfonyl) benzamide, essentially free of other physical forms, this form is crystalline and has a powder rentgenogrammetry peaks at 3390, 1620, 1250, 1250 and 885 cm-1.

A new physical form (hereinafter referred to as form D) can be easily obtained essentially free of other physical forms, and has a much better morphological stability than any of the forms a or B.

When in this description is the link to the form D, essentially free of other physical forms, it mostly means that at least 90 wt. compounds present in this physical form, more preferably at least 95%, for example, 96, 97, or 98%

In this description of the spectra of x-ray powder were determined with the use of the sample material, installed in a standard holder Philips with deep stuffing in the scan range of 4-40o2 2 and a countdown 4 point intervals of 0.02oto get the record distance depending on the intensity and radiation for this range. An example of the spectrum of x-ray diffraction on the powder to form D is shown in Fig.1.

Infrared spectra were determined using a 0.5% dispersion of the sample material on the disk of bromide of potassium in the wave number range 4000-400 cm-1. An example of an infrared spectrum of form D will be detected, what form D has an endothermic maximum, determined by differential scanning calorimetry (heating rate of 10oC/min) at temperatures above 180oC, for example 189oC.

In accordance with another characteristic of the invention, a method for obtaining the shape of D connections, essentially free of other physical forms, which is the formation of crystals from a solution of the compound in a solvent selected from methanol, propanol, isopropanol, ethyl acetate, acetonitrile and dimethoxyethane. Found that methanol provides a particularly good yield crystals with high purity and therefore it is preferred.

Usually the solution is prepared by dissolving the source compound in the solvent, heating with irrigation, reduce the amount of solvent by evaporation and then cooling the mixture. For example, when the solvent is methanol, the compound is usually dissolved at a concentration of 1 kg/15-25 liters of solvent, then the volume of solvent is reduced to obtain a concentration of 1 kg/8-12 liters of solvent and the resulting mixture is cooled to room temperature.

As indicated, the compound has properties reaction to the yen according to the method described in the aforementioned European patent application N 432984, were analyzed binding of receptor-ligand and the test aerosol in Guinea pigs. The results showed that the shape of D gives the value of pKi (the result of the analysis of binding) is equal to approximately 9.4 and the value of the ED50about 1.1 µmol/kg

Thus, it counteracts the effect of one or more metabolites of arachidonic acid, known as leukotrienes, for example, WITH4, D4and/or E4that are known to be strong spasmogens, causing cramps (especially in the lungs), increasing vascular permeability, and contribute to the development of diseases such as, for example, asthma, and inflammatory processes (see j. L. Marx, science, 1982, 215, 1380-1383) and endotoxin shock (see j. A. cook and others, journal of Pharmacol, Exp. Ther. 1985, 235, 470) and traumatic shock (n Denzlinger and others. "Science, 1985, 230, 330). Thus, this connection can be used to treat diseases caused by leukotrienes, and those that require counteract their effect. Such diseases include, for example, allergic lung disorders such as asthma, hay fever and allergic rhinitis, and certain vospitatel zabolevania and endotoxine and traumatic shock.

Form D connection can be assigned separately, for example by inhalation in the form of fine powder or in the form of a pharmaceutical preparation.

According to another characteristic of the invention, a pharmaceutical composition, which contains a form D of compound essentially free of other physical forms, and pharmaceutically acceptable carrier.

The pharmaceutical preparation can be prepared in the usual way, and it can be usually in the form of tablets, capsules or suspensions for oral administration; in the form of suspensions for inhalation using a nebulizer or atomizer with metered dose; and in powder form together with a pharmaceutically acceptable inert solid diluents, for example lactose, for reception via inhalation.

Form D can also be used as an intermediate product for the preparation of pharmaceutically acceptable solution of the compound, if required composition in the form of a solution.

Dose form D, assigned to the patient will depend on the weight of the patient and severity of the disease requiring treatment, and route of administration of drugs. For reception via inhalation dose aerosol will typically contain from 0.01 to 2.0 mg of form D, predpochtite the daily dose for a patient weighing 70 kg would be 0.01 to 16 mg, preferably of 0.02-4 mg For oral administration can use a tablet or capsule containing 250 mg (e.g., 5-100 mg) form D. a Typical daily dose prescribed inside, will be from 0.01 to 25 mg/kg (for example, 0.1 to 5 mg/kg).

The following examples illustrate the invention.

Example 1. A solution of the compound prepared by dissolving forms In (2,02 kg) in methanol (40 l) at 60oC. Then the solution is cooled to 50oC, filtered and again heated to remove 20 l of methanol by distillation. The resulting solution was cooled to 55oC and kept at this temperature for 1 h, again cooled to 20oC and then kept at this temperature for 1 h the mixture was filtered and the crystalline solid material on the filter is washed twice with methanol (11,5 l, 11,0 l). Then the product is dried under vacuum on the filter and dried under vacuum dryer at 50oC to obtain 1,555 kg form D connection.

As stated, the form can be obtained by the method described in example 3 of European patent application N432984. Description of the final stage of this method is presented below.

In a mixture of 4-(5-carboxy-1-methylindol-3-yl-methyl)-3-methoxy-N- (2-methylphenylsulfonyl) benzamide (103,5 g) is not surpassed their nitrobenzophenone) (2.0 l), which is stirred for 2 h, add (R)-2-methyl-4,4,4-craftorsullenart (42.6 g); and the reaction mixture was stirred overnight (about 18 hours, incomplete reaction), then heated for 2 h (complete reaction) for irrigation. The cooled reaction mixture is diluted with ethyl acetate (2 l), washed with 1N hydrochloric acid (twice) and brine, dried (MgSO4) and evaporated. The remainder (138,6 g) is combined with the crude product from such processes (28,0 g) and purified by chromatography with instant evaporation, extracted with methylene chloride; ethyl acetate (series 1:0, 9:1 and 3:1), obtaining a solid substance that is converted into a powder with a simple double-ether, obtaining the crude (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4 - triftoratsetatov)-indole-3-ylmethyl]-N-(2-methylphenylsulfonyl) benzamid (to 135.2), which will recrystallized from ethanol (1.2 l) and acetone (0.3 l) (concentrated by boiling to about 0.9 liters and cooled) and dried under vacuum to obtain the forms In (117,1 g, 65% recovery) as a white crystalline solid; melting point 141,5-143,5oC; nuclear magnetic resonance, NMR (300 MHz,DMSO-d6):a 1.01 (d, 3H, CH3), of 2.0-2.2 (m, 2H, CF3CH2), of 2.3-2.5 (m, 1H, CH of CH3), 2,61 (S, 3H, Ar-CH3

Analysis for C31H32F3N3O5S;

Calculated C 60,48; H 5,24;N 6, 83

Found, C 60,47; H 5,27;N 6,67

Example 2. In the flask is charged with compound (100.0 g) in amorphous form (Form a) and methanol (2000 ml) and begin purging with nitrogen. The mixture is then heated to irrigation and incubated for 30 min or until a clear solution. After that, the solution is cooled to a temperature in the range of 50-55oC and the nitrogen purge is stopped. Then the solution was filtered into another flask and began purging with nitrogen. The filtered solution is heated to irrigation and incubated under irrigation for 10 min to ensure complete dissolution. Then 1000 ml of distilled methanol. The rest of the solution allow to cool to ambient temperature and was incubated for 1 h at 15-20oC. the Crystalline product consisting of form D, filtered, washed with methanol (100 ml) and dried in a dryer at 55oC under vacuum. Found that this method provides an output form D approximately 90%

Comparative example 1. Using a mortar with a pestle, crush 0.5 g form within 5 min. melting point of the obtained solid substance was 119-129oC that the character is still present some form C. 0.5 g of the form D was ground for 5 min in a mortar with a pestle. The melting point of the obtained solid substance was equal to 180-183oC and it was observed that did not happen any morphological changes.

Example 3. Recipe of the form D can be, for example, as follows:

(i) Tablet 1 mg tablet

Form D 100,0

Lactose 77,5

Polyvinylpyrrolidone 15,0

Croscarmellose sodium 12,0

Microcrystalline cellulose 92,5

Magnesium stearate 3,0 300,0

(ii) Tablet 2 mg tablet

Form D 20,0

Microcrystalline cellulose 410,0

Starch 50,0

Ether of glycolic acid sodium starch 15,0

Magnesium stearate 5,0 500,0

Tablet 3 mg tablet

Form D 20,0

Microcrystalline cellulose 100,0

Lactose 360,0

Ether of glycolic acid sodium starch 15,0

Magnesium stearate 5,0 500,0

(iv) Aerosol mg/balloon

Form D 20,0

Oleic acid 10,0

Trichloronitromethane 5000,0

DICHLORODIFLUOROMETHANE 10000,0

Dichlorotetrafluoroethane 5000,0

The prescription capsules in the table.2 1. LiOH/H2O

2. (COCl)2< / BR>
3. (4R, 5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone.

4. Sodium bis (trimethylsilane), IU is at, concentrate HCl.

Key

WSDCl Hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

DMAP dimethylaminopyridine

THF Tetrahydrofuran

1. Physical form ( -3-methoxy-4-[1-methyl-5-(2-methyl-4, 4, 4-triftoratsetatov)indole-3-ylmethyl] -N-(2-methylphenylsulfonyl)benzamide, essentially free of other physical forms, which is crystalline and has a powder x-rays with characteristic peaks at 2 = 14,0; 19,4; 22,0; 22,4 and 24.7oand infra-red spectrum (0.5% in RBr) with characteristic peaks at 3390, 1620, 1250 and 885 cm-1.

2. The method of obtaining physical form-3-methoxy-4-[1-methyl-5-(2-methyl-4, 4,4-triftoratsetatov)indole-3-ylmethyl] -N-(2-methylphenylsulfonyl)benzamide under item 1, characterized in that the-3-methoxy-4-[1-methyl-5-(2-methyl-4, 4, 4-triftoratsetatov)indole-3-ylmethyl] -N-(2-methylphenylsulfonyl) benzamide dissolved in methanol under conditions of reflux distilled at a concentration of 1 kg/15 25 l of methanol, followed by reduction of the solvent to obtain a concentration of 1 kg / 8 12 l of methanol and cooled to room temperature.

3. Pharmaceutical composition having the properties of leukotriene antagonist containing-3-methoxy-4-[1-methyl-5-(2-methyl-4, 4, 4-triptorelin the jaś fact, that contains the specified connection in the effective number of in physical form described in paragraph (1 free of other forms, which is a crystal having a powder x-rays with characteristic peaks 2 = 14,0; 19,4; 22,0; 22,4 and 24.7oand infra-red spectrum (0.5% in RBr) with characteristic peaks at 3390, 1620, 1250 and 885 cm-1.

 

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