Vitreous form 8-[3-[n-[(e)-3-(6-acetamidophenyl-3-yl) agrilogic]-n-methylamino]-2,6 - dichloraniline]-2 - methylinosine, its preparation and pharmaceutical composition

 

The invention relates to a vitreous form 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic] -N-methylamino] -2,6-dichloraniline] -2-methylinosine, how you can get it by heating the crystalline modification a or a mixture of crystalline modification a and crystalline modification of hydrate 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic]-N-methylamino] -2,6-dichloraniline] -2-methylinosine at a temperature below its melting point and then cooled. Also described pharmaceutical composition. This vitreous form has good solubility and, therefore, useful to obtain drugs used in the treatment of diseases mediated by bradykinin. 6 C. and 2 h.p. f-crystals, 6 ill., table 1.

The invention relates to a vitreous form 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic] -N-methylamino] -2,6-dichloraniline] -2-methylinosine (hereinafter in the description indicated FR173657) and to pharmaceutical compositions containing it.

Background of the invention FR173657 is a compound of formula (I) described in Japanese patent laying 2780/1995 or in the publication Journal of Medicinal Chemistry, 1998, Vol. 41, 21, 4062-4079:

FR173657 has excellent activity as an antagonist of bradykinin. However, FR173657 described in the aforementioned patent layout, is in amorphous form, as obtained by curing the solvent. This amorphous form has a melting temperature, widely varying in the range from 133 to 139oWith, and its stability in solid form is very bad. Thus, the problem is that it is difficult to manufacture and supply the products of such quality that they are stable enough for use as pharmaceuticals.

For FR173657 characteristic crystallographic polymorphism, and were obtained crystalline high purity with good stability in the solid state and easy to get drugs, with a more preferred three crystalline modifications, designated as crystalline modification A, crystal modification and crystalline modification of (Japanese patent laying 316677/1998). However, despite the good stability in the solid state and the ability to release, poser modification, that makes it impossible for her to obtain stable quality. Crystalline modification is the most stable, and there is no problem with its reception, but the difficulty of implementing this form is that its ability to escape significantly below capacity release crystalline modification A. Crystalline modification With also problematic in that its stability in the solid state below the stability of the crystalline modification and In its ability to release below the ability to release the crystalline modification A. Therefore, more research is needed to explore other more stable forms of FR173657 for drugs.

On this basis, there was a thorough study of FR173657 and the resulting vitreous form of FR173657 high purity with good stability in the solid state, good solubility, good ability to release that can be obtained with stable quality, and this is the subject of this invention.

Fig.1: Infrared absorption spectrum of the vitreous form of FR173657.

Fig. 2: Profile of differential scanning calorimetry (DSC) of the vitreous form of FR173657.

Krasny absorption spectrum of the hydrated FR173657 (crystalline modification B).

Fig. 5: Infrared absorption spectrum of the hydrated FR173657 (crystalline modification C).

Fig.6: Results of determination of solubility of Example 8.

Description of the invention, the Term "vitreous form" refers to a solid amorphous substance that is found in the vitreous state and which is obtained by cooling a liquid substance in the molten state without crystallization. In this description for simplicity, other solid amorphous substances that are not in a glassy state, referred to as "amorphous form".

Vitreous form of FR173657 has the following properties:

Measuring conditions: infrared absorption spectrum: received in accordance with the method Nuala (Nujol), differential scanning calorimetry (DSC): the heating rate of 10oC/min,

Physico-chemical properties of the vitreous form of FR173657: (a) specific peaks in the infrared absorption spectrum: 1684, 1662, 1524, 1236 and 836 cm-1(infrared absorption spectrum shown in Fig.1); (b) differential scanning calorimetry (DSC): endothermic peak due to the transition, is shown in the field from 115 to 122oWith the top in the field from 126 to 128o(Profile differential scanning kavanian amorphous form, crystalline form or a mixture of amorphous and crystalline forms of FR173657 or their solvate [i.e., hydrate, ethanolate etc. ] at temperatures below their melting temperature and then cooled in the molten state.

The melting temperature varies depending on the state of FR173657 or MES, which can be processed (depending on whether it is amorphous or crystalline, or on the ratio of components in the mixtures thereof), but any temperature at which melts the original connection FR173657 or MES, suitable for this method. Usually the original connection FR173657 or MES melts in the range of from about 130 to 220oC.

The method of heating the starting compound FR173657 or MES to a temperature not lower than the melting temperature is not specifically limited. For example, the original connection FR173657 or MES is fed into the container while cooling, at room temperature or under heating and then heated to a temperature not lower than the melting temperature to obtain a melt, or it is served in a container, heated to a temperature close to its melting point or higher to obtain a melt. After melting so it may not be the 0 minutes and then subjected to cooling.

The cooling method is not specifically limited. Usually simply removed the heating system for spontaneous cooling.

The obtained vitreous form of FR173657 can be ground or reduced mechanically to obtain pharmaceutical preparations.

The original connection FR173657 or MES can be amorphous, crystalline, or mixtures thereof. Crystalline MES FR173657 can be obtained by any convenient means, for example by a method comprising mixing FR173657 in the solvent by heating and subsequent cooling to obtain a crystalline precipitate; a method comprising dissolving FR173657 in the solvent in an acid medium, followed by adding a base and optionally in water or aqueous solvent to neutralize obtaining a crystalline precipitate; the method including maintaining crystal FR173657 on the water steam or vapor of an organic solvent; a method including any of these methods in various combinations, etc., in which connection FR173657 can be obtained in amorphous form in accordance with the known method, for example, described in Japanese patent laying 2780/1995.

The solvent used for deposition Krista is opravy alcohol and so on, acetone, N,N-dimethylformamide, dioxane, tetrahydrofuran, ethyl acetate, acetonitrile, dimethyl sulfoxide, etc. and mixtures thereof. More preferred are aqueous alcohol such as aqueous methanol, aqueous ethanol, etc.,; water-acetone and mixtures of solvents of water and an organic solvent, for example a mixture of water and ethyl acetate.

Crystalline modification A, crystal modification and crystalline modification C, mentioned above, can also be obtained, for example, in accordance with the methods described in the examples below, receipt, or similar.

Vitreous form of FR173657 of the present invention has a strong activity as an antagonist of bradykinin and are useful for the treatment and/or prevention of diseases mediated by bradykinin or its analogues, such as Allergy, inflammation, autoimmune disease, shock, pain, etc., in humans or animals.

For therapeutic purposes the vitreous form of FR173657 of the present invention can be used in the form of pharmaceutical preparation containing one of these compounds as an active ingredient in a mixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid iodone or intra-articular; external, such as local, enteral, intrarectal, razvlekatelnoe, inhalation, ocular, nasal or sublingual, injection. The pharmaceutical preparations may be capsules, tablets, pills, granules, suppositories, solution, lotion, suspension, emulsion, ointment, gel, cream, etc. If you want, these drugs can include excipients, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives.

Although the dose of the vitreous form of FR173657 will vary depending on the age and condition of the patient, for the prevention and/or treatment of the above diseases can be effective average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the vitreous form of FR173657. Usually you can enter the number in the range from 0.1 mg/kg to about 1000 mg/kg of body weight per day.

It is believed that the vitreous form usually crystallizes very quickly and its stability is very small. However, the testing confirmed that the vitreous form of FR173657 of the present invention does not crystallize and are not degraded even when heated, in wet conditions or physical treatment and is very stable.

Vitreous forms the AI compared with known forms of FR173657 and has a higher solubility and a better ability to escape, than crystalline modification of FR173657. Therefore, it is useful to obtain and delivery with quality sufficient stability, so that they approached for drugs.

In more detail, the invention is explained using the following examples of the preparation and examples, which, however, are not intended to limit the scope of the present invention.

Getting 1 To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6 - dichloraniline]-2-methylinosine (100 mg), (E)-3-(6-acetamidophenyl-3-yl)acrylic acid (56,1 mg) and N, N-dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (43,4 mg) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (56,9 mg) in a stream of nitrogen at 0oC and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and was extracted with chloroform. The organic layer was washed sequentially with an aqueous solution of saturated sodium bicarbonate, water and saturated salt solution, dried over magnesium sulfate and then the solvent was removed under reduced pressure. The residue was purified by thin-layer chromatography (methanol:dichloromethane 1:10, about. /about. ) and utverjdali diethyl ether and ethyl acetate to obtain 8-[3-[N-[(E)-3-(6-acetaminophe solids. So pl. pages 133-139oC.

NMR (Dl3,): 2,22 (3H, s), is 2.74 (3H, s), with 3.27 (3H, s) to 3.67 (1H, DD, J= 16.5, and 5,5 Hz), of 3.96 (1H, DD, J=16.5, and 5,5 Hz), 5,62 (1H, d, J=11,0 Hz), 5,67 (1H, d, J=11,0 Hz), 6,46 (1H, d, J=16.0 Hz), was 6.73 (1H, ush.t, J=5.5 Hz), 7,21-7,33 (3H, m), 7,38-7,51 (3H, m), 7,52 (1H, d, J=16.0 Hz), 7,82 (1H, DD, J= 8,5, 1.5 Hz), 8,03 (1H, d, J=8.5 Hz), 8,13-of 8.25 (2H, m), with 8.33 (1H, d, J= 1.5 Hz).

Getting 2
FR173657 (7 g) was added to methanol (720 ml) at 60oAnd boiled under reflux with stirring for 5 minutes. The mixture was cooled to a temperature below 30oC and was stirred for 2 hours at a temperature in the range from 20 to 30oC to obtain the precipitate. The mixture containing the crystalline precipitate was filtered and the resulting crystalline precipitate was washed with methanol (14 ml) and dried in vacuum at 40oIn the received raw anhydrous crystalline compound FR173657 (6.3 g) (hereinafter in the description called crude crystalline FR173657). It contained about 5% of methanol.

Getting 3
To a mixture of crude crystalline FR173657 (100 g) and pure water (500 ml) was added concentrated hydrochloric acid (28,1 ml) and the resulting mixture was stirred at a temperature below 10oWith the dissolving crystalline product. Added carbon powder (5 g) and the mixture permesas hydrochloric acid (1.4 ml). The obtained filtrate was added to a mixture of acetone (700 ml) and triethylamine (35,87 g) at 55oC, stirred at this temperature for 5 minutes and then boiled under reflux for 20 minutes. Then the mixture was cooled to 40oC and the crystalline product was collected by filtration. The crystalline product was washed with 50% acetone and dried in vacuum, the obtained crystalline FR173657 (crystalline modification A) (88,7 g).

The infrared absorption spectrum of the obtained product is shown in Fig. 3.

Getting 4
To a mixture of crude crystalline FR173657 (50 g) and pure water (250 ml) was added concentrated hydrochloric acid (14.1 ml) with stirring at 5oWith the dissolving crystal. To the mixture was added carbon powder (2.5 g) and the mixture was stirred for 30 minutes. Carbon powder was filtered off, washed with diluted hydrochloric acid. The obtained filtrate was added to a mixture of ethyl acetate (350 ml) and triethylamine (17,93 g) at 70oAnd boiled under reflux with stirring for 2 hours. After that, the mixture was cooled to 20oC, then stirred at this temperature for an additional 2 hours and the resulting crystalline product was collected f the ri 40oWith, as a result received it FR173657 (crystalline modification B) (44,51 g).

Infrared absorption spectrum shown in Fig.4.

Getting 5.

To a mixture of crude crystalline FR173657 (260 g) and pure water (1300 ml) was added concentrated hydrochloric acid (73 ml) and was stirred for 10 minutes at a temperature of 5oWith the dissolving crystal. Obtained after filtration the precipitate was washed with diluted hydrochloric acid. The filtrate is added dropwise within 30 minutes at 20oC was added to a mixture of acetone (6500 ml), pure water (4680 ml) and triethylamine (93,3 g), which was added to the seed crystal modification (26 mg). The resulting mixture was stirred at the same temperature for 2.5 hours, then was cooled to 3oWith and additionally stirred for 2 hours. The crystalline product was collected by filtration, washed with 50% acetone (520 ml) and dried in vacuum at 40oWith, as a result received it FR173657 (crystalline modification C) (236,68 g).

The infrared absorption spectrum of the obtained product is shown in Fig. 5.

Example 1
The plate was placed in a warm thermostat with air circulation, were subjected to idling to heat treatment at 230oWith and oratory 160oC. After confirming the set temperature of the plates hydrated FR173657 (crystalline modification of (A) uniformly distributed on the plate and was heated. After the temperature reached 160oWith, it was kept at this temperature for 30 minutes and then left to cool to obtain a vitreous form of FR173657.

Infrared absorption spectrum shown in Fig.1
Profile of differential scanning calorimetry (DSC) is shown in Fig.2.

Example 2
The plate was placed in a warm thermostat with air circulation, were subjected to idling to heat treatment at 230oC and cooled to a temperature below 100oC. Then thermostat is again heated to a fixed temperature 220oC. After confirming the set temperature of the plates hydrated FR173657 (crystalline modification B) evenly distributed on the plate and was heated. After the temperature reached 220oWith, it was kept at this temperature for 30 minutes and left to cool to obtain a vitreous form of FR173657.

Infrared absorption spectrum and the profile in differential scanning calorimetry (DSC) of the obtained product costat air circulation, subjected idle to heat treatment at 230oC and cooled to a temperature below 100oC. Then thermostat was again heated to establish a fixed temperature 160oC. After confirming the set temperature of the plates hydrated FR173657 (crystalline modification C) evenly distributed on the plate and was heated. After the temperature reached 160oWith, it was kept at this temperature for 30 minutes and left to cool to obtain a vitreous form of FR173657.

Infrared absorption spectrum and the profile of differential scanning calorimetry (DSC) of the obtained product was identical with the spectrum and the profile of the vitreous form of example 1.

Example 4
The plate was placed in a warm thermostat with air circulation, were subjected to idling to heat treatment at 230oC and cooled to a temperature below 100oC. Then thermostat was again heated to establish a fixed temperature 160oC. After confirming the set temperature of the plates hydrated FR173657 (a mixture of crystalline modification a and crystalline modification C) evenly distributed on the plate and was heated. After the temperature of the substance dlavigne form of FR173657.

Infrared absorption spectrum and the profile of differential scanning calorimetry (DSC) of the obtained product was identical with the spectrum and the profile of the vitreous form of Example 1.

Example 5
Vitreous form of FR173657 15 mg
Lactose is the Appropriate number of
The croscarmellose sodium 10 mg
The hypromellose 2 mg
Magnesium stearate 1 mg
The above components were granulated and the standard method produced the pills in a standard way were covered with a film of reception of tablets, film-coated and contain the vitreous form of FR173657.

Example 6
Vitreous form of FR173657 15 mg
D-mannitol is an Appropriate number of
Nizkozameshhennoj hydroxypropylcellulose 10 mg
Crystalline cellulose 20 mg
Hydroxypropylcellulose 2 mg
Magnesium stearate 1 mg
The above components were granulated and the standard method produced the pills in a standard way were covered with a film of reception of tablets, film-coated and contain the vitreous form of FR173657.

Example 7
Vitreous form of FR173657 15 mg
Lactose is the Appropriate number of
Nizkozameshhennoj hydroxypropylcellulose 20 mg
Crystalinity was grained and standard way made pills, which standard way were covered with a film of reception of tablets, film-coated and contain the vitreous form of FR173657.

Example 8 - determination of solubility
Determination of solubility were carried out in accordance with the method of determining the solubility of the Japanese Pharmacopoeia (JP) XIII - method of mixing. As an experienced solution used 900 ml of distilled water. Set the stirring speed of 50 rpm./minutes of the Vitreous form of FR173657 (100 g) was added to the experimental solution and as samples in each dimension were selected aliquots of 10 ml of Each sample was filtered through 0.45 μm filter and analyzed by liquid chromatography high resolution.

As control was used crystalline modification A, the crystalline modification V, the crystalline modification and mixture of the crystalline modifications and hydrate FR173657.

The results of the experiment are shown in Fig.6.

The presented results show that the vitreous form of FR173657 of the present invention has a higher solubility than any of the crystalline polymorphic modifications FR173657.

Example 9 - determination of stability
The results of determining the stability of the vitreous form FR1736 invention does not crystallize, does not decompose even when heated or in wet conditions, or after physical processing and stable during prolonged storage.


Claims

1. Vitreous form 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic]-N-methylamino]-2,6-dichloraniline]-2-methylinosine.

2. Vitreous form 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic] -N-methylamino] -2,6-dichloraniline] -2-methylinosine, which is obtained by heating crystalline form 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic] -N-methylamino] -2,6-dichloraniline]-2-methylinosine or MES to a temperature not lower than its melting point and then cooled.

3. Vitreous form under item 2, which is obtained by heating the crystalline modification a or a mixture of crystalline modification a and crystalline modification of hydrate 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic] -N-methylamino] -2,6-dichloraniline]-2-methylinosine at a temperature below its melting point and then cooled.

4. Vitreous form 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic] -N-methylamino] -2,6-dichloraniline] -2-methylinosine, which in differential scanning C up to 128oC.

5. Vitreous form 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic] -N-methylamino] -2,6-dichloraniline] -2-methylinosine, which does not crystallize partially or completely and does not degrade during long-term storage.

6. The method of obtaining the vitreous form 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic] -N-methylamino] -2,6-dichloraniline] -2-methylinosine, which comprises heating a crystalline form 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic] -N-methylamino] -2,6-dichloraniline]-2-methylinosine or MES at a temperature below its melting point and then cooled.

7. The method according to p. 6, which comprises heating a crystalline modification a or a mixture of crystalline modification a and crystalline modification of hydrate 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic] -N-methylamino] -2,6-dichloraniline]-2-methylinosine to a temperature not lower than its melting point and then cooled.

8. Pharmaceutical composition for prevention and/or treatment of diseases mediated by bradykinin or its analogues, comprising as active ingredient a glassy form according to any one of paragraphs.1-4 or 5 in combination with a pharmaceutically acceptable

 

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