Parecoxib sodium crystalline salt

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to parecoxib sodium salt in crystalline form that possesses properties of selective inhibitor of cyclooxygenase-2 (COX-2) and can be used in treatment of, for example, inflammatory diseases and pain. Proposed crystalline forms show characteristic peaks of powder X-roentgenogram obtained with using Cu-source of radiation and expressed as angles 2θ and chosen from groups consisting of at least values 5.6; 9.6; 11.0 and 14.5 ± 0.2 angle (form A), and 4.2; 8.3; 12.4; 16.7; 17.5; 20.8 and 24.7 ± 0.2 angle (form B), and 8.8; 11.3; 15.6; 22.4; 23.5 and 26.4 ± 0.2 angle (form E) and wherein each form is anhydrous and non-solvated. Also, invention relates to a method for preparing crystalline form A and to a pharmaceutical composition.

EFFECT: improved preparing method, valuable properties of drug.

21 cl, 5 tbl, 12 dwg, 1 sch, 7 ex

 

The SCOPE of the INVENTION

The present invention relates to crystalline forms of the sodium salt parecoxib, pharmaceutical compositions containing these crystalline forms, and methods of using such compositions for the treatment mediated by cyclooxygenase-2 (SOH-2) violations.

BACKGROUND of INVENTION

Nonsteroidal anti-inflammatory drugs (NSAID) are widely used to treat inflammation and pain, for example, arthritis and headaches. These drugs are effective, but their long-term use may be limited by gastrointestinal side effects, including dyspepsia and abdominal pain, and in some cases, a ruptured stomach ulcer or duodenal ulcers and/or bleeding. Development of selective inhibitory SOH-2 drugs was a revolutionary event in the treatment of inflammation and pain, giving the opportunity to combine therapeutic efficacy of traditional NSAID with significantly improved profile gastrointestinal safety.

It is believed that inhibition of the enzyme cyclooxygenase (SOH) is at least the primary mechanism by which NSAIDs exert their characteristic anti-inflammatory, antipyretic and analgesic action through the inhibition of C the importance of prostaglandins. Conventional NSAIDs, such as Ketorolac, diclofenac, naproxen, and their salts inhibit both constitutive downregulation of MOR-1 and associated with inflammation or caused by inflammation of the SOH-2-isoform of cyclooxygenase at therapeutic doses. It turns out that the inhibition of MOR-1, which produces prostaglandins necessary for the function of normal cells, is the cause of some negative side effects that are associated with the use of conventional NSAID. In contrast, selective inhibition of MOR-2 without significant inhibition of MOR-1 leads to anti-inflammatory, antipyretic, analgesic and other useful therapeutic action while minimizing or excluding such negative side effects. Thus, selectively inhibiting SOH-2 drugs provide the main progress in this area. These medicines are manufactured in the form of various orally deliverable dosage forms.

Parenteral routes of administration, including subcutaneous, intramuscular and intravenous injection, provide numerous advantages over oral delivery in certain situations for a large number of medicines. For example, injecting drug usually leads to the achievement of terapevticheskii effective concentration of the drug in the serum for more than a short time, than can be achieved by oral administration. This is especially true for intravenous injection, by means of which the drug is injected directly into the bloodstream. Parenteral administration also leads to a more predictable concentrations of the drug in the serum, are excluded because of loss in the gastrointestinal tract due to metabolism, binding with food and other reasons. Due to similar reasons parenteral often can reduce the dose. Parenteral administration is generally preferred method of delivery of drugs in critical States and is also useful in the treatment of patients who do not interact with others, are unconscious or otherwise unable or unwilling to take oral drug therapy.

Relatively few NSAID are commercially available in injectable form. Non-selective NSAID, such as salt, tromethamine and Ketorolac, which are available for parenteral use are effective analgesics, but are associated with side effects typical of such non-selective NSAID. These side effects include ulceration and bleeding in the upper gastrointestinal tract, especially in the older generation; reduced therefore the reduction function, that potentially leads to fluid retention and exacerbation of hypertension; and inhibition of platelet function that potentially predispose the subject to increased bleeding, for example, during surgical operations. These side effects seriously restrict the use of parenteral drugs nonselective NSAID.

Parecoxib described in U.S. patent No. 5932598 in the name of Talley et al., is representative of a class of water-soluble prodrugs of selective MOR-2-inhibiting drugs. Parecoxib quickly becomes essentially in the water-insoluble selective MOR-2-inhibitory drug of valdecoxib after administration to the patient. Parecoxib turns into valdecoxib also when exposed to water, for example, when dissolved in water. High solubility in water parecoxib, especially salts parecoxib, such as sodium salt, compared to the most selective MOR-2-inhibiting drugs, such as celecoxib, valdecoxib, is of interest to develop parecoxib for parenteral use. Parecoxib having the following structural formula (I), finds himself in vitro weak inhibitory activity against MOR-1 and MOR-2, whereas valdecoxib (II) has a strong inhibitory activity against SOH-2, but is weak Inga is forom MOR-1.

Sodium salt parecoxib has the structural formula (III)shown below.

In the above-mentioned U.S. patent No. 5932598 in example 18 described sodium salt parecoxib. Parecoxib can be synthesized by the method described in examples 13 and 14, with the substitution of a suitable sulfonamida and anhydride.

There is a need for a stable crystalline form parecoxib suitable as the active pharmaceutical ingredient (API), called here a "drug substance", which can be further processed to obtain a pharmaceutical composition for therapeutic use.

Crystal structure of the sodium salt parecoxib not described in the above-cited U.S. patent No. 5932598, with the exception of the description of the melting point to 271.5-272,7°C. However, the described method includes a step of crystallization from ethanol, the stage in which, as shown here below, is formed MES ethanol. The melting point is not an indicator forms a solid state, as all crystalline forms, is still identical, discover similar melting point, in some cases, after the phase transformation.

To produce a marketable medicinal substance anhydrous nonsolvated cristalli the definition forms are usually preferred compared to solvate and hydrate for a variety of reasons, including the tendency of such anhydrous resolutiony forms to exercise increased physical stability. Thus, there is a particular need in this area in anhydrous resolutional crystalline form of sodium salt parecoxib, especially for such a crystalline form having a low hygroscopic property.

SUMMARY of the INVENTION

Here sodium salt parecoxib in crystalline form, which is essentially anhydrous and essentially resolutional. Now were identified various such anhydrous and nonsolvated crystalline form.

In the first embodiment, the proposed form A. This crystalline form of the sodium salt parecoxib is anhydrous and resolutional and is characterized by at least the picture of the x ray powder patterns (PXRD), having at least two values 2θselected from the group consisting of values of 5.6 and 9.6, 11.0 and 14.5 degrees.

It should be clear that all information here links to size 2θ are approximate and may include normal measurement error, depending on the equipment and adjust, for example, a bug ±0.2 degrees 2θ.

In the second embodiment, the proposed form C. This crystalline form of the sodium salt pair is exiba is anhydrous and resolutional and characterized, at least PXRD pattern having at least two values 2θselected from the group consisting of quantities 4,2, 8,3, 12,4, 16,7, 17,5, 20,8 and 24.7 degrees.

In the third embodiment, the proposed form E. This crystalline form of the sodium salt parecoxib is anhydrous and resolutional and is characterized by at least PXRD pattern having at least two values 2θselected from the group consisting of a magnitude of 8.8, 11,3, 15,6, 22,4, 23,5 and 26.4 degrees.

It is also proposed drug substance sodium salt parecoxib, in which at least about 90%, preferably at least about 95%, more preferably, essentially all the sodium salt parecoxib is one or more anhydrous resolutionunit crystalline forms described above. This drug substance is stable when stored intermediate product, which can be further processed, for example, by dissolving or dispersing in an aqueous medium together with one or more parenteral acceptable excipients followed by lyophilization of the resulting solution or suspension to obtain personalemail injectable composition suitable for therapeutic use.

Also proposed is a method of treatment SOH-2-indirectly what about the disease in a patient, moreover, this method includes the introduction to the patient a therapeutically effective amount of a pharmaceutical composition containing such medicinal substance sodium salt parecoxib and at least one pharmaceutically acceptable excipient.

Also, a method of using such drug substance sodium salt parecoxib in the manufacture of drugs for the treatment of MOR-2-mediated diseases.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 shows the PXRD pattern of form a sodium salt parecoxib in example 4.

Figure 2 shows an infrared spectrum with Fourier transform (FTIR) form a sodium salt parecoxib in example 5.

Figure 3 shows thermogram of differential scanning calorimetry (DSC) of form a sodium salt parecoxib in example 6.

Figure 4 shows the profile of the moisture sorption at 25°for the form And example 7.

Figure 5 shows the PXRD pattern of form of sodium salt parecoxib in example 4.

Figure 6 shows the FTIR spectrum of form of sodium salt parecoxib in example 5.

7 shows the DSC thermogram of form of sodium salt parecoxib in example 6.

On Fig shows the profile of the moisture sorption at 25°for the form In example 7.

Figure 9 shows the PXRD pattern of form E sodium salt parecoxib in example 4.

Figure 10 shows the spectra is R FTIR form E sodium salt parecoxib in example 5.

Figure 11 shows the DSC thermogram of form E sodium salt parecoxib in example 6.

On Fig shows the profile of the moisture sorption at 25°for the form E according to example 7.

DETAILED description of the INVENTION

It was found that the sodium salt parecoxib exists in the form of an unexpectedly large number anhydrous resolutiony crystalline forms. Detection and characterization of these crystalline forms, each of which shows the benefits of receiving, cleaning, storing and preparation of sodium salt parecoxib, provide the main advantage in this area by improving the economic feasibility an important new therapeutic agent.

Also found numerous hydrate and solvate. They have a tendency to instability, gradually releasing the water or solvent and turning into other forms of stable States. It is possible that some values of 2θlisted here as the characteristic PXRD pattern of form a, b or E, can also occur in the hydrate or the MES. However, the new waterless nonsolvated crystalline forms of the present invention is easily distinguished from such hydrate or solvate due to the stability of their PXRD pattern under conditions where hydrate and solvate are unstable due to the release of water and RA is the God of the crystal lattice.

Form And

The first of the new waterless resolutiony crystalline forms of picture shows PXRD having at least two values 2θselected from the group consisting of values of 5.6 and 9.6, 11.0 and 14.5 degrees, and is described here as a form of A. alternatively or in addition, the form may be characterized by PXRD pattern having a value of 2θlocated essentially in accordance with table 1 in example 5. Alternatively or in addition, the form may be characterized by the PXRD pattern essentially in accordance with Fig 1.

Alternatively or in addition, form a can be characterized by a FTIR spectrum essentially in accordance with figure 2.

Alternatively or in addition, form a can be characterized by a DSC thermogram essentially in accordance with Fig 3.

In one preferred embodiment of the invention the proposed drug substance sodium salt parecoxib, where at least about 90%, more preferably at least about 95% and still more preferably, essentially all the sodium salt parecoxib is present in the form of A. This drug is suitable in the amount of at least about 1 g, preferably at least about 10 g, more preferably in ENISA least about 100 g, and most preferably, at least about 1 kg, for storage on an industrial scale sodium salt parecoxib and for further processing in the manufacture of the form of the medicinal product sodium salt parecoxib suitable for therapeutic administration.

Form

The second of the new waterless resolutiony crystalline forms of picture shows PXRD having at least two values 2θselected from the group consisting of quantities 4,2, 8,3, 12,4, 16,7, 17,5, 20,8 and 24.7 degrees, and is described here as a form of C. alternatively or in addition, the form may be characterized by PXRD pattern having a value of 2θlocated essentially in accordance with table 2 in example 5. Alternatively or in addition, the form may be characterized by the PXRD pattern essentially in accordance with figure 5.

Alternatively or in addition, the form may be characterized by a FTIR spectrum essentially in accordance with 6.

Alternatively or in addition, the form may be characterized by a DSC thermogram substantially as according to Fig.7.

In another preferred embodiment of the invention the proposed drug substance sodium salt parecoxib, where at least about 90%, more preferably at least approximately the nutrient 95% and even more preferably, essentially all the sodium salt parecoxib is present in the form Century.

Form E

The third of the new waterless resolutiony crystalline forms of picture shows PXRD having at least two values 2θselected from the group consisting of a magnitude of 8.8, 11,3, 15,6, 22,4, 23,5 and 26.4 degrees, and is described here as a form of E. alternatively or in addition, form E can be characterized by PXRD pattern having a value of 2θlocated essentially in accordance with table 3 in example 5. Alternatively or in addition, form E can be characterized by the PXRD pattern essentially in accordance with the Fig.9.

Alternatively or in addition, form E can be characterized by a FTIR spectrum essentially in accordance with figure 10.

Alternatively or in addition, form E can be characterized by a DSC thermogram essentially in accordance with 11.

In another preferred embodiment of the invention the proposed drug substance sodium salt parecoxib, where at least about 90%, more preferably at least about 95% and still more preferably, essentially all the sodium salt parecoxib is present in a form that is

Obtaining sodium salt parecoxib

Sodium salt parecoxib suitable p and any anhydrous resolutiony crystalline forms or any of medicinal substances sodium salt parecoxib, described above, can be obtained in any suitable way, including by methods known in themselves. In one such method, the synthesis of sodium salt parecoxib (III) includes five chemical steps, starting from commercially available starting materials, and is shown in scheme 1.

Scheme 1

In the first stage in the reaction vessel load 210 kg deoxybenzoin (IV), 711 litres of ethanol and 77 liters of 80% aqueous acetic acid. In the alternative case can be used glacial acetic acid (63 liters) and water (16,5 litres). The mixture is heated to 70°and add 71 liter of 50% aqueous hydroxylamine and 55 gallons of water. The mixture was kept at 70°C for at least 1 hour. In the reaction are checking to ensure that the number of non-reacted deoxybenzoin (IV) is not more than 0.5%.

The mixture is cooled and maintained at 45°With, while adding water (266 liters) for crystallization of the product. In the mix you can make the seed, if the crystallization begins. The temperature of the mixture support at 45°C for at least 1 hour and then slowly add water (816 liters) for a complete precipitation of the product. The mixture is cooled to 20°and incubated at 20°C for at least 1 hour.

Read the t distinguish, washed with a mixture of ethanol and water (at least 420 litres, with the ratio of ethanol to water is 1:2) and then water (at least 168 liters). The product is dried at temperatures up to 55°C in vacuum until the residual amount of water is not more than 0.5%, while receiving the reaction of 1,2-diphenylethanone (V) with a regular output 223 kg (106 wt.%).

In the second stage in the reaction vessel is loaded by the reaction of 1,2-diphenylethanone (V) (93 kg) and tetrahydrofuran (THF, 620 liters).

The solution is cooled and added dropwise n-exility (248 kg) while maintaining the temperature of 10°With or below. For washing lines transfer use the minimum number of heptane and liquid after rinsing added to the reaction mixture.

After adding n-hexalite the reaction mixture is cooled to -15°or lower and add ethyl acetate (237 liters). The reaction mixture was quenched by adding it to the solution of sodium chloride (41 kg) in water (474 litres) while maintaining the temperature at 15°With or below. The reaction vessel and lines transfer rinse with ethyl acetate (118 liters).

The layers are separated and the organic phase washed with sodium bicarbonate solution (28.4 kg) in water (474 litres). The organic phase is diluted with toluene (355 liters) and the mixture is distilled at atmospheric pressure to remove about two thirds of the mass. The hot solution is diluted with heptane (100 liters), cooled to 5°and incubated at 5°C for at least 1 hour. The precipitated product is separated and washed with a mixture of heptane and toluene (at least 110 litres, with the ratio of heptane to toluene 1:1).

The product is dried in vacuum at temperatures up to 50°C losses during drying (LOD) will be not more than 0.5%, while receiving 4,5-dihydro-5-methyl-3,4-diphenyl-5-isoxazole (VI) with a regular output 72 kg (77 wt.%).

In the third stage in the reaction vessel load 4,5-dihydro-5-methyl-3,4-diphenyl-5-isoxazole (VI) (152 kg) and triperoxonane acid (TFA, 116 liters). The mixture is cooled and added dropwise chlorosulfonic acid (705 kg) while maintaining the temperature of the reaction mixture below 25°C.

After complete addition, the reaction mixture is slowly heated to 60°C and maintained at 60°C for 1 hour. The reaction mixture is cooled and quenched by adding it to a mixture of water (456 liters) and toluene (570 liters), which is maintained at a temperature below 25°during this addition. The reaction vessel and lines transfer rinse with a mixture of water (152 liters) and toluene (61 liter). The layers are separated and the organic phase washed with water (220 liters).

The organic phase is treated with an aqueous ammonium hydroxide (190 liters) and the mixture is heated to 35°and incubated at 35°C for at least 30 minutes. In the reaction are checking on what I guarantee, what is the pH of the aqueous phase is not less than 9.

Add isopropyl alcohol (729 liters) and the mixture is incubated at 35°C for at least 1 hour. The mixture is cooled to 20°and incubated at 20°C for at least 1 hour. The precipitated product is isolated and washed with isopropyl alcohol (304 liter) and then with water (at least 101 litre).

The crude product is dissolved in hot methanol (709 liters). The solution is filtered to remove sediments and diluted with additional methanol (355 liters) and water (274 liters). The mixture is heated to 70°to dissolve the solids and then cooled slowly to initiate the crystallization of the product. In the mix you can make the seed, if the crystallization starts at the time when the temperature reaches 45°C. After crystallization occurs, the mixture is stirred at 50°C for at least 1 hour and then slowly cooled to 5-10°C and maintained at this temperature for at least 1 hour. The product is isolated and washed with a mixture of methanol and water (at least 95 liters when the ratio of methanol to water is 3:1). Alternatively the product can be purified by recrystallization from a mixture of ethanol (1300 liters) and water (68 liters) using the same procedure, which is described above.

The product is dried in vacuum at temperatures up to 100&x000B0; With up until the amount of residual solvents, certain LOD or gas chromatography, is not more than 0.5%, while receiving 4-(5-methyl-3-phenyl-4-isoxazolyl)benzosulfimide (VII) with a regular output 103 kg (62 wt.%).

In the fourth stage in the reaction vessel load 4-(5-methyl-3-phenyl-4-isoxazolyl)benzosulfimide (VII) (21 kg) and propionic anhydride (86 kg). The resulting suspension is heated to 50°and add sulfuric acid (21 ml). The reaction mixture is heated to 80°and incubated for at least 30 minutes.

The mixture is slowly cooled to 50°to initiate crystallization of the product. The mixture was kept at 50°C for at least 30 minutes after initiation of crystallization. In the mix you can make the seed, if the crystallization starts at 50°C. the Mixture is slowly cooled to 0°and incubated for at least 1 hour to complete the crystallization.

The product is separated, washed with methyl tert-butyl ether (80 litres) and partially dried on the filter until then, until the scan will not show that LOD is not more than 5%, thus obtaining n-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propanamide (VIII) in the form of a wet sludge, which is transferred directly to the fifth stage without further purification or drying.

In the fifth stage of the wet sediment, Paul is obtained in the fourth stage, dissolved in absolute ethanol (12.6 kg/kg (VIII), based on dry weight) at 45°and the mixture is filtered to remove particles.

In a separate reaction vessel receiving sodium hydroxide solution (approximately 5 wt.%) in absolute ethanol and both molarity of a solution is determined by titration. The calculated quantity of sodium hydroxide solution is added through a filter in the line to the solution (VIII) in ethanol and the mixture is incubated at 45°and add a seed to initiate crystallization.

After depositing the seed mixture is heated to 50°C, incubated for at least 30 minutes and then cooled to 0°to complete the crystallization. The mixture was stirred at 0°C for at least 30 minutes and the product is isolated and washed with cold absolute ethanol (at least 88 kg).

Finally, the product is dried in vacuum at temperatures up to 135°thus the sodium salt parecoxib (III) with a regular output of 17.2 kg (82 wt.%).

It should be clear that the above method is proposed for illustrative purposes. Variants of the above method, is not beyond the bounds of the present invention, including the terms and scope of the method can easily be done by a specialist in this field of technology.

Receipt of forms a, b and E sodium salt parecoxib

Unexpectedly it was found that the time of the fifth stage of the method described above, small changes in drying conditions cause the formation of various anhydrous solvated and hydrated crystalline forms. At least part of the obtained sodium salt parecoxib is usually in the form of MES ethanol. You can get the ethanol solvate of the sodium salt parecoxib with different stoichiometry, i.e. more or less solvate of ethanol, which is directly related to the efficiency of drying.

Regardless of the crystalline form of the sodium salt parecoxib obtained in the fifth stage, if the temperature was raised to approximately 210°during or after drying, the sodium salt parecoxib turns into form A. When cooled sodium salt parecoxib is stored in the form of A.

In accordance with this offered the first method for the form And the sodium salt parecoxib containing stage heating crystalline form of the sodium salt parecoxib other than the forms And, to a temperature of from about 210°C up to the melting point of sodium salt parecoxib over a period of time sufficient to convert the sodium salt parecoxib in the form, and cooling the formed form a sodium salt parecoxib to the ambient temperature.

In addition, it was found that a mixture of forms a and MES ethanol sodium salt parecoxib can be converted essentially in pure form And heating the mixture at ambient pressure for about 3 hours out who sustained fashion at 150° C.

In accordance with this proposed second method of obtaining the shape And sodium salt parecoxib, including the stage of heating the MES ethanol sodium salt parecoxib in the presence of the form And the sodium salt parecoxib to a temperature of from about 150°C up to the melting point of sodium salt parecoxib for a period sufficient to convert MES ethanol in the form, and cooling the formed form a sodium salt parecoxib to the ambient temperature.

Also it was found that the amorphous form of sodium salt parecoxib, which can be obtained by dissolving any solid form of sodium salt parecoxib in water, followed by lyophilization, is transformed into the form And when heated from about 125°With up to approximately 130°in the absence of moisture.

Accordingly, proposed a third way for the form And the sodium salt parecoxib, including the stage of heating the amorphous or liofilizovannyh sodium salt parecoxib, essentially in the absence of moisture, to a temperature of approximately 125°C up to the melting point of sodium salt parecoxib for a period sufficient to convert the amorphous or liofilizovannyh sodium salt parecoxib in the form, and cooling the formed form a sodium salt parecoxib to the temperature surrounding the it environment.

A method of obtaining a medicinal substance sodium salt parecoxib containing at least 90% of the forms And involves the stages (a) crystallization of sodium salt parecoxib of make solvent (e.g. ethanol) to obtain the crystalline form of the sodium salt parecoxib and (b) heating the formed crystalline sodium salt parecoxib at a temperature of approximately 110°With up to approximately 230°to obtain the desired drug substance sodium salt parecoxib.

At levels of relative humidity (RH) is higher than approximately 60% RH, form And turns over time gidratirovannuyu crystalline form. Complete metamorphosis in the hydrate occurs, for example, after keeping the form And under the influence of about 75% RH for a period of approximately 3 to approximately 7 days. It was found that when the hydrate is dried at ambient temperature, for example, drying over effective dessicant, such as R2About5form a solid state is not converted back to the form, but instead, becomes a form Century.

In line with this, the method for obtaining the form of sodium salt parecoxib, including the stage of drying the hydrated crystalline form of the sodium salt parecoxib over dessicant at temperatures below, th is the temperature, which causes the formation of form a, with the formation of the form of sodium salt parecoxib.

Form E sodium salt parecoxib can be obtained by recrystallization of MES ethanol sodium salt parecoxib from heptane to form crystals form E.

Properties forms a, b and E sodium salt parecoxib

Isotherms of sorption of moisture for forms A, b and E when the ambient temperature is shown in figure 4, 8 and 12, respectively. Form And absorbs less than 1% moisture at RH below approximately 60%, but at RH above approximately 60% has a tendency to adsorb water and even liquefied. Forms b and E are less hygroscopic than the form And, thereby detecting a weak tendency for sorption of water even when RH to approximately 80%.

Lower hygroscopicity forms b and E compared with the form As may be agreed by reference to the relative thermodynamic stability of these forms of solid state. As shown in the diagram, the energy/temperature Fig, form a has a higher energy level than the form b and E, which are similar to each other. It is believed, without claims on theory that forms b and E are less hygroscopic than the form And, because they have a lower energy level, which is the more thermodynamically stable States.

The relative ease with which the form may be obtained from other forms of solid-state sodium salt parecoxib on an industrial scale, for example, a method of heating and cooling, is unexpected and provides basic commercial advantage form A. After receiving the form And exhibits a high degree of stability and in this respect provides an advantage over hydrate and a solvate, for example, it is believed that the result of the method proposed in the above-cited U.S. patent No. 5932598 is MES ethanol. The existence of different hydrate and solvate with different stechiometry leads to a change of product, which is overcome by the present invention. When you want more low hygroscopicity, shape and form, we have the advantage in this respect over form A.

The usefulness of the forms a, b and E sodium salt parecoxib

As indicated previously, the new crystalline form of the sodium salt parecoxib proposed by the present invention are particularly suitable for use as a drug substance or API, which you can store up until it is ready for further processing to obtain the pharmaceutical composition. These forms can, if necessary, to enable as such together with one or more pharmaceutically acceptable excipients in the drug in the solid state, such as a tablet or capsule for oral administration or gel or patch to the local in which edenia. If necessary, the particle size of these crystal forms may be reduced or made more uniform by milling or grinding, or by other physical methods before receiving the drug.

In the alternative case, the new crystalline form can be transformed into a non-crystalline form, for example, a solution or amorphous form, when receiving the pharmaceutical composition. For example, new crystalline forms can be considered as a stable intermediate products of the method.

In one embodiment of the present invention, a method for obtaining a pharmaceutical composition useful in the treatment of MOR-2-mediated disorders, and the method includes the stage of dissolution in the aqueous environment of medicinal substance sodium salt parecoxib, where at least 90% of the sodium salt parecoxib is in one or more forms from the forms a, b and E, together with at least one pharmaceutically acceptable excipient, with formation of a solution.

This solution can be ready to use injectable composition. In the alternative case, such a solution may be subjected to additional stages of the freeze-drying to obtain a solid pharmaceutical composition in the form of particles containing sodium salt parecoxib. This composition can be vos is set by adding a parenterally acceptable aqueous diluent with the formation of an injectable solution of sodium salt parecoxib. It is implied that the term "solution"as used in relation to material that you want to lyophilisate includes a suspension and a true solution.

In accordance with the present invention, preferably, at least about 90%, more preferably at least about 95% of the drug substance, which is dissolved in the aqueous medium before the formation of the pharmaceutical composition, was form a or form B, or form, that is, Most preferably, when such a drug is essentially a pure phase form a, form b or form E.

therapeutic method of use

The medicinal substance according to the invention after the conversion or inclusion in a pharmaceutical composition, as described above, is useful for the treatment and prevention of a wide range of disorders mediated MOR-2, including, but not limited to, disorders characterized by inflammation, pain and/or fever. Such compositions are especially valuable as anti-inflammatory agents, such as agents for the treatment of arthritis, an additional advantage is that they are significantly less harmful side effects, especially with the systemic administration than song common NSAID, which deprived select the activity in relation to MOR-2 compared to MOR-1. Thus, compositions according to the invention are particularly useful as alternatives to conventional NSAID where such NSAIDs are contraindicated, for example, for patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a history of disease with recurrent gastrointestinal damage; for the treatment of gastrointestinal bleeding, coagulation disorders including anemia such as gipoprotrombinemiey hemophilia or other bleeding problems; kidney disease, or for administration to patients before surgery, or patients receiving anticoagulants.

Consider the compositions are useful in the treatment of various arthritic disorders, including but not limited to the above, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis.

Such compositions are useful in the treatment of asthma, bronchitis, menstrual pain, premature labor, tendinitis, bursitis, allergic neuritis, cytomegalovirus infection, apoptosis including HIV-induced apoptosis, lumbago, liver disease including hepatitis related to skin conditions such as psoriasis, eczema, burns, dermatitis and damage to the ultraviolet radiat is her including sunburn, and postoperative inflammation.

Such compositions are useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis.

Such compositions are useful in treating inflammation in such diseases as headache type migraine, periarteritis nodosa, thyroiditis, gipoplasticheskaya anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetic, disease neuromusculo compounds, including heavy gravis, a disease of the white matter, including multiple sclerosis, sarcoidosis, nephrotic syndrome, behceta, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury including brain edema, myocardial ischemia, and the like.

Such compositions are useful in the treatment of eye diseases such as retinitis, conjunctivitis, retinopathy, uveitis, ocular photophobia, and of acute damage to the eye tissues.

Such compositions are useful in the treatment of inflammation of the lungs, such as pneumonia associated with viral infections and cystic fibrosis, and when resorption of bone, such as bone resorption associated with osteoporosis.

Such com is osili are useful in the treatment of some disorders of the Central nervous system, such as cortical dementias including Alzheimer's disease, neurodegeneration and damage to the Central nervous system resulting from stroke, ischemia and trauma. The term "treatment" in this context includes partial or total inhibition of dementia, including Alzheimer's disease, vascular dementia, preinfarction dementia, presenilny dementia, alcoholic dementia and senile dementia.

Such compositions are useful in the treatment of allergic rhinitis, respiratory distress syndrome, syndrome, endotoxin shock and liver disease.

Such compositions are useful in the treatment of pain, including but not limited to the above, postoperative pain, dental pain, muscular pain, and pain resulting from cancer. For example, such compositions are useful for calming or relief of pain, fever and inflammation in various conditions, including rheumatic fever, influenza and other viral infections, including runny nose, sore lower back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and alkiliruushim spondylitis, bursitis, burns and damage after the surgery the definition and dental procedures.

Such compositions are useful for the treatment and prevention-related inflammation, cardiovascular disorders, including cardiovascular disease, disease of the coronary arteries, aneurysm, vascular rejection of grafts, atherosclerosis, arteriosclerosis, including atherosclerosis, heart transplant, myocardial infarction, embolism, stroke, thrombosis, including venous thrombosis, angina including unstable angina, inflammation of the coronary plaque caused by bacteria inflammation, including inflammation, Chlamydia-induced inflammation, induced by viruses, and inflammation associated with surgical procedures such as vascular transplantation, including coronary artery revascularization procedures including angioplasty, stentofon placement, endarterectomy, or other invasive procedures involving arteries, veins and capillaries.

Such compositions are useful for treating angiogenesis disorders in the patient, for example, for the inhibition of tumor angiogenesis. Such compositions are useful in the treatment of neoplasia, including metastasis; ophthalmological conditions such as corneal rejection of the transplant, eye revascularization, retinal revascularization, including the formation of new blood vessels after which uridine or infection, diabetic retinopathy, macular degeneration, retrolental fibroplasia and-neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological, but non-malignant conditions such as hemangiomas, including baby hemangioma, angiofibroma of the nasal part of the pharynx and avascular necrosis of bone, and disorders of the female reproductive system such as endometriosis.

Such compositions are useful in the treatment of precancerous diseases, such as senile keratosis.

Such compositions are useful in the prevention, treatment and inhibition of benign and malignant tumors and neoplasias, including neoplasia metastasis, for example, in colorectal cancer, cancer of brain, bone cancer, neoplasia, formed from epithelial cells (epithelial carcinoma)such as carcinoma, basal cell adenocarcinoma, gastrointestinal cancer such as cancer of the lip cancer of the oral hole, the esophagus cancer, cancer of the small intestine, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, such as cancer squamous cell and basal cell cancer, prostate cancer, renal carcinoma cells, and other known cancers that have de is the effect on the epithelial cells throughout the body. It is assumed that alterations, for which the compositions of the invention are particularly useful are gastrointestinal cancer, Barrett esophagus, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer. Such compositions can be used in the treatment of patients with adenomatous polyps, including patients with familial adenomatous polyposis (FAP). In addition, such compositions can be used for preventing the formation of polyps in patients with risk of FAP.

In particular, the composition can be used in the treatment, prevention and inhibition lentiginous melanoma peripheral parts of the body, senile keratoses, adenocarcinoma, aminokislotnoi carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, carcinoma of the Bartholin glands, basal cell carcinoma, breast cancer, carcinoma, bronchial glands, capillary hemangioma, carcinoids, carcinosarcoma, cavernous hemangioma, cholangiocarcinoma, chondrosarcoma, papilloma or carcinoma of the choroid plexus, kidney cancer, T-cell lymphoma (mycosis fungoides), cystadenoma, dysplastic nevi, tumor endodermal sinus, endometrial hyperplasia, endometrial stromal sarcoma, endometrial adeno is antinomy, ependymomas, epitelialnogo angiomatosis, abnormal Ewing sarcoma, fibrolamellar sarcoma, focal nodular hyperplasia, gastronomy, germinoma, glioblastomas, glucagonoma, hemangioblastoma, hemangioendothelioma, hemangioma, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intraepithelial neoplasia, megapixeles squamous neoplasia, invasive squamous cell carcinoma, Kaposi's sarcoma, both sarcoma, leiomyosarcoma, lentigo malignant melanoma, malignant melanoma, malignant mesothelial tumor, Protocol, medulloepithelioma, melanoma, meningioma, mesothelioma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma, nodular melanoma, ovenoven cell carcinoma, oligodendrogliomas, osteosarcoma papillary serum adenocarcinoma, pineal tumors, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cancer, retinoblastoma, rhabdomyosarcoma, sarcoma, serum carcinoma, small cell lung cancer, carcinoma of the soft tissues, somatostatin-secreting tumor, squamous carcinoma, squamous cell cancer, submesothelial carcinoma, superficial melanoma, undifferentiated carcinoma, uveal melanoma, verrucose carcinoma, lipoma, well what about the differentiated carcinoma and Wilm tumor.

Such compositions inhibit induced prostanoid smooth muscle contraction by inhibiting synthesis contractile of prostanoids and hence may be used in the treatment of dysmenorrhea, premature labor, asthma and related eosinophils violations. They can also be used to reduce bone loss, especially in posleprodazhnyj women (i.e. for the treatment of osteoporosis and for the treatment of glaucoma.

Compositions according to the invention is preferably used for the treatment of rheumatoid arthritis and osteoarthritis, pain (especially pain after surgery of the mouth, pain after General surgery, pain after orthopedic surgery and acute exacerbations of osteoarthritis), for the prevention and treatment of headaches and migraines, for the treatment of Alzheimer's disease for chemoprevention of colon cancer.

The introduction can be carried out by any means, including parenteral, oral, rectal, intra-lungs, nasal, ear and the local path. Local application of the composition of sodium salt parecoxib received from one or more of the forms a, b and E, can be particularly useful when treating any kind of skin disorders having an inflammatory component, regardless of whether the violation malignant, non-malignant or precancerous, including the image is of the rumen and ketosis and including burns and sun damage for example, sunburn, wrinkles, etc. Such compositions can be used to treat inflammation resulting from various skin damages, including, without limitation, damage caused by viral diseases, including herpes infection (e.g., skin ulcers, genital herpes), herpes zoster and varicella. Other damage or lesions on the skin that can be treated with such compositions include bedsores (decubitus ulcers), hyperproliferative activity in the epidermis, prickly heat, psoriasis, eczema, acne, dermatitis, scabies, growths and rosacea. Such compositions may also facilitate the healing process after surgical procedures, including cosmetic procedures such as chemical peeling, laser treatment, dermabrasion, cosmetic surgery on the face to remove wrinkles, eyelid surgery, etc.

Besides the fact that the composition of the invention are useful for treatment of humans, they are also useful for veterinary treatment of animals-human companions, exotic animals, farm animals, etc., especially mammals, including rodents. More specifically, the composition of the invention are useful for veterinary treatment of MOR-2-mediated disorders in horses, dogs and cats.

Real com is osili can be used in combination therapies with opioids and other analgesics, including narcotic analgesics, Mu receptor antagonists, receptor antagonists Carr, non-narcotic (i.e. not without addiction) analgesics, inhibitors capture monoamine regulating adenosine agents, cannabinoid derivatives, antagonists of substance P, antagonists of the receptor neirokinina-1 and blockers of sodium channels among other medicines. Preferred combination therapies include use of the composition according to the invention with one or more compounds selected from aceclofenac, acemetacin, ε-acetamidocinnamic acid, acetaminophen, acetaminophe, acetanilide, acetylsalicylic acid, S-adenosylmethionine, alclofenac, Alfentanil, allylprodine, alminoprofen, aloxiprin, Alphaprodine, aluminum bis(atsetilsalitsilata), amfenac, aminofluorescein, 3-amino-4-hydroxybutiric acid, 2-amino-4-picoline, aminopropylene, aminopurine, amixetrine, ammonium salicylate, ampiroxicam, amtolmetin of guacil, Anileridine, antipyrine, of antipyrine salicylate, entretenida, Upasana, aspirin, balsalazide, bendazac, benorilate, benoxaprofen, benzoperylene, benzydamine, benzylmorphine, berberine, bioprofile, Bezitramide, α-bisabolol, bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bromocriptine, BU etin, buglakovoj acid, bucolome, bufexamac, bumadizone, buprenorphine, butacaine, butibufen, butorphanol, atsetilsalitsilata calcium, carbamazepine, corbetena, carprofen, karsilama, chlorbutanol, chlorination, choline salicylate, cinchophen, cinmetacin, ciramadol, clidanac, cloretazine, clonitazene, clonixin, kopirati, clove, codeine, codeine bromide, codeine phosphate, codeine sulfate, cropropamide, crocheted, desomorphine, dexoxadrol, dextromoramide, dezocine, diampromide, diclofenac, defenitly, differered, diflunisal, Dihydrocodeine, dihydrocodeinone of enol acetate, dihydromorphine, dihydroxyaluminum atsetilsalitsilata, dimenoxadol, dimepheptanol, dimethylthiambutene, dioksifenilalanina, Dipipanone, dipyridyl, dipirona, dithiazole, droxicam, emorfazone, spinarova acid, epirizole, eptazocine, etanercept, Etisalat, ethenzamide, ethoheptazine, stokesey, ethylmethylthiambutene, Ethylmorphine, etodolac, etofenamate, etonitazene, eugenol, felbinac, fenbufen, fenclova acid, fendosal, fenoprofen, fentanyl, fentiazac, farinola, feprazone, floctafenine, flufenamic acid, flunoxaprofen, fluorenone, flupirtine, floraqueen, flurbiprofen, postsale, hentiesbaai acid, glafenine, glucometry, glycol salicylate, guaiazulene, hydroc the don, hydromorphone, hydroxypethidine, ibufenac, ibuprofen, ibuproxam, imidazole salicylate, indomethacin, indoprofen, infliximab, interlekin-10, softalk, solarola, isomethadone, isolaccia, isoxepac, isoxicam, Ketobemidone, Ketoprofen, Ketorolac, p-lactatemia, lefetamine, Levorphanol, lexipafant, lofentanil, lonazolac, lornoksikama, loxoprofen, lysine atsetilsalitsilata, atsetilsalitsilata magnesium, meclofenamic acid, mefenamovoy acid, meloxicam, meperidine, meptazinol, mesalamine, metazocine, methadone, methotrimeprazine, medicinova acid, metafolin, metopon, mofebutazone, maffesoli, morazone, morphine, morphine hydrochloride, morphine sulfate, morphine musk, myrophine, nabumetone, nalbufina, 1 naphthylisocyanate, naproxen, narceine, nefopam, Nicomorphine, naftazone, niflumova acid, nimesulide, 5'-nitro-2'-propoxyethanol, norlevorphanol, Normethadone, normorphine, norpipanone, olsalazine, opium, oxaceprol, exametazime, oxaprozin, oxycodone, Oxymorphone, oxyphenbutazone, papaveretum, phrenilin, pharsalia, pentazocine, personsal, fenatsetina, phenadoxone, phenazocine, phenazopyridine hydrochloride, finokalia, Phenoperidine, Phenoperidine, phenylacetylglutamine, phenylbutazone, fenilsalitsilata, phenyramidol, pictorion, piminodine, Pipa is the Uzon, piperylene, pyrazole, Piritramide, piroxicam, pirprofen, pranoprofen, proglumetacin, proheptazine, promedol, propacetamol, propiram, propoxyphene, propifenazona, proquazone, proteinwas acid, nomifensine, Remifentanil, Amazonia methyl sulfate, salicylamide, salicin, salicylamide, salicylamide-o-acetic acid, salicylates acid, salsalate, silverina, simetria, sodium salicylate, Sufentanil, sulfasalazine, sulindaka, superoxide dismutase, suprofen, skibotn, talniflumate, tenidap, tenoxicam, terfenadine, tetrandrine, thiazolidinedione, tiaprofenic acid, tiaramide, Tilidine, tinoridine, tolfenamic acid, tolmetin, tramadol, trapezina, Viminale, xenazine, xenoprofile, zaltoprofen, ziconotide and zomepirac (see The Merck Index, 13thEdition (2001), Therapeutic Category and Biological Activity Index, lists, here entitled "Analgesic", "Anti-inflammatore" and "Antipyretic").

Especially preferred combination therapies include use of the composition according to the invention with an opioid compound, more specifically, when the opioid compound is codeine, meperidine, morphine or its derivatives.

The connection is introduced in combination with a composition according to the invention, can be manufactured separately from it and enter any suitable means, including oral, rectal, parenteral or local the application to the skin or to another place. In the alternative case, the compound that is administered in combination with the present composition can be made with it in the form of a composition in the form of a plate coated.

In the embodiment of the invention, especially when the SOH-2-mediated condition is headache or migraine, the present composition is administered in combination therapy with vetmousetrap, preferably, a derivative of xanthine, having vasomodulatory action, more preferably, with alkylresorcinols connection.

Combination therapies, in which alkylresorcinol compound is administered together in the composition, provided here, are included in this version of the invention, regardless of whether alkylating vetmousetrap, and regardless of whether therapeutic efficacy of the combination to any degree to vasomodulatory action. The term "alkylating" here includes xanthine derivatives having one or more1-4-alkyl, preferably methyl substituents, and pharmaceutically acceptable salts of such derivatives of xanthine. Especially preferred are dimethylxanthine and trimethylxanthine, including caffeine, theobromine and theophylline. Most preferably, alkylresorcinol compound is caffeine.

Vasomotor or Ala is xantanovy component of combination therapy can be introduced into any suitable dosage form by any suitable means, including oral, rectal, parenteral or local application to the skin or to another place. Vasomotor or alkylating can be optionally prepared in conjunction with the present composition in the form of a single percutaneous dosage forms. Thus, percutaneous composition according to the invention optionally contains as valdecoxib or its prodrug, or salt, and vasomotor or alkilinity, such as caffeine, in total and relative amounts that are therapeutically effective.

EXAMPLES

The following examples contain detailed descriptions that illustrate the invention without limiting its scope in any way. All percentages are mass, unless otherwise noted. Source material, sodium salt parecoxib used in each of the following examples are in accordance with the above scheme 1.

Example 1: the form And

The form And the sodium salt parecoxib received each of the following methods.

1. An aqueous solution of sodium salt parecoxib lyophilized. The resulting amorphous sodium salt parecoxib placed in a Cup of DSC in the absence of moisture and subjected to heating at a rate of 10°C/minute. Crystallization of sodium salt parecoxib occurs as exothermic process at approximately 125-130°C. the Form And to the of itallow confirm one or more of the PXRD, FTIR, DSC and sorption of moisture, as described below.

2. A mixture of form a and MES ethanol sodium salt parecoxib in the total amount of 10 g was placed in a drying Cabinet at 150°and at ambient pressure for 3 hours. The resulting solid is cooled in the vessel-dessicator containing dessicant Drierite, and the form And crystals confirm one or more of the PXRD, FTIR, DSC and sorption of moisture, as described below.

3. Found that the form E sodium salt parecoxib turns into a form And as a transition in the solid state, observed using DSC as an endothermic process in a broad band of approximately 210°C. the Form And confirm one or more of the PXRD, FTIR, DSC and sorption of moisture, as described below.

The form And characterized data PXRD, FTIR, DSC and sorption of moisture, as shown in figure 1-4, respectively.

Example 2: Retrieving form

The form of the sodium salt parecoxib received each of the following methods.

1. The form And the sodium salt parecoxib exposed to conditions with RH of approximately 75% in a few days to get hydrated crystalline form. Gidratirovannuyu form then dried over dessicant. The form In the formed solids confirm one or more of the PXRD, FTIR, DSC and sorption of moisture, described the lower is.

2. MES ethanol sodium salt parecoxib obtained by recrystallization of 11.5 g of sodium salt parecoxib in 100 ml of ethanol by heating to boiling on a hot plate with magnetic stirring and then cooled in ambient conditions to room temperature. Separately, approximately 1 g of seed crystals of form added to 450 ml of heptane. Their MES of ethanol is collected by vacuum filtration and immediately transferred into a suspension in heptane containing seed crystals of form C. the Resulting suspension is heated to boiling under reflux for 4 hours with vigorous stirring with a magnetic stirrer. The crystals are collected by vacuum filtration and dried at 40°in high vacuum over night, and In the form of crystals confirm one or more of the PXRD, FTIR, DSC and sorption of moisture, as described below.

The form In the characterized data PXRD, FTIR, DSC and sorption of moisture, as shown in figure 5-8, respectively.

Example 3: the form E

Form E sodium salt parecoxib obtained as follows. Sodium salt parecoxib in the form of crystals MES ethanol, obtained by the process 2 of example 2, is transferred to 450 ml of heptane without making seed. The resulting suspension is heated to boiling under reflux in accordance with the s 4 hours with vigorous stirring with a magnetic stirrer. The crystals are collected by vacuum filtration and dried at 40°in high vacuum over night, and form E crystals confirm one or more of the PXRD, FTIR, DSC and sorption of moisture, as described below.

Form E characterized data PXRD, FTIR, DSC and sorption of moisture, as shown in Fig.9-12, respectively.

Example 4: PXRD

Data of powder x-ray diffraction (PXRD) were collected diffractometer Siemens D5000 or Inlet Multipurpose using Cu-Kα-radiation at a voltage of 30 kV and current of 30 mA. Inel was equipped with a sensitive position detector, which takes into account all of the detected data of the diffraction at the same time. The diffractometer was calibrated against internal standards of silicon and mica, along with the direct beam. Capillary measurements were carried out in 1 mm sealed glass capillary mounted on the goniometer head in capillary furnace. For capillary measurements diffractometer was calibrated against the silicon and the direct beam.

Diffraction patterns for forms a, b and C sodium salt parecoxib shown in figures 1, 5 and 9, respectively, and the diffraction peaks for each form are listed in tables 1, 2 and 3, respectively.

Table 1< / br>
Peaks PXDR to form a
d-length (E)the goal 2θ (±0,2)Intensity (%)
15,75,6100,0
9,39,610,3
8,011,0a 12.7
6,114,56,0
of 5.416,56,5
4,022,01,3
3,724,03,7
3,5to 25.32,5

Table 2< / br>
Peaks PXDR for the form B
d-length (E)Angle 2θ (±0,2)Intensity (%)
20,94,274,3
10,68,381,1
7,212,339,3
7,212,422,7
6,912,8100,0
6,813,08,0
6,014,81,0
of 5.416,422,0
5,316,714,6
5,216,1the 9.7
5,1of 17.5 32,4
the 4.718,70,9
4,420,18,6
4,320,63,0
4,320,88,1
a 3.922,74,0
a 3.922,92,6
3,723,821,4
3,724,223,4
3,624,774,9

Table 3< / br>
Peaks PXDR for the form E
d-length (E)Angle 2θ (±0,2)Intensity (%)
10,08,826,2
7,911,3a 12.7
6,912,8100,0
5,815,3of 5.4
the 5.7the 15.622,4
5,117,445,0
the 4.718,725,7
4,5to 19.94,1
4,221,1the 3.8
4,1a 21.53,2
4,022,4 40,8
a 3.922,725,5
the 3.823,511,5
3,724,20,9
3,625,05,8
3,525,79,6
3,425,9a 3.9
3,426,435,2
3,326,87,4
3,227,82,6

Example 5: FTIR spectroscopy

Infrared spectra with Fourier transform (FTIR) were recorded by a spectrophotometer Nicolet Nexus 670 FT-IR. The specimens were scanned using assistive devices to obtain attenuated total reflectance (ATR) Nicolet SMART DuraSamp1IR. The samples were scanned at a resolution of 4 cm-1averaged only 64 view from 4000 to 400 cm-1.

FTIR spectra of forms a, b and E sodium salt parecoxib in the range from 4000 to 500 cm-1shown in figure 2, 6 and 10, respectively.

Example 6: DSC

The differential scanning calorimetry (DSC) was collected Mettler-Toledo DSC 821. The temperature and enthalpy were calibrated with indium and zinc standards. The samples were analyzed either sealed or punctured by a pin 40 Ál aluminum h is skach at a temperature of from 25° With up to 300°. The heating rate was 10°/minute and the speed of blowing nitrogen was 50 ml/minute.

The DSC thermogram for form A, b and E sodium salt parecoxib shown in figure 3, 7 and 11, respectively.

Form And showed a single melting endotherm with beginning approximately 273,1° (ΔNt= to 23.8 kJ/mol). The form showed endotherm beginning approximately 195,9° (ΔNt= 20,71 kJ/mol), representing the transformation in the form And then clear the melting endotherm for the form And when 273,7°C. Form E showed a broad endotherm with a beginning about to 206.6° (ΔNt= 18.3 kJ/mol), representing the transformation in the form And then clear the melting endotherm for the form And when 273,2°C. Microscopy hot stage it was confirmed that the conversion to forms b and E in the form And before melting are solid phase transitions.

On the basis of the rules of the heat of transition is considered that the form and form E enantiotropic refer to form a, this means that there is a change in the connection stability between forms near the transition temperature Tt. The definition of Ttfor forms b and E on the form And held through the use of data eutectic melting.

Eutectic mixture received from the reference connection (RC) and each of the forms a, and the sodium salt parecoxib. Then, the data of the heat of fusion was used for calculating the difference of free energies between the crystalline forms at the eutectic temperature (equation 1):

where xejand xeirepresent the molar proportion of the crystalline forms i and j, respectively, in eutectic; (Gj-Gj) is the difference of free energies between the crystalline forms i and j at Tei; ΔHmejand ΔHmeirepresent the enthalpy of the eutectic melting point of the crystalline forms j and i, respectively; Teiand Tejrepresent temperature eutectic melting of the crystalline forms i and j, respectively; ΔCpijrepresents the change of heat capacity at the ends of the eutectic melting point and R is the ideal gas constant.

Data eutectic melting for forms A, b and E with the selected reference compounds are given in table 4.

Table 4< / br>
Data eutectic melting for forms A, b and E
Form AndFormForm E
the melting point °274-276Phase transformationPhase ol the rotation
RC is phenacetin
xe0,250,250,25
Tethat °With (average)118,2of 124.7of 124.7
ΔNmekJ/mol24,6425,9927,08
RC is benzanilide
xe0,170,180,18
Tethat °With (average)155,6of 156.6156,2
ΔNmekJ/molweighing 28.3231,9531,42
RC is sulopenem
xe0,420,420,42
Tethat °With (average)171,7USD 170.1USD 170.1
ΔNmekJ/mol25,8236,8334,62

Data eutectic melting confirm, while the relationship between forms a and either B, or E. Other thermodynamic parameters obtained from charts ΔG-T (ΔS and ΔG/T-/T (Δ H), are given in table 5. ΔN for pairs of the form S/form a and form/shape And dimension calorimetry solutions as proposed in table 5 for comparison.

Table 5< / br>
Thermodynamic parameters
Forms/TransitionΔH (kJ/mol)ΔS (j/mol/K)Tt(°C)
LT = form, HT = form16,63 [15,34*]38,1163,3
LT = form E, HT = form17,15 [17,94*]39,2163,9
LT = low temperature form

HT = high-temperature form

*ΔN from the data of heat of solution

Discovered that the forms b and E are quite close in energy, at the same time discovered that the form And has a higher energy in relation to the form and shape that is, the Order of stability is correlated with the true data density of the crystalline forms, measured using helium by pycnometric one (form, 1,46±0.01 g/cm3; form F, 1,42±0.01 g/cm3; form And, 1,34±0.01 g/cm2).

According to the definition of the difference of free energies between the crystalline forms is zero at the transition temperature. The temperature of the transition is, shown above in table 5, were calculated according to equation II:

Similar junction temperature for pairs of the form S/form a and form/shape And are associated with a slight difference of energies between E and C. Similar free energies of the form E and make it difficult to establish the fact that the form is more thermodynamically stable at ambient temperature. For example, the data of heat of solution and eutectic melting suggest that the form E is more stable, while the DSC data suggest that the form is the more stable form on the basis of the energies of the transition.

Example 7: Sorption moisture

These sorption of moisture collected at 25°and RH from 0% to 80% using the analyzer's dynamic water vapor sorption Surface Measurement Systems. Window balance was for dm/dT 0,0003 or maximum time of 120 minutes.

Profile of sorption of moisture form a sodium salt parecoxib at 25°shown in figure 4. Form And sorbirovanna less than 1% of moisture over the range 0-60% RH, but radigales at RH above 60%.

Profiles sorption moisture forms b and E sodium salt parecoxib shown in Fig and 12, respectively. Found that both the form and the form E, are less hygroscopic than form A, sorbera less than 1% of moisture over the full test d is apatone RH 0-80%.

1. Sodium salt parecoxib in crystalline form having characteristic peaks in the powder x-ray obtained using Cu-radiation source, expressed in degrees 2θselected from the group at least consisting of values of 5.6 and 9.6, 11.0 and a 14.5±0,2° (form And), 4,2, 8,3, 12,4, 16,7, 17,5, 20,8 and 24.7±0,2° (form In), 8,8, 11,3, 15,6, 22,4, 23,5 and 26.4±0,2° (form E), which is essentially anhydrous and essentially resolutional.

2. Sodium salt parecoxib according to claim 1, having the characteristic peaks in the powder x-ray obtained using Cu-radiation source, expressed in degrees 2θat least consisting of values of 5.6 and 9.6, 11.0 and a 14.5±0,2°, which is a form of A.

3. Sodium salt parecoxib according to claim 1, which is a form And having at least a picture of the powder x-rays, essentially corresponding to Fig 1.

4. Sodium salt parecoxib according to claim 1, which is a form And having at least an infrared spectrum with the Fourier transform, essentially corresponding to figure 2.

5. Sodium salt parecoxib according to claim 1, which is a form And having at least a thermogram of differential scanning calorimetry, essentially corresponding to Fig 3.

6. Sodium salt parecoxib according to claim 1, having the characteristic peaks then is Savoy x-rays, obtained using Cu-radiation source, expressed in degrees 2θat least consisting of values 4,2, 8,3, 12,4, 16,7, 17,5, 20,8 and 24.7±0,2°, which is a form of Century

7. Sodium salt parecoxib according to claim 1, which is a form having at least a picture of the powder x-rays, essentially corresponding to figure 5.

8. Sodium salt parecoxib according to claim 1, which is a form having at least an infrared spectrum with the Fourier transform, essentially corresponding to Fig.6.

9. Sodium salt parecoxib according to claim 1, which is a form having at least a thermogram of differential scanning calorimetry, essentially corresponding to Fig.7.

10. Sodium salt parecoxib according to claim 1, having the characteristic peaks in the powder x-ray obtained using Cu-radiation source, expressed in degrees 2θat least consisting of values of 8.8, 11,3, 15,6, 22,4, 23,5 and 26.4±0,2°that is the form that is

11. Sodium salt parecoxib according to claim 1, which is a form of E that have at least a picture of the powder x-rays, essentially corresponding Fig.9.

12. Sodium salt parecoxib according to claim 1, which is a form of E, having at least an infrared spectrum with the Fourier transform, essentially corresponding to figure 10.

13 Sodium salt parecoxib according to claim 1, which is a form of E, having at least a thermogram of differential scanning calorimetry, essentially appropriate 11.

14. Sodium salt parecoxib with the content of at least about 90% of one or more anhydrous resolutiony crystalline form according to claim 1, having the properties of a selective inhibitor of cyclooxygenase-2 (MOR-2), as the active ingredient to obtain a pharmaceutical composition.

15. Sodium salt parecoxib on 14 content of at least about 95% of one or more anhydrous resolutiony crystalline forms.

16. Sodium salt parecoxib on 14, essentially representing only one or more anhydrous resolutiony crystalline forms.

17. Sodium salt parecoxib on 14 representing resolutionyou crystalline form A.

18. Sodium salt parecoxib on 14 representing resolutionyou crystalline form C.

19. Sodium salt parecoxib on 14 representing resolutionyou crystalline form E.

20. The method of obtaining sodium salt parecoxib containing at least about 90% of the form And having the properties of a selective inhibitor of cyclooxygenase-2 (MOR-2), as the active ingredient is La pharmaceutical composition, includes stage (a) crystallization of sodium salt parecoxib of make solvent to obtain crystalline form of the sodium salt parecoxib and (b) heating the formed crystalline sodium salt parecoxib at a temperature of from about 110 to about 230°With obtaining the specified connection.

21. Pharmaceutical composition useful in the treatment of MOR-2 mediated diseases, containing a therapeutically effective amount of the medicinal substance in the form of sodium salt parecoxib on 14 and at least one pharmaceutically acceptable excipient.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a method for synthesis of aromatic sulfonyl halides by interaction of substituted phenolic compound with halogensulfonic acid and trifluoroacetic acid. Also, invention involves a method for synthesis of 4-[5-methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide of the formula (1) that is useful in treatment of disorders associated with cyclooxygenase-2 and involves interaction of a precursor-compound chosen from group consisting of compounds of the formula (2) and formula (3) with halogensulfonic acid in the presence of trifluoroacetic acid to yield a halogensulfonated compound, and interaction of a halogensulfonated compound with ammonium source to yield compound (isoxazol-4-yl)-benzenesulfonamide of the structural formula (1).

EFFECT: improved method of synthesis.

147 cl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the following formulae:

and , and to a pharmaceutical composition possessing the PPAR-ligand binding activity and comprising the indicated compound, and a pharmaceutically acceptable vehicle. Also, invention relates to a method for treatment of patient suffering with physiological disorder that can be modulated with the compound possessing the PPAR-ligand binding activity. Method involves administration to the patient the pharmaceutically effective dose of indicated compound or its pharmaceutically acceptable salt.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 104 ex

Antagonist npy y5 // 2264810

FIELD: medicine, pharmacology.

SUBSTANCE: the present innovation deals with applying pharmaceutical composition as an antagonist of NPY Y5 receptor that contains the compound of formula I

, moreover, it deals with compounds of formula I and method for treating obesity and suppressing food intake, as well.

EFFECT: higher efficiency of therapy.

18 cl, 13 ex, 6 tbl

The invention relates to new substituted the isoxazoles of General formulas I, II, III, IV, V, where R1selected from lower alkyl, carboxyamide, alkoxycarbonyl, aminocarbonyl, aminocarbonylmethyl and so on; R2choose from alkylsulfonyl, hydroxysulfonic and aminosulfonyl; R3selected from phenyl or 6-membered heterocycle containing one nitrogen atom, and phenyl may be optionally substituted by one or more radicals independently selected from alkyl, cyano, halogenoalkane, hydroxyalkyl and so on; provided that R2is aminosulfonyl, if R2- substituted phenyl radical is in the 3-position isoxazol; R4selected from lower alkyl, hydroxyl, carboxyl, halogen, lower carboxyethyl and so on; R5selected from methyl, hydroxy and amino; R6selected from phenyl or 6-membered heterocycle containing one nitrogen atom, and phenyl may be optionally substituted by one or more radicals independently selected from lower alkylsulfonyl, lower alkyl, cyano, lower halogenoalkane and so on; R7selected from lower alkyl, hydroxyl, carboxyl, halogen, lower carboxyl and so on; R8represents one or more radicals and so on

The invention relates to a new derivative of pyrazole, substituted bentilee group in position 4 of the pyrazole ring, and herbicide

The invention relates to new isoxazol derivative, compositions containing them, methods of obtaining and use as herbicides

The invention relates to new derivatives of 4-benzoimidazole formula I where R is hydrogen or-CO2R4; R1- C3-6-cycloalkyl; R2- halogen, n-alkyl, possibly substituted by one or more halogen atoms, or5, -S(O)pR6; R3IS-S(O)qR7; X IS -(CR9R10)t-; n = 0, 1, and 2; when n is greater than 1, the groups R2may be the same or different; R4, R5and R6-n-alkyl; R7-n-alkyl, possibly substituted by one or more atoms of hydrogen, C3-C6alkenyl straight chain or phenyl; R9and R10is hydrogen or C1-C6-alkyl straight chain; p and q = 0, 1, or 2; t is an integer from 1 to 4, when t > 1, group-CR9R10may be the same or different; or acceptable for agriculture salt

FIELD: chemistry of heterocyclic compounds, organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (Ib): or pharmaceutically acceptable hydrate of salt of indicated compound wherein R5 means oxygen atom (O); R6 means hydrogen atom (H); X means -CH2-, -CH(OH)(CH2)n- or -CH(NR11R12)- wherein n = 0; R11 and R12 mean independently hydrogen atom or (C1-C9)-alkyl or nitrogen atom (N), either R11 and R12 taken in common form 5-10-membered aromatic or nonaromatic carbocycle wherein 1-4 carbon atoms in ring are replaced independently with N, O or sulfur (S) atom and wherein at least of them represents nitrogen atom; R1, R2, R3, R4, R7, R8, R9 and R10 mean independently hydrogen atom or -A-B wherein A means -SO2-; B means -NZ1Z2, 5-10-membered aromatic or nonaromatic carbocycle wherein 1-4 carbon atoms in ring are replaced independently with N, O or S and wherein any of these atoms is unsubstituted or substituted with one or more groups comprising (C1-C10)-alkyl, (C1-C5)-alkylene-OC(O)-(C1-C5)-alkyl; Z1 and Z2 mean independently H or (C1-C10)-alkyl that is unsubstituted or substituted with one or more groups -N(Z3)(Z4) wherein Z and Z4 mean independently H or (C1-C5)-alkyl that is unsubstituted or substituted with one or more hydroxy-groups; either N, Z3 and Z4 taken in common form unsubstituted or substituted 5-10-membered aromatic or nonaromatic carbocycle wherein 1-4 carbon atoms in ring are replaced independently with N, O or S and wherein one of these atoms represents nitrogen atom.

EFFECT: valuable medicinal properties of compounds.

42 cl, 4 tbl, 2 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a method for treatment of a patient with inflammatory disease or risk for its development. Method involves administration to a patient the following drugs: (i) tricyclic antidepressant, for example, amoxapine and (ii) corticosteroid, for example, prednisolon. Medicinal agents (i) and (ii) are administrated simultaneously or in interval in limits for 14 days in doses sufficient for inhibition of inflammation or reducing risk for its development. Also, invention relates to a pharmaceutical composition and pharmaceutical package containing medicinal agents (i) and (ii). Also, invention relates to a method for identification of combinations of compounds used in treatment of inflammation by assay of decreasing levels of pro-inflammatory cytokine in contact of immune cells with the combination of compound-candidate with (i) or (ii). Invention provides expanding assortment of anti-inflammatory agents and combinations, identification of such combinations and reducing toxicity in carrying out the anti-inflammatory treatment.

EFFECT: valuable medicinal properties of combinations, improved method of treatment.

36 cl, 3 tbl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes a method for preparing a composition containing ibuprofen that represents active substance possessing anti-inflammatory, analgesic and antipyretic effects. Method involves covering ibuprofen or its salts with hydroxymethylpropylcellulose, methylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose or gelatin as a binding agent wherein part of binding agent is from 0.1 to 10 wt.-%, and part of ibuprofen or its salts is from 90 to 99.9 wt.-% as measured for dry weight. The composition can be pressed directly to form solid medicinal formulations showing hardness and stability against abrasion, stability in storage and wherein active substance is released in desired time, Medicinal preparation can be used directly for making tablets of different size and with different dose of ibuprofen.

EFFECT: improved preparing method, improved pharmaceutical properties of composition and tablets.

10 cl, 5 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): possessing properties of inhibitor of inflammatory cytokines release from cells. In compound of the formula (I) R is chosen from: (a) fragment of the formula -OR3 wherein R3 is chosen from group consisting of phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3-N-acetylaminophenyl, 2-methoxyphenyl, 4-methoxyphenyl and 3-benzo[1,3]dioxol-5-yl; (b) fragment of the formula: wherein R6 is chosen from group consisting of hydrogen atom, methyl, ethyl, vinyl, cyclopropyl, cyclohexyl, methoxymethyl, methoxyethyl, 1-hydroxy-1-methylethyl, carboxy-group, 4-fluorophenyl, 2-aminophenyl, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-(propanesulfonyl)phenyl, 3-benzo[1,3]dioxol-5-yl, pyridine-2-yl, pyridine-3-yl, or (c) fragment of the formula: wherein R6 is chosen from group consisting of hydrogen atom, methyl, ethyl, vinyl, cyclopropyl, cyclohexyl, methoxymethyl, methoxyethyl, 1-hydroxy-1-methylethyl, carboxy-group, phenyl, 4-fluorophenyl, 2-aminophenyl, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-(propanesulfonyl)phenyl, 3-benzo[1,3]dioxol-5-yl, pyridine-2-yl, pyridine-3-yl; each radical R2 is chosen independently from group consisting of (a) hydrogen atom; (b) -(CH2)jO(CH2)nR8; (c) -(CH2)jNR9aR9b; (e) -(CH2)OCO2R10; (g) -(CH2)jOCON(R10)2 wherein each radical R8, R9a, R9b and R10 represents independently hydrogen atom, (C1-C4)-alkyl; or R9a and R9b can form in common 5-6-membered heterocyclic ring comprising 1-2 heteroatoms chosen from nitrogen and/or oxygen atoms; or two radicals R10 can form in common 5-6-membered heterocyclic ring comprising 1-2 heteroatoms chosen from nitrogen and/or oxygen atoms; j represents index 0; n represents index 0. Also, invention relates to a pharmaceutical composition and a method for inhibition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 2 sch, 8 tbl, 13 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to anthranylamidepyridine amides of selective effect as inhibitors of VEGFR-2 and VEGFR-3. Invention describes compounds of the general formula (I): wherein A, B and D represent independently of one another nitrogen atom or carbon atom wherein at least one nitrogen atom is in a ring; E represents aryl comprising 6-12 ring carbon atoms or heteroaryl comprising 5 or 6 ring atoms and comprising in ring instead carbon atom similar or different heteroatoms chosen from nitrogen or sulfur atoms, or represents group -COOR8, -CONR2R3 or -C≡C-R9; G represents nitrogen atom or group -C-X; L represents nitrogen atom or group -C-X; M represents nitrogen atom or group -C-X; Q represents nitrogen atom or group -C-X and wherein a ring comprises maximally one nitrogen atom; X represents hydrogen atom; W represents hydrogen or halogen atom; R1 represents aryl similarly or differently optionally mono- or multi-substituted with halogen atom, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl or group =O and wherein aryl comprises 6-12 ring carbon atoms, or heteroaryl comprising from 3 to 16 ring atoms and comprising in ring instead carbon one or more similar or different heteroatoms, such as oxygen, nitrogen or sulfur and it can be mono-, bi- or tricyclic and condensed additionally condensed with benzene ring; R2 and R3 represent independently of one another hydrogen atom or aryl similarly or differently mono- or multi-substituted with halogen atom, cyano-group, (C1-C6)-alkyl, phenyl, hydroxy-(C1-C6)-alkyl, halogen-(C1-C6)-alkyl or group -NR6R7, -OR5, (C1-C6)-alkyl-OR5-(C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkenyl wherein aryl comprises 6-12 ring carbon atoms, or heteroaryl comprising from 3 to 6 ring atoms and comprising in ring instead carbon one or more heteroatoms, such as nitrogen or sulfur; or R2 and R3 in common with nitrogen atom form (C3-C8)-ring that can comprise optionally one more nitrogen or oxygen atom or it can comprise group -N(R10); R5 represents hydrogen atom; R6 and R7 represent independently of one another hydrogen atom or (C1-C6)-alkyl; R8 represents (C1-C6)-alkyl mono- or multi-substituted optionally with halogen atom or benzyl; R9 represents hydrogen atom or tri-(C1-C6)-alkylsilyl; R10 represents hydrogen atom or (C1-C6)-alkyl, and their isomers, enantiomers and salts also. Also, invention describes a medicinal agent based on compounds of the formula (I). Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

8 cl, 2 tbl, 162 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of cyclic amine of the general formula (1): , their pharmaceutically acceptable salts or hydrates wherein each among R1, R2 and R3 represents independently hydrogen atom, halogen atom, hydroxy-group, (C1-C8)-alkoxy-group; each among W1 and W2 represents independently nitrogen atom (N) or -CH; X represents oxygen atom (O), -NR4, -COONR4 or -NR4CO; R4 represents hydrogen atom, (C1-C8)-alkyl, (C3-C6)-alkynyl, substituted or unsubstituted phenyl, unsubstituted benzyl, unsubstituted indanyl wherein substitute(s) of phenyl represent(s) 1-3 groups or atoms chosen from (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkoxy-group substituted with 1-3 halogen atoms, (C1-C8)-alkylthio-group, (C1-C8)-alkylsulfonyl, halogen atom, trifluoromethyl group and (C1-C3)-alkylenedioxy-group; each among l, m and n represents number 0 or 1. Proposed compounds possess inhibitory effect on cell adhesion and/or cell infiltration and can be used as a medicinal agent and pharmaceutical composition based on thereof.

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical composition.

6 cl, 1 tbl, 439 ex

FIELD: medicine.

SUBSTANCE: invention relates to perorally delivered pharmaceutical composition including low water-soluble preparation and liquid solvent containing at least one pharmaceutically acceptable solvent, at least one pharmaceutically acceptable fatty acid, and at least one pharmaceutically acceptable organic amine, wherein (a) sufficient part, for example at least 15 mass % of preparation being in dissolved or solubilized form in solvent liquid, and (b) fatty acid and organic amine represent in such total and relative amounts that composition self finely emulsifies in simulated gastric juice. Also disclosed is method for production of said composition.

EFFECT: composition containing preparations with law water-solubility in appropriate concentrations without delay of resorption thereof in body.

24 cl, 10 tbl, 7 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts or solvates wherein m represents 0, 1, 2 or 3; each R1 represents halogen atom or (C1-C6)-alkylcarbonyl; Z1 represents a bond or group -(CH2)q wherein q represents 1 or 2; Z2 represents a bond or group -CH2 under condition that both Z1 and Z2 don't represent a bond simultaneously; Q represents oxygen or sulfur atom or group -CH2 or -NH; R2 represents group of the formula: ; n = 0; each R4, R5, R6 and R7 represents hydrogen atom; R8 represents hydrogen atom or (C1-C6)-alkyl group; R15 represents -C(O)NR17R18 or -NHC(O)R20; t represents 0, 1, 2 or 3; each R16 represents halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, phenyl or (C1-C6)-alkyl; each R17 and R18 represents hydrogen atom or (C1-C6)-alkyl; R20 represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or 5-6-membered heterocyclic system that can be substituted with (C1-C6)-alkyl. Compounds of the formula (I), their salts and solvates possess a modulating activity with respect to chemokine MIP-1α receptors and can be used in medicine.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

19 cl, 64 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a preparation containing granulates and extra-granulated compositions. Granulated composition comprises numbers of hardened granules form a melt and containing the constant phase of non-steroid anti-inflammatory drug (NSAID). NSAID is chosen from racemic naproxen, racemic flurbiprofen, racemic ibuprofen and racemic ketoprofen. Granules are prepared by the complete melting of NSAID. Extra-granulated composition comprises a water-insoluble absorbing agent. Absorbing agent represents at least one inorganic substance, stearic acid or its insoluble salt, starch substance, cellulose substance or their mixture, polytetrafluoroethylene powder. The preparation doesn't comprise silicon dioxide. The proposed preparation is used in pain treatment and/or inflammation, and/or fever. The preparation shows improved properties for tabletting, in particular, good fluidity and provides preparing small tablets. The preparation as a single dosed formulation releases high percent of NSAID for relatively short period.

EFFECT: improved and valuable pharmaceutical properties of preparation.

37 cl, 53 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel aromatic compounds that can be used in treatment of diseases or pathological states accompanying by inflammation, for example, chronic inflammation diseases. Invention describes compound of the formula (II): wherein G means phenyl, pyridinyl, pyrazolyl and wherein G is substituted with one or some groups R1, R2 or R3; Ar means naphthyl; X means (C5-C8)-cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo-groups, phenyl, furanyl, pyridinyl or pyrazolyl; Y means a bond or saturated either unsaturated branched or unbranched (C1-C4)-carbon chain wherein one or some methylene groups are optionally and independently substituted with oxygen (O) or nitrogen (N) atoms; Y is optionally substituted with oxo-group; Z means phenyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, pentamethylenesulfoxidyl wherein each of them is optionally substituted with 1-3 (C1-C6)-alkyls or group -CONH2, (C1-C6)-alkyl, nitrile, hydroxy-group, (C1-C6)-alkoxy-group, secondary or tertiary amine wherein amine nitrogen is bound covalently with (C1-C3)-alkyl or (C1-C5)-alkoxyalkyl, tetrahydrofuranyl-(C1-C3)-alkyl, nitrile-(C1-C3)-alkyl, carboxamide-(C1-C3)-alkyl; R1 means independently in each case (C1-C10)-alkyl which is optionally partially or completely halogenated and optionally substituted with 1-3 hydroxy-groups, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl wherein each of them is optionally substituted with 1-3 groups -CN, halogen atom, (C3-C6)-alkynyl branched or unbranched carbon chain and one or some methylene groups is optionally replaced for atom O and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R2 means branched or unbranched (C1-C6)-alkyl that is optionally partially or completely halogenated, branched or unbranched (C1-C4)-alkoxy-group that in each case is optionally partially or completely halogenated, halogen atom, (C1-C6)-alkoxy-group, hydroxy-group, mono- or di-(C1-C4)-alkyl-amino-group, group -OR6, nitro-group or group mono- or di-(C1-C4)-alkyl-amino-S(O)2 that is optionally partially or completely halogenated, or group -H2NSO2; R3 in each case means independently phenyl, pyridinyl, pyrimidyl, pyrrolidinyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, (C1-C4)-alkynyl group or branched or unbranched (C1-C6)-alkoxy-group wherein each of them is optionally partially halogenated, -OR18 or (C1-C6)-alkyl optionally substituted with group -OR18, amino-group or mono- either di-(C1-C5)-alkyl-amino-group, (C2-C6)-alkynyl branched or unbranched carbon chain wherein one or some methylene groups are optionally replaced for atom O, and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R6 means (C1-C4)-alkyl that is optionally partially or completely halogenated; in each case R18 means independently hydrogen atom, (C1-C4)-alkyl; W means atom O, and its pharmaceutically acceptable derivatives. Also, invention describes a pharmaceutical composition containing these compounds and a method for treatment of disease mediated by cytokines and based on indicated compounds. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

12 cl, 1 tbl, 38 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds that possess affinity for adenosine A2A-receptors and represent compounds of the general formula: wherein R1 and R2 represent independently hydrogen atom, lower alkyl, tetrahydropyrane-2,3- or 4-yl, -(CH2)n-O-lower alkyl, -C(O)-lower alkyl, -(CH2)n-C(O)-lower alkyl, -(CH2)n-C(O)-NR'R'', -(CH2)n-phenyl substituted optionally with lower alkyl, lower alkoxy-group or -(CH2)n-pyridinyl, -(CH2)n-tetrahydropyrane-2,3- or 4-yl, -C(O)-piperidine-1-yl; or R1 and R2 in common with nitrogen atom (N) to which they are added form the ring 2-oxa-5-azabicyclo[2,2,1]hept-5-yl; R3 represents lower alkoxy-group, phenyl substituted optionally with halogen atom, -(CH2)n-halogen or -(CH2)n-N(R')-(CH2)n+1-O-lower alkyl, or represents pyridinyl substituted optionally with lower alkyl, halogen atom or morpholinyl; n means 1 or 2; R'/R'' represent independently of one another hydrogen atom or lower alkyl, and their pharmaceutically acceptable acid-additive salt. Except for, invention relates to a medicinal agent showing affinity to adenosine A2A-receptors containing one or some compounds by any claims 1-11, and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compounds and agents.

13 cl, 38 ex

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