3-[ (5-methyl-2-furanyl)methyl] -n-(4 - piperidinyl) -3h - imidazo (4,5-b)pyridine - 2-amine-2 - hydroxy-1,2,3 - propanetricarboxylate having antiallergic activity, the method of its production and antiallergic composition

 

(57) Abstract:

Usage: in the chemistry of heterocyclic substances, in particular in the method of obtaining 3-/ (5-methyl-2-furanyl) methyl/-N-(4-piperidinyl)-3H-imidazo/ 4,5-b pyridine-2-amine-2 - hydroxy-1,2,3 - propanetricarboxylate with anti-allergic properties. The inventive product 3-/(5-methyl-2-furanyl) methyl/-N-(4-piperidinyl)-3H - imidazo/4,5-b pyridine - 2-amine-2-hydroxy-1,2,3 - propanetricarboxylate with so pl. 192°C, the activity at a dose of 0.01 to 10 mg/kg of body weight, has a high stability to light and moisture than Dimineata salt koberstine. Reagent 1: roberston. Reagent 2: citric acid. Reaction conditions: heating the reactants in the environment of the solvent followed by cooling the reaction mass, the branch target of the crystalline product and, if necessary, by crystallization. 3 S. p. f-crystals, 18 PL.

3-[(5-Methyl-2-furanyl)methyl] -N-(4-piperidinyl)-3H-imidazo [4,5-b] pyridine-2-amine as an intermediate product used for the preparation of anti-allergic compounds /1/. Also known pharmacological properties, in particular anti-allergic activity mentioned intermediate compounds, as well as its composition and application. Well salt compared with the previous compounds, having the form of a salt or base.

The present invention relates to new salts, namely, 3-[(5-methyl-2-furanyl)-methyl] -N-(4-piperidinyl)-3H-imidazo [4,5-b] pyridine-2-amine 2-hydroxy-1,2,3-propanetricarboxylate (1:1), which is represented by two formulas:

HN- - (1)

Free base corresponding salt of formula I is known as roberston and according to the new salts of the formula I in the future will be called citrate koberstine.

Referred to free base and dinitrate treatment, the dihydrochloride hemihydrate and (Z)-2-atindimubona (1:2) salt described in U.S. patent No. 4 835 161 [2] unfortunately, all of these previously known salts and bases have the disadvantage they have insufficient physical and chemical stability. When storing mentioned salts and bases are progressive decomposition and often increases the amount and number of contaminants. In the future this problem is compounded by the requirements of the environmental conditions of light, heat, humidity, acidity, basicity and oxygen.

Free base koberstine light and when the light is significantly immensae molecular chain. When storing this connection, having a yellow color at a relative humidity of 60% or 90% color change until ASCA solid mass. Dinitro salt and dihydrochloride polyhydrate salt have a disadvantage, because they significantly decompose in the water environment, and therefore, they are not subject to the expression of the standard formula, especially in the compositions of the liquids. The dihydrochloride palpitates salt is a hygroscopic compound and changes color from light yellow to dark yellow and finally to brown.

(Z)-2-atindimubona (1: 2) or an acidic salt of maleic acid decomposes even at room temperature, and the decrease of the molecular chain increases significantly when lighting or temperature increase. Long-term observations show that it is impossible to store for future use sample of this salt as a reference, as are formed of at least two impurities.

From the specified follows that neither the salt nor the basis of previously known are not suitable enough for either traditional expressions formula, nor for pharmaceutical use.

It has been unexpectedly discovered that the above problems can be avoided or minimized by the use of citrate salt koberstine. This new salt is not photosensitive, is much more stable than previously known salts and bases on the>Usually citrate koberstine can be prepared by dissolving koberstine in a suitable solvent, heating the solution, adding a sufficient amount of citric acid, cooling the reaction mixture and separation of the transparent target product. Thus obtained citrate koberstine further subjected to re-crystallization for purification.

Free base koberstine mentioned above, and used as source material for the preparation of salts of citric acid, can be prepared tratitional the method described in U.S. patent N 4888426 /1/.

The term "suitable solvent", which is used for cooking citrate koberstine determines any lower alcohol or ketone, in which is dissolved doberstyn, the composition of the solvent included primary, secondary and tertiary alcohols and related ketones having from 1 to 6 carbon atoms. Namely, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 1,1-dimethyl-ethanol, cyclohexanol and the like compounds. Suitable ketone solvents-acetone, butanone, 4-methyl-2-pentanone, cyclohexanone and the like. A mixture of two or more of the above solvents the solvents or their mixtures with water. In particular, the water content of the solution can reach 25-35% (by volume). Preference is given to using as solvents are the lower alcohols, in particular methanol or ethanol. Methanol is most preferred.

Solutions koberstine in the above-mentioned solvents have a high concentration, most typically, the ratio by volume koberstine to the solvent of 0.3 mol/l to 1.2 mol/l, preferably 0.5 mol/l 1 mol/L. These solutions prepared in the traditional way by mixing all components at ambient temperature. Appropriate processing solution activated carbon 5% by weight koberstine. Both types of solution, which includes or does not include activated charcoal should be mixed within one hour, preferably within half an hour, then filtered through infusorial land that is pre-moistened with a solvent. Sometimes the filtering occurs with some difficulty, to speed up this process adds an additional amount infusorial land in the solution. The precipitate is washed with a small amount of solvent, is used mainly to 25% of the original volume of solvent. The combined filtrates are heated at a temperature of, access to the I acid was added in portions to a hot concentrated solution or solid crystals, or dissolved in a small amount of water. The acid is added at such a speed that the temperature of the solution easily held at a constant level. Equally, you can use citric acid anhydrous or monohydrate. The molar ratio of citric acid to koberstine can be 0,9:2, preferably from 0.95: 1.5, and in particular 1,0:1,1. Stirring the solution continuously at 55-65aboutC for about one hour, preferably within half an hour. Then the solution is slowly cooled at ambient temperature. Such slow cooling can be done efficiently, if you turn off the heating source and its removal, which will contribute to the heat exchange with the environment. If the volume is very large compared to the surface area of the reaction vessel, the cooling process is much slower, in this case it is possible to use any known methods of cooling. After cooling the reaction mixture, the precipitated crystals need to degidrirovanii before filtering. Evaporation of crystals citrate koberstine can be done by continuous stirring of the mixture after reaching room temperature. The process of evaporation can continue in those who first solvent with a small amount of cold solvent. The resulting product is then dried by traditional means, for example, vacuum or temperature rise, in particular 40-60aboutWith, preferably 50aboutC. the Yield obtained citrate koberstine is 80-95% with high methanol content, convergence results (reproducibility) of about 93-94% Quality of citrate does not depend on the choice of solvent.

Thus obtained citrate koberstine you can further clean the secondary crystallization in a suitable solvent. The term "suitable solvent" used in the process of re-crystallization citrate koberstine determines the solvent of lower alcohol, or a mixture of lower alcohols with water. In particular, it applies a mixture, where the water content is up to 30% solution (by volume). For the process of re-crystallization is used methanol, ethanol, 1-propanol, 2-propanol and similar compounds. Solutions of citrate koberstine used for the process of re-crystallization, have a high concentration near the saturation point of the solute in the solvent and is traditionally prepared from supersaturated solutions of salts in the above-mentioned solvents of lower alcohols. Preferably isgo amount of added water, for example, in the later stages of the process. When using methanol, the ratio of mass to volume of citrate koberstine to methanol can reach 0.3 g/ml:0.7 g/ml, in particular, 0.4 g/ml:0.6 g/ml, preferably 0.45 g/ml:0.55 g/ml of the said solution in a solvent of lower alcohol is stirred and heated to the temperature of the return stream. To completely dissolve the citrate, heated to a heterogeneous mixture of water is added dropwise. It is preferable to add water at such a speed that the temperature of the reagent mixture was maintained at the temperature level of phlegmy. Keeping a constant temperature in the heated solution of citrate koberstine can be easier, if you add the pre-warmed water having a temperature of return flow of the salt solution. After complete addition of water the resulting solution is stirred and heated at a temperature of return flow within one hour, preferably for about half an hour. The reactive mixture is cooled spontaneously at room temperature, the crystallization process starts at a temperature of approximately 45aboutC. the Crystals evaporated at room temperature during the day, preferably 0-10 hours the Precipitate is filtered and washed with a small quantity is vacuum conditions and at an elevated temperature of about 40-60aboutC.

In some cases, you can use the additional step of purification using activated charcoal during re-crystallization. For example, after complete addition of water during re-crystallization is added activated carbon 5% by weight of citrate, in the future, the mixture was stirred and heated for one hour, better within half an hour. Received the warm solution is filtered through infusorial the earth, which is pre-heated humidified mixture of solvents. The precipitate is washed similar to the heated mixture of solvents, combined filtrates spontaneously cooled to room temperature. The resulting crystals are collected and dried as described above.

Connection citrate koberstine is an antihistamine and antiserotonin compound used as an antiallergic drug. Specified new salt has, in addition, physico-chemical stability, further combined in quantities with good solubility and bioequivalency salt of (Z)-2-atendimento (1: 2). As previously known salt and free base citrate has favorable pharmacokinetic orientation when obyedinayutsya for use in suitable pharmaceutical compounds, for example, solid preparations for oral administration of pills, tablets, powders, capsules, etc., liquid forms for oral administration of solutions, suspensions, syrups, elixirs, etc., previously Known similar compounds and the above-mentioned compounds can be obtained by homogeneous mixing of the active component citrate koberstine with one or more suitable carrier and/or with additives and turning the mixture into the form that is assigned to the application.

For ease of use and standardized dosage you mentioned farmacevticheskie connection to Express in units of dosage. Examples of such dosage units may be tablets, capsules, pills, powders, wafers, injectable solutions, suspensions, full teaspoon full tablespoon, etc., and many others.

Suitable daily dosage of citrate koberstine is predpolozitelnoi 0.01 to 10 mg/kg body weight, in particular 0.05 and 5 mg/kg body weight, preferably 0.1 and 2 mg/kg of body weight.

Another feature of the invention the use of citrate koberstine for the manufacture of medical products for the treatment of patients suffering from allergic diseases, or those astma etc.

However, another feature of the invention relates to a method of treating patients suffering from allergic diseases or disorders, by appointing anti-allergic effective amount of citrate koberstine these patients.

The examples below are intended to illustrate and not to limit the use of the present invention. Unless otherwise noted, all parts are represented by mass.

Experimental part

P R I m e R 1. To a mixture of 60,73 h 3-[(5-methyl-2-furanyl)methyl]-N-(4-piperidinyl)-3H-imidazo [4,5-b]-pyridine-2-amine(nobelactive) in 195 ml of methanol was added 3,3 h activated charcoal (Norit A Supra R) and 9.1 h infusorial land. The reagent mixture is stirred for half an hour at 20aboutC and filtered through infusorial land, which was then washed with 40 ml of methanol. The combined filtrates were heated to 50aboutWith and added 41 h of citric acid monohydrate. The mixture was stirred for half an hour at 60-65aboutWith, and then spontaneously cooled to room temperature. The mixture was mixed cut (all night) and filtered. The precipitate was washed with 80 ml of methanol and dried under vacuum at 50aboutWith the release of the product masturbaciya (1:1) (citrate koberstine) T. R. 192,0aboutC.

P R I m m e R 2. The stirred mixture of 40 h citrate koberstine (as prepared in example 1) in 80 ml of methanol was heated to the temperature of the return stream. Added about 25 ml of water and continuously stirred for half an hour at the temperature of the return stream. The solution was spontaneously cooled to room temperature, 20aboutWith, and further immediately (all night) was stirred. The crystalline precipitate is filtered with methanol and dried in vacuum at 50aboutWith the release of citrate koberstine was 37,4 h (94%).

P R I m e R 3. The stirred mixture of 40 h citrate koberstine (as prepared in the example ) in 80 ml of methanol was heated at the temperature of the return stream. Added about 25 ml of water and 2 h of activated charcoal, stirred continuously for half an hour at the temperature of the return stream. The solution was filtered through infusorial land, which was filtered by the pre-heated mixture of 16 ml of methanol and 5 ml of water. The combined filtrate was spontaneously cooled to room temperature, and then mixed immediately (all night). The crystalline product was collected, rinsed with methanol and dried under vacuum at a temperature of 50about

Portions consisting of 150 mg base koberstine, dimelaena koberstine and citrate koberstine were weighed in glass vessels. These vessels received light radiation within 7 days in the light Cabinet with 16 white fluorescent lamps (Sylvania F 20T 12/D Daylight 6500K). The light intensity was 17000 Lux, the average temperature in the Cabinet was approximately 40aboutC. After 3 and 7 daylight portion 50 mg of each sample was dissolved in 10 ml of a mixture of methanol and water (2:3 by volume) and were analyzed (HpLC) liquid chromatography high resolution, with reversed phases.

Column: 12,5 cm Supersphere RP select B (4 )

Flow: 1.5 ml/min

The elution solvents:

A: 0,75% ammonium acetate in water

B: acetonitrile

C: tetrahydrofuran

The mode of elution are shown in table. 1.

Table. 2 shows the relative retention time (RRT; for koberstine) and concentration (%) of each product decomposition, determined at a concentration of 0.1% in the analyzed samples.

Because the base and dimelaena koberstine undergo significant decomposition under the action of daylight, citrate koberstine remains stable in storage conditions and had not observed any of the rum typical pharmaceutical compositions in unit dosage, suitable for systemic and local assignments for warm-blooded animals according to the present invention.

The term "Active ingredient" (A. 1), which is used everywhere in the examples, refers to the citrate koberstine.

P R I m e R 5 (oral drops).

500 g A. 1. was dissolved in 0.5 l of 2-hydroxypropanoic acid and 0.5 l of the polyethylene glycol at 60-80aboutC. After cooling to 30-40aboutWith added 35 ml of polyethylene glycol mixture well stirred. Then was added a solution of 1750 g of sodium derivative of saccharin in 2.5 l of purified water and stirring was added 2.5 l of fragrance, cocoa butter and polyethylene glycol g.s. to a volume of 50 l, obtaining the solution drops for oral administration, where A. 1. is 10 mg/mm, the resulting solution was filled into suitable vessels.

P R I m e R 6 (solutions for oral administration).

9 g of methyl-4-hydroxybenzoate and 1 g of propyl-4-hydroxybenzoate was dissolved in 4 l of boiling purified water. In 3 l of this solution were dissolved first 10 g of 2,3-dihydroxy atendimento acid, and then 20 g A. 1. The resulting solution was combined with the remaining part of the first solution was then added to 12 liters of 70% 1,2,3-propanetriol and 3 l of sorbitol, 40 g of sodium produced the initial solution was combined with the first solution, added g water. s. up to a volume of 20 liters, providing solution for oral administration containing 5 mg A. 1. in full teaspoon (5 ml). The resulting solution was poured into suitable vessels.

P R I m e R 7 (capsules).

20 g A. 1. 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g magnesium salt of stearic acid are intensively mixed together.

g.s. as long as you want

The resulting mixture is then filled into 1000 hardened gelatin capsules, each of which contained 20 mg A. 1.

P R I m e R 8 (tablets, film-coated).

The preparation of the contents of the tablets.

A mixture consisting of 100 g A. 1. 570 g lactose and 200 g starch is well mixed, then moistened with a solution of 5 g sodium dodecyl sulfate and 10 g of polyvinyl pyrrolidone (Kollidou K 90) in 200 ml of water. Mix the wet powder was sieved, dried and again sieved, then added 100 l of microcrystalline cellulose (Avicel ) and 15 g hydrogenated vegetable oil (Sterotex ). All this was well mixed and compressed into tablets was 10,000 tablets, each containing 10 mg of active Ingrid is risovannogo ethanol was added a solution of 5 g of ethyl cellulose (Ethocel 22 cps) in 150 ml of dichloromethane. Then added 75 ml dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol was melted and dissolved in 75 ml DeLorean. The resulting solution was added to the first solution was then added 2.5 g of magnesium salt octadecanoic acid, 5 g of polyvinylpyrrolidone and 30 ml of concentrated colour suspension (Opaspray K-1-2109 and the entire mixture is homogenized. The contents of the tablets were covered with the mixture in a special apparatus.

Comparative physico-chemical data.

The hygroscopicity of the product was investigated to the following:

500 mg of the product was stored at ambient temperature in desiccator over a saturated solution of NaBr, relative humidity (RH) was 60% Other 500 mg of the product kept at ambient temperature over a saturated solution of Li2SO4relative humidity was 85% of the Periodically determined the change in the weight and appearance of the samples. After 5.5 days, the samples were kept for 2 days at 25aboutC and 45% RH. Then determined the moisture content in the samples using the method of coulometric titration.

After storage at 60% RH and ambient temperature in techerator environment for 0,66 day resulted in a color change from yellow to brown. Further, the connection was partially radigales and formed a sticky, solid mass.

Percentage change in mass of the free base koberstine during storage at 60 and 85% RH at ambient temperature are given in table. 3 in the function from time

(1) the increase of mass in percent after storage for 5.5 days at 60% RH or 85% RH and subsequent aging for 2 days at 25aboutC / 45% RH.

The initial water content of free base koberstine was 0.12 wt. as determined using coulometric titration. After storage for 5.5 days at 60% RH and subsequent aging for 2 days at 45% RH, the water content is reached 2,58 wt. After storage for 5.5 days at 85% RH and then for 2 days at 45% RH, some of the water content in the sample was 10,78 wt.

Further tests of the free base koberstine on the light resistance was carried out according to the following procedure:

A portion of the base koberstine mass of 150 kg was weighed in a glass container. The container was irradiated for 7 days in length Cabinet, lighted tube 16 lamps cool white fluorescent light (Sylvania F20T 12/D Daylight 6500 K). The light intensity was 17000 what if in 10 ml methanol-water (2:3 V/V) and analyzed using a highly effective liquid chromatography (HPLC).

HPLC is an analytical technology, with which the solute share in the dynamic differential migration process in the system consisting of stationary phase column and a mobile phase, known as "eluent". Technology post based on the use of columns with small holes [inner diameter (1D) 2-5 mm] and small particles (3-10 μm) fillers, which enable rapid equilibrium between the mobile and stationary phases. The separation of the various components of the sample is obtained by the distribution of the connection between the stationary and the liquid phase, the specified distribution is specific to each connection. In this case, the connection is more or less retarded in its flow through the system as a result of interaction with the material of the pole, so the connection goes separated from other solutes extracted sooner or later.

After separation of the various components of the sample is measured UV absorbance of the selected solution for a certain period of time.

The components of the mixture can be identifitsirovany according to their relative time of the hold is in. RRT is determined from the formula

RRT where tithe time measured from time of injection to the peak maximum of the compound i in the chromatogram;

trefthe time measured from time of injection to the peak maximum of the reference compounds (here koberstine) defined using the same column and at the same temperature.

The time for which the connection is separated from the pillar depends, among other factors, on the type and concentration of eluent used. In the case of complex mixtures compromise between a satisfactory separation of the components and a reasonable analysis time is achieved by using a "gradient separation. This means that the composition of the eluent is changed depending on time. In this case used a linear gradient, which means that the composition of the eluent is determined at different points in time and between these moments of change in the composition of the eluent is linear.

Quantitative determination of compounds represented in the sample is performed using external calibration. Analyze selected from the sample solution as a reference solution containing a known quantity of the investigated compounds.

The relative concentration in wt/wt (Blast peak of compound i in the sample solution

airthe peak area of compound i in the reference solution

Circoncentration (mg/ml) of compound i in the reference solution

Casconcentration (mg/ml) analyte koberstine in the sample solution

fi(taken into account only if connection i is salt) against molecular weight (MW) of salt to the molecular weight of the base

< / BR>
The conditions of the experiment

System 1.

Post: 12.5cm Super spher RP Select B (4 μm)

Definition: UV at 220 nm

Flow rate: 1.5 ml/min

Volume of injection: 10 ál

The temperature of the column and solvent: ambient

Eluent:

A: 0,75% ammonium acetate in water

B: acetonitrile

From: tetrahydrofuran

Type of separation: linear gradient. The data are given in table. 4.

The results of the testing grounds koberstine described above are summarized in table. 5, in which the relative concentration (%) of each product, which was determined at the concentration of 0.1% is shown in comparison with the corresponding RRT koberstine, after 3 and 7 days of the lighting pattern.

From the results of the above tests can be done sledujushshei conclusion.

Free base koberstine hygroscopic that the por is Ino is destroyed by the light.

In view of the limited physico-chemical stability of the free base koberstine became apparent need for other more stable forms of salt koberstine.

At the end of 1986 were synthesized (Z)-2-butenedioate (1:2) or Dimineata salt, dehydrocorydaline salt and dinitrate salt koberstine.

Hygroscopic properties of these salts koberstine investigated during the tests as described above.

During the whole experiment at 60% RH and ambient temperature color three forms salts koberstine remained unchanged.

After soaking for 0,66 days at 85% RH and ambient temperature color dehydrochlorinating salt has changed from yellow to temnerature. Color other salts remained unchanged.

Percentage change in mass of each of the described salt koberstine during storage at 60% RH and 85% RH and ambient temperature are given in table. 6 functions of time.

(1) the increase of mass in percent after storage for 5.5 days at 60% RH or 85% RH, followed by additional aging for 2 days at 25about/45% RH.

The initial water content of the specified form of salt (wt.) and the content of in is and for 2 days at 25about/45% RH, shown in the table. 7.

From the results above, it is obvious that dehydrocorydaline salt is hygroscopic. In addition it was found that this salt is highly soluble (>100 mg/ml) in aqueous solutions. The high solubility of the specified salt in combination with a strong tendency to absorb moisture makes this salt is unsuitable for use in tablets, because some drugs will dissolve in its own adsorbed film of moisture and strong acidic environment can increase the destruction of the existing grounds. On the other hand, dinitrate salt water has no significant impact. However, this salt is also not suitable for use as a pharmaceutical product, because in the harsh acidic conditions of formation dinitrate salt, the molecule splits into N-(4-piperidinyl)-3H-imidazo [4,5-b] pyridine-2-amine:

H-N - NNHHNO3< / BR>
Rapid destruction koberstine in acidic conditions, as described above, is shown below.

Dimineata salt is only slightly hygroscopic and at the time specified salt was the best when choosing from the available forms koberstine.

However, as the continuation of tests with uchenykh compounds. This problem was further exacerbated in the required environmental conditions, for example, light, heat, acid and alkaline.

Because Dimineata salt was not practical, continued the search form salts, characterized by the stability of physicochemical properties during long term storage.

In August 1989, was first synthesized the compound 2-hydroxy-1,2,3-propanetricarboxylate /1:1/ or monocerata salt koberstine and admitted to the serial test for stability. In the following paragraphs the results of comparative tests bimaleate salt and Mononitrate salt.

Three parties Mononitrate salt was analyzed using HPLC directly after synthesis, and again 4 months after storage in ambient conditions. The relative amount of koberstine defined for each batch are shown in table. 8.

Similar HPLC analysis bimaleate salt revealed the presence of 2 major (>0.1 percent) of the decay products, which took place directly after the synthesis of the salt. Using spectroscopic analysis and comparison of the relative retention time, it was found that the decay products have the following structurecad for two parties of Dimineata koberstine, defined in different moments of time:

Unlike Mononitrate salt Dimineata salt koberstine decays much and this decay increases during storage.

Analysis using HPLC, referenced above, Mononitrate salt and bimaleate salt through a 9.6 and 12.7 months old storage was performed under the following experimental conditions:

System 2.

Column: 10 cm Hypersil ODS (3 μm)

Definition: UV at 290 nm

Flow rate: 2 ml/min

Volume of injection: 10 ál

The temperature of the column and solvent: ambient

Eluent: A: 0.5% of NH4H2PO4in water

B: acetonitrile

From: tetrahydrofuran

Type of separation: linear gradient. The data are given in table. 10.

Demolet doberstyn directly after synthesis (time 0 months) was analyzed using HPLC under the following experimental conditions:

System 3.

Column: 10 cm Hypersil ODS (3 μm)

Definition: KF at 300 nm

Flow rate: 2 ml/min

Volume of injection: 10 ál

The temperature of the column and solvent: ambient

Eluent: A: 10% (NH4)2CO3in water

B: acetonitrile

From: tetrahydrofuran

Type of separation: linear gradient. The data are given in Tropicana above. In addition to storing the sample at 60% RH and 85% RH, another sample Mononitrate salt was kept at 95% RH in desiccator over a saturated solution of K2SO4. After storage for 13 days at 60% RH; 85% RH and 95% RH, the samples were kept for one day at 22,5aboutWith 47% RH.

The increase of mass in percentage during storage at 60% RH and 85% RH and 95% RH at ambient temperature depending on the time shown in the table. 12.

(1) the increase of mass in percent after storage for 13 days at 60% RH and 85% RH and 95% RH, followed by additional aging in one day when 22,5aboutC/45% RH.

The initial water content in the product amounted to 0.39% as determined by coulometric.

For mononitratee salt certain values of water content after storage for 13 days after 60% RH, 85% RH and 95% RH, followed by exposure to one day when 22,5aboutC/47% RH were as follows:

60% RH 1,41%

85% RH 1,41%

95% RH 1,43%

As Dimineata salt koberstine and monocerata salt koberstine were admitted to accelerated stability testing in the following modes:

The storage period up to 12 months at room temperature (RT) and 40-65% RH.

Period ptx2">

The retention period of up to three months, during which the product is directly exposed to the daylight at ambient temperature and RL.

Periodically, the samples contained in various storage conditions, were analyzed using HPLC. For bimaleate salt HPLC was performed under the following experimental conditions:

System 4

Column: 10 cm Hypersil ODS (3 μm)

Definition: UV at 290 nm

Flow rate: 2 ml/min

Volume of injection: 10 ál

The temperature of the column and solvent: ambient

Eluent: A: 0.5% of NH4H2PO4in water

B: acetonitrile

From: tetrahydrofuran

Type of separation: linear gradient. The data are given in table. 13.

HPLC Mononitrate salt was performed under the following experimental conditions:

System 5.

Column: 10 cm Hypersil c. 18 BDS (3 μm)

Definition: UV at 220 nm

Flow rate: 1.5 ml/min

Volume of injection:10 ál

The temperature of the column and solvent: ambient

Eluent: A; 0,75% ammonium acetate in water

B: acetonitrile

From: tetrahydrofuran

Type of separation: linear gradient. The data are given in table. 14.

For mononitratee salt decay was not observed on all parties throughout ISI decay has increased over time. The main degradation products were detected aldehyde (D1) and Gidropress (DC 2) compounds described above. The following Table summarizes the number of produktov decay DC1 and DC2 (in percent) for different storage conditions for different periods of time. The data are given in table. 15.

In addition, stability in solution bimaleate salt and Mononitrate salt koberstine tested using the following procedure:

50 mg of each salt were placed, respectively, in 5 ml water, 5 ml of 0.1 G. of HCl and 5 ml of NaOH. The mixture was kept at a temperature of 100aboutC and analyzed after a certain period of time using HPLC.HPLC for bimaleate salt was performed under the conditions of the system 3, while HPLC for mononitratee salt when system conditions 1.

Number (percentage) of the decay products bimaleate salt and Mononitrate salt defined at a concentration of 0.1% for the different storage conditions, described above, is summarised below in function of time. The degradation products were identifitsirovany with masspectrometry. The data are given in table. 16.

Structures of various compounds decay (DC) are the following

H-N - NH'-

From table. above, showing raceamerica decay in all three environments.

The structure of the decay products is different for both salts.

The collapse takes place almost immediately for bimaleate salt and Mononitrate salt in 0.1 G. of HCl and water.

Monocerata salt is significantly more stable in the 1 N. NaOH than Dimineata Sol: the collapse of mononitratee salt begins after 8 h, while demolet destroyed almost immediately.

Stability bimaleate salt and Mononitrate salt oxidizing conditions tested in accordance with the following procedure:

50 mg of each salt was added in 5 ml of water and 0.25 ml of 30% hydrogen peroxide solution and kept at 60aboutC. Reference samples were prepared in a similar manner, without the addition of hydrogen peroxide.

Periodically, the samples were analyzed using HPLC. For bimaleate salt HPLC was performed under the conditions of the system 3. HPLC for mononitratee salt was performed during the system 1.

Number (percentage) of the decay products bimaleate salt and Mononitrate salt, some at concentrations of 0.1% are listed in the table. 17 functions of time.

The connection structure collapse of the DC 10 was identified using massspectrometry as:

H-NNH

From the tables above, which describes the results of maleate salt is more intense it leads to the formation of three compounds of collapse after one hour storage. In contrast, the decay Mononitrate salt is less intensive, i.e., only one connection breakup is formed after 1 h of storage.

Stability tests bimaleate salt and Mononitrate salt in artificial lighting conditions was performed using the procedure described above. HPLC Mononitrate salt were carried out in conditions 1 and bimaleate salt in terms of system 3, UV detection was last at a wavelength of 252 nm.

Mononitrate salt was not observed decay during the whole experiment.

On the other hand, demolet showed increasing decay during the course of the experiment. The appropriate number of decay products in percentage, defined at concentrations of 0.1% are listed in the table. 18.

It is clear therefore that monocerata salt has a high physical and chemical stability compared with the free base, dehydrochlorinating, dinitrates and bimaleate salt koberstine. This new salt is not light sensitive, stable under conditions of accelerated testing and not exposed to moisture. Due to superior the mi.

1. 3- [(5-Methyl-2-furanyl)methyl] -N-(4-piperidinyl)-3h-imidazo(4,5-b) pyridine-2-amine-2-hydroxy-1,2,3-propanetricarboxylate General formula

< / BR>
having antiallergic activity.

2. A method of obtaining a connection on p. 1, characterized in that 3-[(5-methyl-2-furanyl)methyl] -N-(4-piperidinyl) -3H-imidazo(4,5-b)pyridine-2-amine is dissolved in a solvent followed by heating the solution to a temperature of phlegmy, adding a sufficient amount of citric acid, cooling the reaction mixture and separation of the crystal of the desired product and, if necessary, recrystallization him.

3. Antiallergic composition containing a salt of 3-[(5-methyl-2-furanyl) -methyl] -N-(4-piperidinyl)-3H-imidazo-(4,5-b)pyridine-2-amino and an inert carrier, characterized in that it contains 3-[(5-methyl-2-furanyl]-N-( 4-piperidinyl)-3H-imidazo(4,5-b) pyridine-2-amine-2-hydroxy-1,2,3 - propanetricarboxylate (1:1) in an effective amount.

 

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