Essentially crystalline melagatran form

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to (i) essentially crystalline melagatran in the form of hydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 21.1, 10.5, 7.6, 7,0, 6.7, 6.4, 6.2, 5.7, 5.4, 5.3, 5.22, 5,19, 5.07, 4.90, 4.75, 4,68, 4.35, 4.19, 4.00, 3.94, 3.85, 3.81, 3.73, 3.70, 3.63, 3.52, 3.39, 3.27, 3,23, 3.12, 3.09, 3.06, 2.75, 2.38, and 2.35 Å and/or water content 4.3%; and (ii) essentially crystalline melagatran in the form of anhydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 17.8, 8.9, 8.1, 7.5, 6.9, 6.3, 5.9, 5.6, 5.5, 5.4, 5.3, 5.2, 5.0, 4.71, 4.43, 4.38, 4.33, 4.14, 4.12, 4.05, 3.91, 3.73, 3.61, 3.58, 3.56, 3.47, 3.40, 3.36, 3,28, 3.24, 3.17, 3.09, 3.01, 2.96, 2.83, 2.54, 2.49, 2.41, 2.38, and 2.35 Å. Invention also relates to a method for preparation of indicated form, a method for interconversion of anhydrite form, to use of indicated compounds as pharmaceutical agent, and to preparation of drugs. Pharmaceutical preparation is suitable for treatment of condition, in case of which inhibition of thrombin is needed or desirable. Invention provides a method for treatment of such condition.

EFFECT: increased chemical stability and solid state stability as compared to amorphous forms of melagatran.

14 cl, 4 dwg, 3 tbl, 9 ex

 

The SCOPE of the INVENTION

This invention relates to new forms of solid state medicines to pharmaceutical compositions containing them and to methods for their preparation.

BACKGROUND of the INVENTION

In the preparation of pharmaceutical compositions, it is important that the medicinal substance was in the form in which it is easy to handle and to deal with him. This is important not only from the point of view of obtaining feasible industrial process, but also from the point of view of the subsequent manufacture of pharmaceutical preparations containing the active connection.

In addition, in the manufacture of pharmaceutical compositions, it is important that after the injection the patient was provided a reliable, reproducible and constant concentration profile of the drug in plasma. This is particularly important in the manufacture of compositions containing antimicrobial agents.

Chemical stability, the stability of the solid state and the retention of the active ingredients are also very important factors. The medicinal substance and the composition containing it, should be able to effectively stored for considerable periods of time without detectable significant changes in physico-chemical characteristics of the active component (e.g., its chemical composition, PL is the surrounding area, hygroscopicity and solubility).

Besides, it is also important to obtain medications in a form that is chemically pure as possible.

Amorphous substances in connection with this can be a significant problem. For example, such compounds are usually difficult to handle and manufacture of drugs, not provide reliable solubility and are often chemically unstable and dirty.

Experts obviously, if the drug can be easily obtained in a stable crystalline form, the above problems can be solved.

Thus, for the manufacture of industrial feasible and pharmaceutically acceptable pharmaceutical compositions it is important, where possible, to provide the drug in essentially crystalline and stable form.

However, it should be noted that this goal is not always achievable. Indeed, it is usually impossible to predict, on the basis of one of the molecular structure, what will be the behavior of the connection during crystallization. This can usually be determined only empirically.

The LEVEL of TECHNOLOGY

In the international patent application WO 94/29336 disclosed a series of compounds that are useful as inhibitors of serine proteases, such as thrombin, including the connection

BUT2C-CH2-(R)Cgl(S)Aze-Pab-H

where Cgl is tikaexception, Aze is azetidine-2-carboxylate and Pab-H is a 4-aminopyrimidines. This compound is also known as melagatran (glycine, N-[(1R)-2-[(2S)-2-[[[[4-(aminoiminomethyl)phenyl]methyl]amino]carbonyl]-1-azetidine]-1-cyclohexyl-2-oxoethyl]-).

The method of synthesis of this compound is described in Example 1 of WO 94/29336, where it is received in the form of the crude substances by evaporation of the solvent of the reaction mixture, followed by a stage of removal of protection. Connection secrete thus in amorphous form.

Is it possible to get melagatran in crystalline form in WO 94/29336 not disclosed. In addition, no information is provided regarding how this connection can be obtained in such form and, more specifically, how it can be obtained in a chemically stable form and/or form stable solid state.

Description of the INVENTION

According to the invention proposed is essentially crystalline form of melagatran, which is in the form of a hydrate. According to an additional aspect of the proposed essentially crystalline form of melagatran, which contains at least 0.5 mol of water per mol of melagatran.

In one of the embodiments of the specified crystalline form is characterized by the curve of differential scanning calorimetry at a speed on the Reva 10° C/min in a stream of nitrogen in a closed Cup with a small hole showing an endothermic effect with the extrapolated initial temperature of approximately 83°and associated thermal effects -125 j/g; pattern x-ray diffraction on the powder, which is characterized by crystalline peaks with d-values 21,1, 10,5, 7,6, 7,0, 6,7, 6,4, 6,2, 5,7, 5,4, 5,3, 5,22, 5,19, 5,07, 4,90, 4,75, 4,68, 4,35, 4,19, 4,00, 3,94, 3,85, 3,81, 3,73, 3,70, 3,63, 3,52, 3,39, 3,27, 3,23, 3,12, 3,09, 3,06, 2,75, 2,38 and 2,35and/or water content of 4.3% (wt./mass.).

According to another aspect of the invention proposed is essentially crystalline form of melagatran, which is in the form of anhydrite, curve characterized by differential scanning calorimetry at a heating rate of 10°C/min in a stream of nitrogen in a closed Cup with a small hole showing an endothermic effect with the extrapolated initial temperature of approximately 210°and associated thermal effects -120 j/gram and/or picture of the x-ray diffraction on the powder, which is characterized by crystalline peaks with d-values 17,8, 8,9, 8,1, 7,5, 6,9, 6,3, 5,9, 5,6, 5,5, 5,4, 5,3, 5,2, 5,0, 4,71, 4,43, 4,38, 4,33, 4,14, 4,12, 4,05, 3,91, 3,73, 3,61, 3,58, 3,56, 3,47, 3,40, 3,36, 3,28, 3,24, 3,17, 3,09, 3,01, 2,96, 2,83, 2,54, 2,49, 2,41, 2,38 and 2,35.

Also, a method for obtaining compounds according to any one of claims 1 to 4, when K is a torus carry out the crystallization of melagatran of the solvent, selected from the group of C1-6allylacetate,1-6alkalemia alcohols, C5-12aliphatic hydrocarbon, C6-10aromatic hydrocarbons, di-C1-6alkalemia esters, di-C1-6alkylene, acetonitrile, water or mixtures thereof.

Preferably in a specified way, the solvent is selected from the group of ethyl acetate, ethanol, isopropanol, isooctane, n-heptane, toluene, diisopropyl ether, methyl isobutyl ketone, acetonitrile, water or mixtures thereof.

In one of the embodiments of the above method, at least one lower alkilany alcohol and/or water is used as solvent, acetonitrile and/or ethyl acetate is used as antibacterial.

In another embodiment of this method, the solvent is essentially not contain water.

In another embodiment of the method, the solvent contains water.

Further, according to the invention is also a method interconversion of compounds-anhydrate according to claim 4 and connection-hydrate according to any one of claims 1 to 3, wherein the crystalline anhydrate or hydrate (as appropriate) is exposed to the atmosphere with an appropriate level of relative humidity.

According to another aspect of the invention proposed above connection for use as pharmaceutical agents that have activity inhibitor of thrombin.

Also offers pharmaceutical PR is preparations for use in the treatment condition, where required or desirable inhibition of thrombin containing the above crystalline form in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Also, according to another aspect of the invention, the application of the crystalline forms as described above, in the manufacture of drugs to treat the condition, when the inhibition of thrombin is required or desired.

According to another aspect of the invention, a method of treatment of a condition where inhibition of thrombin is required or desired, wherein the patient in need of such treatment is administered a therapeutically effective amount of a compound as described above.

The authors found that melagatran can easily get one or more than one form, which are essentially crystalline and stable by nature.

Thus, according to the first aspect of the invention, the proposed melagatran in essentially crystalline form (below referred to as "compounds of the invention").

Although the authors found that it is possible to obtain melagatran in forms that are more than 80% crystalline, essentially crystalline," the authors include more than 20%, preferably more than 30% and preferably more than 40% Krista is symbolic. Degree (%) crystallinity can be determined by the experts, using x-ray diffraction on the powder (XRPD). You can also use other methods, such as NMR, FT-IR (Fourier transform infrared spectroscopy), Raman spectroscopy, differential scanning calorimetry (DSC) and microcalorimetry.

Compounds according to the invention can be in the form of MES, hydrate or mixed MES/hydrate. The solvate may be formed from one or more than one organic solvent, such as lower alkalemia (for example, C1-4alkalemia) alcohols (e.g. methanol, ethanol or isopropanol), or a mixture thereof.

The authors found that the compounds according to the invention unexpectedly have improved stability compared to melagatran, obtained as described in WO 94/29336.

The term "stability"as defined here, includes the chemical stability and the stability of the solid state.

In "chemical stability", the authors include the fact that the connection can be stored in an isolated solid form or in the form of a solid preparation, in which it can be presented in a mixture with pharmaceutically acceptable carriers, diluents or adjuvants under normal storage conditions, with an insignificant degree of chemical destruction or decay.

In "the stability of the solid state", the authors include the fact that that connection can be stored in an isolated solid form or in the form of a solid preparation, in which it can be presented in a mixture with pharmaceutically acceptable carriers, diluents or adjuvants under normal storage conditions, with an insignificant degree of change of a solid state (e.g., crystallization, recrystallization, phase transition solid state, hydration, dehydration, solvation or desolvatation).

Examples of "normal storage conditions" include a temperature between -80 and + 50°With (preferably between 0 and 40°and more preferably ambient temperature, such as 15-30°C), pressure between 0.1 and 2 bar (10-200 kPa) (preferably atmospheric pressure) and/or lighting to Suite 460 ultraviolet (UV)/visible light for long periods of time (i.e. six months or more). In these conditions, the compounds according to the invention can be less than 15%, more preferably less than 10% and especially less than 5% of chemically destroyed/contamination or a change in a solid state, as appropriate. Experts obviously, the above upper and lower limits of temperature and pressure represent the marginal values of the normal conditions of storage and that some combination of these extreme values will not be tested in the normal storage (for example, temperature 50°and a pressure of 0.1 bar (10 kPa)).

The term "normal storage conditions" may also include values of relative humidity between 5 and 95% (preferably from 10 to 75%). However, in the case of some of the crystalline forms according to the invention, changes in conformation or the crystal structure of hydration and/or dehydration can result from prolonged exposure to some extreme values of relative humidity at normal temperatures/pressures. For example, the authors found that the crystalline form of melagatran, which are in the form of a hydrate (e.g., monohydrate), can be stored at 10%relative humidity or higher, when the ambient temperature/atmospheric pressure with a slight degree of dehydration. However, the authors also found that the crystalline form of melagatran, which are in the form of anhydrite, should be stored at less than 40% (preferably less than 30%, more preferably less than 20%) relative humidity at ambient temperature/atmospheric pressure, to maintain a slight degree of hydration.

Thus, although the compounds according to the invention have greater stability of the solid state than the form of melagatran known from the prior art, some compounds on izopet the tion are more stable in the solid state, than others. In connection with these specialists, it is obvious that storage conditions can be adjusted so that they are close to the crystalline form, which is stored.

According to further aspect of the invention, a method for obtaining compounds according to the invention, in which the crystallization of melagatran.

Although melagatran can crystallize in the presence of the solvent system or without it (for example, crystallization may occur from the melt, in supercritical conditions, or may be achieved by sublimation), the authors prefer to crystallization occurred from a suitable solvent system.

The authors found that it is possible to obtain crystalline melagatran preferably by crystallization, followed by dissolving and/or suspendirovanie connection, or, more preferably, from the reaction solutions in which this connection was formed.

The solvent system may include one or more than one organic solvent, such as allylacetate (for example, linear or branched C1-6allylacetate, such as ethyl acetate, isopropylacetate and butyl acetate), lower (for example, linear or branched C1-6preferably C2-4) alkalemia alcohols (e.g. ethanol, isopropanol), aliphatic and aromatic Ugledar the water (for example, the isooctane, n-heptane and toluene), dealkylation (for example, methyl ethyl ketone and methyl isobutyl ketone), dialkyl ethers (e.g. diisopropyl ether and acetonitrile. You can use any mixture of the above solvents. Organic solvents can also be mixed with water or aqueous solutions.

Different crystalline forms may have different solubility in different organic solvents at any given temperature. In this regard, the above-mentioned solvents can be used as "antibacterial" (i.e. a solvent in which the compounds according to the invention poorly soluble) and can thus contribute to the process of crystallization. Lower alkalemia alcohols are preferred solvents. When the lower alkalemia alcohols are used as solvent, other solvents, as defined above, can be applied as antibacterial (particularly acetonitrile and ethyl acetate).

When crystallization occurs from the reaction solution in which melagatran was formed, suitable solvents include lower alkalemia alcohols (e.g. methanol, ethanol or isopropanol), which can be mixed with water.

Crystallization of the compounds of the present invention from a suitable solvent system, you can run, reaching Perens is recorded in the solvent system, which contains melagatran (for example, by cooling, evaporation of the solvent and/or by adding a suitable antibacterial). Crystallization can also be made by reducing the solubility of a substance by adding salt (such as NaCl).

Specialists it is obvious that the concentration in solution of a compound that is necessary to crystallize, and the used solvent system can influence the crystallization temperature and time of crystallization.

Compounds according to the invention can be in the form of MES, hydrate or mixed MES/hydrate.

Compounds of the present invention can also be in the form of anhydrite. (The term "anhydrate" when used in this context also includes compounds that are ansolutely"). To ensure that the resulting anhydrate, the solvent from which crystallization occurs, it should be dried before or during the crystallization process in order to reduce the water content below the critical level, which preferably does not exceed at the time of crystallization. The solvent can be dried during the process of crystallization, for example, by reducing the water content in the mixture of compounds that need to crystallize, and a suitable organic solvent/water solvent system (e.g., the velichivaja amount of organic solvent, which is present, and/or removing water education azeotrope with subsequent distillations). "Critical level" of water depends on such factors as temperature, concentration in solution compounds, which need to crystallize, the combination of pollution and the solvent system used, but can be defined outside of the invention.

Thus, anhydrate can be obtained by crystallization from a solvent system comprising one or more than one organic solvent (such as low (e.g.2-6) alkalemia alcohols (e.g. ethanol, isopropanol, acetonitrile and/or ethyl acetate) and/or water, and the solvent system is essentially free from water or bring into this state during crystallization. "Essentially free of water", the authors include the fact that the water content in the solvent system below, which will lead to the formation of, at most, 20% of monohydrate for any single system of solvents and the set of conditions of crystallization.

In order to guarantee that the resulting monohydrate in a solvent from which crystallization occurs, there should be water. The water content should preferably be above a critical level during crystallization (the "critical level" depends on factors, by mentioning is mentioned above in relation to obtaining anhydrate). Thus, the crystalline monohydrate can be obtained by crystallization of melagatran from a solvent system containing water and/or one or more than one organic solvent including ethyl acetate, ethanol, isopropanol, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, and mixtures thereof.

In order to guarantee that the received MES, as part of the solvent system from which crystallization occurs, there should be a suitable organic solvent, capable of forming MES. You can also get a solvate, which is in the form of "mixed" MES/hydrate. For example, the authors found that mixed lower alkalemia (for example, C2-4alkalemia) alcohol (e.g. methanol, ethanol and/or isopropanol) solvate/hydrate can be obtained by crystallization of the compounds according to the invention from a mixture of lower alilovic alcohols (e.g. methanol, ethanol and/or isopropanol), water and antibacterial (e.g., acetonitrile), for example as described below.

As it is obvious to experts obtained crystalline form depends on the kinetics and thermodynamics of the crystallization process. In certain thermodynamic conditions (solvent system, temperature, pressure and concentration of the compounds according to the invention) one crystalline form may be the more stable, than the other (or even any other). However, other crystalline forms, which can have a relatively relatively low thermodynamic stability, can be kinetically preferred. Thus, among other things, the kinetic factors such as time, the aggregate of contamination, mixing, presence of seeds, and so forth, can also affect what form will appear. Thus, experts can adapt the techniques discussed here, as appropriate, in order to obtain different crystalline forms of melagatran.

In order to ensure that such crystalline forms as described herein, is obtained in the absence of other crystalline forms described herein, the crystallization is preferably carried out by persecution germ and/or seed crystals of the desired crystalline form in the complete absence of nuclei and/or seed crystals of other crystalline forms described here.

Compounds of the present invention, which are anhydrate contain no more than 3%, preferably 1% and more preferably of 0.5% (wt./mass.) water is water (crystal water or other) or not. The solvate, hydrates and mixed hydrate/solvate contain not less than 0.5 mol of solvent and/or water (as appropriate) per mole of melagatran.

PR is doctitle compounds of the present invention are those which are in the form of a hydrate, such as a monohydrate. According to further aspect of the invention the proposed connection of the present invention, which contains at least 0.5, and preferably of 0.85 and more preferably 0.90 mol of water per mol of melagatran, is this water (crystal water or other) or not.

The authors also found that the compounds according to the invention in one crystalline form can be transformed into other crystalline forms.

For example, the crystalline monohydrate may also be formed by decanting other crystalline forms (e.g., anhydrous and/or other solvate) in water or a mixture of a sufficient quantity of water and one or more organic solvents (such as ethanol, isopropanol, ethyl acetate, acetonitrile or methyl isobutyl ketone). The resulting slurry may preferably be baited crystals of the crystalline monohydrate in order to guarantee that will be the appropriate transformation.

Moreover, the drying temperature and the drying time can affect the properties of the solid and/or solid state compounds of the present invention (for example, solvate, hydrate or mixtures thereof). For example, in the case of hydrates, dehydration can occur at low humidity and/or elevated temperaturaci/or reduced pressure. For example, after the formation of the crystalline monohydrate there is a critical level of humidity, the drying below which can lead to the loss of crystalline water and the transformation of a solid state in anhedral. On the contrary, anhydrate can turn (fully or partially) in monohydrate in those cases when they are exposed to the atmosphere with relative humidity, which is quite high.

Obtaining and identification of inter alia anhydrate, monohydrate and solvate/hydrate forms of the compounds according to the invention are described below. Different crystalline forms of the compounds according to the invention (for example, anhydrate and monohydrate) can be easily identified using the methods of x-ray diffraction on the powder (XRPD), for example as described here.

Compounds of the present invention can be separated using methods known to experts in the art, for example by decantation, filtration or centrifugation.

The authors found that in applying the methods of crystallization such as the one described here, it is possible to obtain compounds according to the invention with a chemical purity, which is higher than melagatran, which is separated in the first case.

Further purification of the compounds according to the invention can be produced using techniques well known to specialists in this area, t is the transport. For example, contamination can be removed by recrystallization from a suitable solvent system (e.g., lower Olkiluoto alcohol, such as ethanol or isopropanol), which may include antibacterial (e.g., isooctane, acetonitrile, ethyl acetate, methyl ethyl ketone), water or a combination of these solvents. Suitable temperature and time of recrystallization depends on the concentration in solution of a compound that is necessary to crystallize, and specific solvents.

When the compound of the present invention is crystallized or recrystallized as described here, the resulting compound is in a form that has an improved chemical stability and stability of a solid state mentioned above.

Pharmaceutical and medical applications

According to the invention the compounds of the present invention can be administered orally, intravenously, subcutaneously, transbukkalno, rectal, dermal, nasal, tracheal, bronchial or any other parenterally, or by inhalation, in the form of a pharmaceutical preparation containing the compound according to the invention in a pharmaceutically acceptable dosage form. However, the authors prefer the connection according to the invention is presented a form suitable for personalnovel parenteral, such as subcutaneous, administration.

Depending on the violation and the patient treated and the route of administration of the compounds can be introduced in different doses.

Suitable drugs include those disclosed in international patent applications WO 94/29336, WO 96/14084, WO 96/16671, WO 97/39770, WO 97/45138, WO 98/16252 and WO 00/12043.

Compounds of the present invention can be further processed before being mixed with a suitable carrier, diluent or adjuvant. For example, crystalline form you can crush or grind into smaller particles.

The authors prefer to preparations containing the compounds according to the invention, was in a form that is suitable for parenteral (e.g. subcutaneous) delivery. In this regard, the connection of the present invention can be mixed with water solvents (for example, international patent application WO 00/12043) in order to obtain a pharmaceutical drug, which is in the form of liquid and/or solution.

A number of compounds of the present invention, which is used in this preparation depends on the condition and the patient should be treated, and connection(s) (s) use, and can be defined in the usual way.

Compounds of the present invention are useful because they possess pharmacological activity. The trail is therefore they are shown as pharmaceuticals.

In particular, the compounds of the present invention are powerful inhibitors of thrombin, for example, as demonstrated in the test described in WO 94/29336. It is expected that the compounds of the present invention will be useful in the treatment of conditions where inhibition of thrombin is required or desirable, including those described, for example, in WO 94/29336 and WO 97/23499, descriptions of which are included in this description by reference.

Suitable doses of the compounds of the present invention therapeutic and/or prophylactic treatment of patients mammals, especially humans, are in the range from 0.4 to 40 mg per day and/or from 0.0002 to 4 mg/kg (preferably from 0.002 to 1 mg/kg) body weight at parenteral and from 2 to 1000 mg per day and/or from 0.001 to 100 mg/kg (preferably from 0.01 to 25 mg/kg) of body weight when administered orally.

For the proposed method, to avoid doubt, in "treatment," the authors include therapeutic treatment, and prevention of the condition.

Compounds of the present invention have the advantage that they are in a form that provides improved ease of processing. In addition, the compounds according to the invention have the advantage that you can get them in forms that have uluchshennoe the chemical stability and the stability of the solid state. Thus, the compounds may be stable when stored for extended periods.

Compounds of the present invention may also have the advantage that they can be obtained with good yields, high purity, in less time, more conveniently and with lower cost than the form of melagatran obtained previously.

The invention is illustrated but in no way limited by the following examples with reference to the attached figures, where:

the Figure 1 shows the diffraction pattern x-ray powder for crystalline forms of anhydrate of melagatran obtained by the method of Example 2;

the Figure 2 shows the diffraction pattern x-ray powder for crystalline form of the monohydrate of melagatran obtained by the method of Example 4;

the Figure 3 shows the diffraction pattern x-ray powder for crystalline forms of anhydrate of melagatran obtained by the method of Example 6.

General methods

Analysis of x-ray diffraction on the powder (XRPD) was performed on the samples obtained according to standard methods, for example, described in C. Giacovazzo et al. (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R. L. (1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York; Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press, London or Klug, H. P. &Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York. X the RCM analyses were performed, using Siemens D5000 diffractometer and/or Philips X'pert MPD.

Differential scanning calorimetry (DSC) was performed using a Mettler instrument DSC820, according to standard methods, for example, described in Hohne, G. W. H. et al. (1996), Differential Scanning Calorimetry, Springer, Berlin.

Thermogravimetric analysis (TGA) was performed using a Mettler Toledo instrument TGA850.

Form obtained according to the Examples below, demonstrated the "essentially" the same XRPD pattern of diffraction and/or DSC thermograms, as other Examples disclosed below, when it was clear from the relevant of pictures/images (assuming the error of the experiment), which was formed by the same crystal form. Thus, within experimental error for the initial temperatures of the DSC can be within ±5°With (for example ±2°C) and for values XRPD distances can be within ±2 in the last decimal digit.

The synthesis of the monohydrate of melagatran

Example 1

a) Boc-(R)Cgl-(S)Aze-Pab-Z

DMAP (3.0 equivalent) and Boc-(R)Cgl-(S)Aze-OH (1.0 equivalent) was dissolved in a mixture of ethyl acetate:acetonitrile (80:20./about.) in volume 18 l/kg Boc-(R)Cgl-(S)Aze-OH (at 20°C. Pab-Z x HCl (1.15 equivalents) were loaded into the resulting solution. Added EDAC×HCl (1.4 equivalent), and the suspension was stirred at 25°C for approximately 3 hours. Selected sample for the oversight of the process. The reaction solution was treated when identified, topraysolar at least 95%conversion. The suspension was then filtered, and the filter residue was washed with a mixture of ethyl acetate:acetonitrile (80:20./vol.). Was added an aqueous solution of sodium chloride (10% wt./mass.), and the pH is brought to 4.0 with hydrochloric acid (4 M). The solution was thoroughly stirred for at least 15 minutes. The aqueous phase was separated, and the organic phase was extracted with aqueous solution of sodium chloride (20% wt./mass.). The solution was thoroughly stirred for at least 15 minutes. The aqueous phase was separated, and the organic phase was extracted with aqueous solution of sodium chloride (10% wt./mass.). the pH was brought to 8.0 with an aqueous solution of potassium carbonate (25% wt./mass.). The solution was thoroughly stirred for at least 15 minutes. The aqueous phase was separated. The ethyl acetate and acetonitrile is evaporated under vacuum (approximately 15 kPa) at a temperature of about 40°as long as the volume in the reactor was approximately 8 l/kg of the original substance. During the process of evaporation was added ethyl acetate (13 l/kg of the original substance). Selected the sample for the analysis of water content.

Then was added ethanol (10% vol./about. the total volume). This solution was used directly in the next stage.

b) H-(R)Cgl-(S)Aze-Pab-Z

1) the Solution from stage (a) was cooled to 10°C. Downloaded methansulfonate acid (7 equivalents per equivalent of Boc-(R)Cgl-(S)Aze-Pab-Z), TF is Riva temperature below 20° C. the Temperature is brought up to a 22°C, and the reaction solution was stirred (4 hours) up until not occurred at least 95%conversion (when determining HPLC (high performance liquid chromatography)). The reaction solution was cooled to 10°and was extracted with cold (10° (C) 25% (wt./mass.) aqueous solution of potassium carbonate (8 equivalents To2CO3) for at least 15 minutes. The temperature is brought to 20°and the aqueous phase was separated. The organic phase was washed with a mixture of an aqueous solution of sodium chloride (10% wt./mass.) and potassium carbonate (1 equivalent To2CO3) for at least 15 minutes. The aqueous phase was separated. The solution specified in the subtitle compound was used directly in the next stage.

2) Specified in the subtitle compound was obtained essentially the same way as described in stage (b)(1) above, except that the temperature was brought to 25°and the reaction mixture was stirred for 5 hours followed by the addition methanesulfonic acid.

b) Bzl-OC(O)-CH2-(R)Cgl-(S)Aze-Pab-Z

1) In the reaction solution from step (b)(1) downloaded additional ethyl acetate, water, and potassium carbonate (3.0 equivalents per equivalent of H-(R)Cgl-(S)Aze-Pab-Z), and the reaction mixture was stirred until then, until the potassium carbonate was not dissolved. Added benzylbromide the Etat (1.2 equivalents per equivalent of H-(R)Cgl-(S)Aze-Pab-Z), and the temperature of the reactor was raised to 40°C. the Temperature was maintained for about 20 hours. Selected sample for HPLC analysis. When was 95%conversion, the temperature was lowered to 20°and the reaction mixture was left to stand for at least 20 minutes. Separating the aqueous phase, and the solution was cooled to 10°C. was Added an aqueous solution of sodium chloride (4% wt./mass.), and brought the pH to 4.0 with 4 M hydrochloric acid solution.

A two-phase system was thoroughly stirred for at least 15 minutes and left to separate for at least 20 minutes. The aqueous phase was separated. Solution was added sodium chloride (4% wt./mass.), and the pH is brought to 4.0 4 M solution of hydrochloric acid. The solution was thoroughly stirred for at least 15 minutes and left to separate for at least 20 minutes. Separated aqueous phase. To the resulting solution was added water, cooled to 10°C. the pH was brought to 2.5 to 4 M solution of hydrochloric acid. A two-phase system was thoroughly stirred for at least 15 minutes and left to separate for at least 20 minutes. The aqueous phase was separated and was slowly loaded into a mixture of potassium carbonate in ethyl acetate. the pH was brought to 7.0 25% (wt./mass.) aqueous solution of potassium carbonate, and the reaction mixture is thoroughly mixed within the least about 15 minutes at 20° With and left to separate for at least 20 minutes. Separated aqueous phase. The ethyl acetate evaporated under vacuum (approximately 10 kPa) at a maximum temperature of 40°as long as the volume in the reaction vessel was approximately 8.5 l/kg Boc-(R)Cgl-(S)Aze-OH. Was added ethyl acetate (5 l/kg Boc-(R)Cgl-(S)Aze-OH) and evaporated again under reduced pressure until such time as the volume in the reaction vessel was approximately 8.5 l/kg. Took a sample for analysis of water content. If the water content was less than 0.5% (wt./vol.), added water to obtain a total water content of 0.5-2.0% (wt./vol.). The temperature was brought up to 45°the reaction solution was made fun of 2% (wt./mass.) specified in the subtitle of the component, and the suspension was thoroughly stirred for 10 hours, then was cooled to 30°With 3 hours and then was stirred for at least 3 hours. Download toluene (5 l/kg specified in the subtitle compound), and the suspension was stirred for at least 15 minutes. The ethyl acetate and toluene evaporated under reduced pressure (approximately 10 kPa) as long as the volume was not the same as it was before adding toluene. Was added toluene (5 l/kg specified in the subtitle compound), and the suspension was stirred for at least 30 minutes. The ethyl acetate and toluene evaporated again under reduced pressure the AI until while volume has not become what it was prior to the addition of toluene. Then added toluene to a total volume of about 11 l/kg specified in the subtitle compound. The suspension was gently stirred for at least 3 hours at 20°C. the Crystals were filtered off and washed with toluene, and dried under vacuum (<150 mbar (15 kPa) at approximately 40°C.

2) Specified in the subtitle compound was obtained essentially the same way as described in stage (b)(1) above, except that:

(1) before lowering the temperature to 20°followed by the addition of benzylbromide, was 96%conversion and

(2) conducted the third extraction at pH 4.0.

g) the Monohydrate of melagatran

1) Ethanol were loaded into the reactor at 20°C. was Added Pd/C (10% wt./mass. Bzl-OC(O)-CH2-(R)Cgl-(S)Aze-Pab-Z), decanted water. (The total amount of water was 6% vol./about. all solvent). Download Bzl-OC(O)-CH2-(R)Cgl-(S)Aze-Pab-Z (from stage (b)(1) above; 8% wt./about. all solvent), and the temperature was raised to 25°C. the pressure of the H23.5 bar (350 kPa) was applied to the reaction mixture, which was intensively stirred for 5 hours. When the reaction has ended (determined by HPLC), has established a temperature of 20°and the reaction suspension was treated with activated carbon (10% wt./mass. the initial substance), decanter who bathes in water (0.5 l/kg educt) for 0.5 hours. The catalyst and the coal was filtered, and the filter residue was washed with ethanol (5 l/kg anhydrate of melagatran). The ethanol is then evaporated under reduced pressure to a volume of 4 l/kg anhydrate of melagatran. Download isopropanol (14 l/kg anhydrate of melagatran), and the solution was again evaporated under reduced pressure (at temperature between 20 and 30° (C) to a volume of approximately 7 l/kg anhydrate of melagatran. The solution was filtered and washed with isopropanol (7 l/kg anhydrate of melagatran). Ethanol/isopropanol evaporated under reduced pressure (at temperature between 20 and 30° (C) to a volume of approximately 4.4 l/kg anhydrate of melagatran. The water content was analyzed and brought up to 0.6-0.7 l/kg anhydrate of melagatran. The solution was heated to 45°and added 20 minutes acetonitrile (6.0 liters/kg anhydrate of melagatran), then started the crystallization seed specified in the title compound (obtained analogously to the method described in Example 4 below; 2% wt./mass. product). The mixture was stirred for approximately 15 hours. Loaded into the vessel acetonitrile (6.5 liters/kg anhydrate of melagatran). The suspension was stirred at 40°C for 3 hours, then was cooled to 20°With 1 hour and finally was stirred at 20°C for at least 1 hour. The crystals were separated by filtration and washed with a mixture of acetonitrile:isopropanol (9:1 (vol./vol.), 3.5 l/kg MC is connected in the connection header), acetonitrile (2 l/kg specified in the connection header) and finally with ethyl acetate (3 l/kg specified in the connection header). The crystals were dried at 40°and 150-200 mbar (15-20 kPa).

2) is listed in the title compound was obtained using essentially the same as described above in method stage (g)(1), except that:

(1) the amount of catalyst used in the beginning, was 12% wt./mass. source materials;

(2) the total amount of water in the reaction mixture was 7% of the masses../about. all solvent;

(3) did not filtering after the second evaporation;

(4) did not control the process for content of water after evaporation (added water (0.6 l/kg) instead of performing zavedeniy to 0.6-0.7 l/kg)

(5) the amount of the washing solvent was:

(I) the system acetonitrile:isopropanol - 3 l/kg anhydrate of melagatran;

(II) acetonitrile - 3 l/kg anhydrate of melagatran and

(III) ethyl acetate - 5 l/kg anhydrate of melagatran;

(6) drying temperature was 45°and

(7) the lower limit pressure during drying was 100 mbar (10 kPa).

The crystals were analyzed by XRPD, TGA, GC (gas chromatography), DSC and titration according to Karl Fischer. They showed essentially the same XRPD pattern and the DSC thermogram, which showed the form obtained according to Example 4.

Crystallization of anhydrite of melagatran

The reaction solution (ethanol:water), containing approximately 64,8 g melagatran obtained analogously to the method described in Example 1 (except for the last stage of crystallization)in a round bottom flask was concentrated by evaporation under reduced pressure, as there was 149 g of the solution. Then the vessel was loaded with 200 ml of absolute ethanol, and the solution was concentrated again as there was 89,5, Formed a white precipitate. Then 250 ml of absolute ethanol were loaded into the vessel, and the suspension was stirred at 30-35°until all dissolved material was not dissolved. The solution was concentrated again as there was 78,9 g of the solution. Added 550 ml of absolute ethanol, and the suspension was stirred at 38°until everything was dissolved. The water content was 0.5% (wt./mass.) when determining titration according to Karl Fischer. The solution was filtered, and the filter was washed with 200 ml of absolute ethanol. The solution was heated to 30°C in an atmosphere of N2and loaded into the vessel acetonitrile parts until the solution became turbid (just downloaded 1380 ml of acetonitrile). The solution was made fun of using the crystals is specified in the header of the product. The suspension was stirred overnight and cooled to ambient temperature. The crystals were washed under reduced pressure 350 ml of a mixture of ethanol and acetonitrile (1:5 (vol./about.)) and the ATEM acetonitrile (300 ml). The crystals were then dried at 40°With (0,1 mbar (0.01 kPa)). After 4 hours of drying, the particles were crushed. Then drying was continued under the same conditions for a further 20 hours.

The crystals were analyzed by XRPD, GC and titration according to Karl Fischer. The result XRPD shown in the table and shown on Figure. Titration according to Karl Fischer showed a 1.1% (wt./mass.) water.

Example 3

85 ml of reaction solution (ethanol)containing melagatran obtained analogously to the method described in Example 1 (except for the last stage of crystallization)were loaded into a round bottom flask of 500 ml, the Solution was concentrated by distillation (pressure: 50 mbar (5 kPa), bath temperature: 70° (C)as there was of 15.3 g of the solution. Was added 63 ml of isopropanol, and the solution was concentrated again, as described above, as there was 14,8, Selected the sample, and the water content was 0,93% (vol./vol.), as determined by titration according to Karl Fischer. Another of 1.16 ml of purified water was added to the solution in order to improve filtering. A round bottom flask was placed in an oil bath maintained during 40°S, and the solution was stirred using a stirrer. 30 ml of acetonitrile was slowly loaded into the mixed solution. 80 mg of seed crystals indicated in the title compounds were added to the solution, which began to crystallize. is Uspenskiy was stirred for another 14 hours at 40° With, and then was added 23 ml of acetonitrile. Stirring is continued at 40°C for 3 hours, then the oil bath was removed, and the suspension was stirred at ambient temperature for 2 hours. The crystals were filtered under vacuum, washed with a mixture of isopropanol and acetonitrile, then pure acetonitrile, and then dried at 40°With under reduced pressure. Output (based on the amount remaining in the mother solution) was 84%.

The crystals were analyzed by XRPD, GC and titration according to Karl Fischer. They showed essentially the same picture XRPD, which showed the form obtained according to Example 2.

The transformation of the crystalline anhydrate of melagatran in the crystalline monohydrate of melagatran

Example 4

Downloaded 2 g anhydrate of melagatran (obtained according to the method described in Example 3) together with 1 ml water, 6 ml of isopropanol and 13.2 ml of acetonitrile in the Erlenmeyer flask 50 ml Flask was placed on the vibrating table and maintained at ambient temperature. The crystals were filtered by applying vacuum through 9 days of stirring/shaking and then were dried at ambient temperature in a fume hood.

The crystals were analyzed by XRPD, DSC, TGA, GC and titration according to Karl Fischer.

The result XRPD shown in table 2 and shown in Figure 2.

DSC showed one EN oterma with an initial temperature of approximately 83° With an associated thermal effect -125 j/g (due to dehydration) and one at approximately 210°With (due to melting).

TGA showed a weight reduction of approximately 4.3% to about 95°corresponding to the monohydrate, and the decomposition ranging from about 220°C. Titration according to Karl Fischer showed a 4.3% (wt./mass.) water.

Example 5

139 kg of ethyl acetate were loaded into the reactor together with 10,3 kg anhydrate of melagatran (from Example 9), then 1.9 kg of purified water (4.5 equivalents). The suspension was stirred for 16-20 hours at 40°C. After cooling to 25°the suspension was stirred for another 2 days. The suspension was then filtered using a filter under pressure, and the reactor and the filter residue was washed 46 kg of ethyl acetate. The crystals were dried under reduced pressure (150±50 mbar (15±5 kPa)and 40°in a few days.

The crystals were analyzed by XRPD, DSC, TGA, GC and titration according to Karl Fischer. They showed essentially the same XRPD pattern and the DSC thermogram, which showed the form obtained according to Example 4. Titration according to Karl Fischer showed a water content of 4.0% (wt./mass.).

The conversion of one of the crystalline forms of anhydrate of melagatran to another crystalline form of anhydrate of melagatran

Example 6

2.5 g of anhydrate of melagatran (from Example 2) was loaded together with 6 ml of isopropanol, 1,0 who litre of water and 13.2 ml of acetonitrile in the Erlenmeyer flask 50 ml The flask was placed on the vibrating table, where she was left for 9 days. The crystals were filtered under vacuum and then dried at 40°and at a pressure of less than 20 mbar (2 kPa) during the night.

The crystals were analyzed by XRPD, DSC, GC and titration according to Karl Fischer.

The result XRPD shown in table 3 and shown in Figure 3.

DSC showed a single endotherm with an extrapolated initial temperature 210°With an associated thermal effect -120 j/,

Example 7

3.0 g of anhydrate of melagatran (from Example 2) were loaded with 0.5 ml water and 20 ml of ethyl acetate into a flask Erlenmeyer, 50 ml Flask was placed on the vibrating table, where she was left for 9 days. The crystals were filtered under vacuum, washed with ethyl acetate and then dried at 40°and a pressure of less than 20 mbar (2 kPa) during the night.

The crystals were analyzed by XRPD, DSC, GC and titration according to Karl Fischer. They showed essentially the same picture XRPD and the DSC thermogram, which showed the form obtained according to Example 6.

Example 8

3.0 g of anhydrate of melagatran (from Example 2) were loaded with 0.5 ml water and 20 ml of the mixture in the Erlenmeyer flask 50 ml Flask was placed on the vibrating table, where she was left for 9 days. The crystals were filtered under vacuum, washed with isobutyl ketone and then dried at 40&#HWS and a pressure of less than 20 mbar (2 kPa) during the night.

The crystals were analyzed by XRPD, DSC, GC and titration according to Karl Fischer. They showed essentially the same picture XRPD and the DSC thermogram, which showed the form obtained according to Example 6.

The transformation of the crystalline monohydrate of melagatran in crystalline anhydrate of melagatran

Example 9

The monohydrate crystals (from Example 1) was dried under reduced pressure (<15-20 mbar (1.5 to 2 kPa)and 40°until the water content became less than 1.0% (wt./mass.).

The crystals were analyzed by XRPD, DSC, GC and titration according to Karl Fischer. They showed essentially the same picture XRPD and the DSC thermogram, which showed the form obtained according to Example 6.

Reduction

(S)Aze - (S)-azetidin-2-carboxylate

Vos - tert-butyloxycarbonyl

Bzl is benzyl

(R)Cgl - (R)-cyclohexylglycine

DMAP - 4-dimethylaminopyridine

EDAC - 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide

b-N - 4-aminopyrimidines

Z - benzyloxycarbonyl

A comparative study of the stability of crystalline and amorphous material

Compared chemical stability at different temperatures and humidity, crystalline melagatran in the form of a hydrate (this form is described and characterized, inter alia, in Examples 1 and 4) and the stability of the amorphous material described in WO 94/29336.

These two forms of melagatran kept pri° C and relative humidity of the environment, as well as at 45°C and a relative humidity of 75%. For analysis was sampled at time intervals shown in the tables below. The results are presented as the total number (percentage) of melagatran when compared with the total area of the chromatogram at the retention time of six weeks.

The analysis was carried out in the plant for liquid chromatography equipped with a UV detector. Related compounds were separated on a column of Symmetry C8 (150·4.6 mm, 5 μm). The connection was suirable isocratically using 20% of CH3SP, 80% sodium phosphate buffer with a pH of 2 and I=0.05 and 5 mm octanesulfonate at a flow rate of 1 ml/min To obtain good results chromatogram of the separation was monitored by measuring the samples, diluted in sodium phosphate buffer with a pH of 2 and I=0.05 to a concentration of 0.2 mg/ml at 237 nm. The collected data were combined and presented as % of the total area, and the calculations involved values exceeding 0.01%.

The presented results clearly show a significantly higher chemical stability tested crystalline forms of melagatran compared with an amorphous substance. As you can see, in the case of amorphous material after three weeks, the amount of impurities present took the rose in 2-3 times. The crystalline hydrate form was observed slightly small increase in impurities in 6 weeks.

1. Essentially, the crystalline form of melagatran, which is in the form of a hydrate.

2. Essentially, the crystalline form of melagatran, which contains at least 0.5 mol of water per mol of melagatran

3. The compound according to claim 1 or 2, characterized by the curve of differential scanning calorimetry at a heating rate of 10°C/min in a stream of nitrogen in a closed Cup with a small hole showing an endothermic effect with the extrapolated initial temperature of approximately 83°C and an associated thermal effect -125 j/g; pattern x-ray diffraction on the powder, which is characterized by crystalline peaks with d-values 21,1, 10,5, 7,6, 7,0, 6,7, 6,4, 6,2, 5,7, 5,4, 5,3, 5,22, 5,19, 5,07, 4,90, 4,75, 4,68, 4,35, 4,19, 4,00, 3,94, 3,85, 3,81, 3,73, 3,70, 3,63, 3,52, 3,39, 3,27, 3,23, 3,12, 3,09, 3,06, 2,75, 2,38 and 2.35 E; and/or the water content of 4.3% (wt./wt.).

4. Essentially, the crystalline form of melagatran, which is in the form of anhydrite, curve characterized by differential scanning calorimetry at a heating rate of 10°C/min in a stream of nitrogen in a closed Cup with a small hole showing an endothermic effect with the extrapolated initial temperature of approximately 210°C and an associated thermal effect -120 j/g; and/or the pattern of x-ray diffraction on the powder, characterized by crystalline peaks with d-values 17,8, 8,9, 8,1, 7,5, 6,9, 6,3, 5,9, 5,6, 5,5, 5,4, 5,3, 5,2, 5,0, 4,71, 4,43, 4,38, 4,33, 4,14, 4,12, 4,05, 3,91, 3,73, 3,61, 3,58, 3,56, 3,47, 3,40, 3,36, 3,28, 3,24, 3,17, 3,09, 3,01, 2,96, 2,83, 2,54, 2,49, 2,41, 2,38 and 2,35 E.

5. A method of obtaining a compound according to any one of claims 1 to 4, in which the crystallization of melagatran from a solvent selected from the group1-6allylacetate,1-6alkalemia alcohols5-12aliphatic hydrocarbon, C6-10aromatic hydrocarbons, di-C1-6alkalemia esters, di-C1-6alkylene, acetonitrile, water or mixtures thereof.

6. The method according to claim 5, where the solvent is selected from the group of ethyl acetate, ethanol, isopropanol, isooctane, n-heptane, toluene, diisopropyl ether, methyl isobutyl ketone, acetonitrile, water or mixtures thereof.

7. The method according to claim 5 or 6, wherein at least one of the lower alkilany alcohol and/or water is used as solvent, acetonitrile and/or ethyl acetate is used as antibacterial.

8. A method of obtaining a compound according to claim 4, which includes the method according to claim 6 or 7, where the solvent is, in essence, does not contain water.

9. A method of obtaining a compound according to any one of claims 1 to 3, which comprises the method according to claim 6 or 7, where the solvent contains water.

10. The way interconversion of compounds-anhydrate according to claim 4 and connection-hydrate according to any one of claims 1 to 3, to the m crystalline anhydrate or hydrate (as appropriate) is exposed to the atmosphere with an appropriate level of relative humidity.

11. The compound according to any one of claims 1 to 4 for use as pharmaceutical agents that have activity inhibitor of thrombin.

12. Pharmaceutical formulation for use in treating the condition in which it is required or desirable inhibition of thrombin-containing compound according to any one of claims 1 to 4 in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

13. The compound according to any one of claims 1 to 4 for use in the manufacture of drugs to treat the condition, when the inhibition of thrombin is required or desired.

14. The method of treatment of a condition where inhibition of thrombin is required or desired, wherein the patient in need of such treatment is administered a therapeutically effective amount of a compound according to any one of claims 1 to 4.



 

Same patents:

The invention relates to a new five-membered heterocyclic compounds of General formula I:

in which W denotes R1-A-C(R13); Y represents a carbonyl group; Z represents N(Rabout); And denotes phenylene; E denotes R10CO; means (C1-C6-alkylene, which may be unsubstituted or substituted (C1-C6)-alkyl; R0indicates if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; Rrepresents H or (C1-C6)-alkyl; R1denotes X-NH-C(=NH)-(CH2)p; p = 0; X denotes hydrogen, -HE, (C1-C6-alkoxycarbonyl or, if necessary, substituted in the aryl residue phenoxycarbonyl or benzyloxycarbonyl; R2, R2a, R2bdenote hydrogen; R3means R11NH - or-CO-R5-R6-R7; R4denotes a divalent(C1-C4)-alkalinity residue; R5denotes a bivalent residue of a natural or unnatural amino acid with a lipophilic side chain, selected from grupy residues, if necessary, replaced byin the aryl residue, and, if necessary, substituted (C6-C12)-aryl residues; R6represents a simple bond; R7denotes Het; R10denotes hydroxyl or (C1-C6)-alkoxygroup; R11means R12-NH-C(O) R12-NH-C(S) or R14a-O-C(O) R12means (C6-C14)-aryl-(C1-C6)-alkyl, if necessary substituted in the aryl residue; R13means (C1-C6)-alkyl; R14aindicates if necessary substituted heteroaryl, heteroaryl-(C1-C6)-alkyl, if necessary substituted in the heteroaryl residue, or R15; R15means R16or R16-(C1-C6)-alkyl; R16mean residue 3-12-membered monocyclic or 6 to 24-membered bicyclic, or 6-24-membered tricyclic ring; Het means a 5-7 membered monocyclic residue of a heterocycle bound over the nitrogen atom in the ring, containing, if necessary, another heteroatom from the group consisting of N, O or S; g and h denote 0 or 1, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, the

The invention relates to substituted derivatives of imidazolidine formula 1

where W denotes the R1-A-C(R13or

where the ring system may be substituted by 1, 2 or 3 identical or different substituents R13and where L denotes C(R13and ml and m2 independently of one another denote 0, 1, 2, 3 or 4, and the sum of m l + m2 is 3 or 4; Y represents a carbonyl group; A represents a direct bond or a bivalent residue of a phenylene, A denotes a divalent (C1-C6)-alkalinity balance, and (C1-C6)-alkilinity the residue is unsubstituted or substituted by one or more identical or different residues from the series (WITH1-C8)-alkyl and (C3-C10-cycloalkyl-(C1-C6)-alkyl, F denotes R10CO., HCO, or R8O-CH2; R is H or (C1-C8)-alkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl or, if necessary, substituted (C6-C14)-aryl, and all residues R are independently from each other may be the continuously or repeatedly substituted by fluorine, or the rest of the X-NH-C(=NH) -R20, X - N, R2- N or (C1-C8) -alkyl; R3- N, (C1-C10) -alkyl, which optionally can be substituted one or more times by fluorine, optionally substituted (C6-C14)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15; R4- (C1-C10)-alkyl, which is unsubstituted or substituted once or many times, equal or different residues from the series hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C10)-alkyl)-aminocarbonyl, (C1-C8-alkoxycarbonyl, R5, R6-CO, R5denotes optionally substituted (C6-C14)-aryl, R6denotes the residue of a natural or unnatural amino acid, R8- N or (C1-C10)-alkyl, and R8independently from each other may be the same or different, R10hydroxy, (C1-C10)-alkoxy, (C1-C8-alkylsulphonyl hydroxy-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C10)-alkyl)-amino, or R8R8N-CO-(C1-C means R12a-O-CO-or R12a-S(OH)2, R12ameans (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl, or R15, R13- N or (C1-C6)-alkyl, which may optionally be substituted one or more times by fluorine, R15means R16-(C1-C6)-alkyl, or R16; R16denotes a 6-membered to 24-membered bicyclic or tricyclic residue, R20denotes a direct bond or (C1-C6-alkylen; R21- N or (C1-C8)-alkyl, R30represents one of the residues R32(R)N-CO-N(R)-R31or R32(R)N-CS-N(R)-R31; R32-CO-N(R)-R31or R12AO-CO-N(R)-R31and R30cannot mean R32-CO-N(R)-R31,ifat the same time W denotes R1-A-C(R13), And denotes a direct bond and R1andR13- N, R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula 1, R32means (C1-C8)-alkyl, which, when neobloc substituted (C6-C14)-aryl, optionally substituted in the aryl (C6-C14)-aryl-(C1-C8)-alkyl or optionally substituted heteroaryl, R33denotes a direct bond, R34denotes a bivalent residue of a number (C1-C8-alkylene, optionally substituted (C6-C14)-Allen; R35denotes a direct bond or a bivalent residue (C1-C8)-alkylene; R36denotes a direct bond, e and h represent independently from each other 0 or 1; in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, process for the preparation of compounds I; pharmaceutical drug that has the ability to inhibit the adhesion and/or migration of leucocytes and/or VLA-4 receptor

The invention relates to substituted derivatives of propanolamine with bile acids of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives, where GS is a group of the bile acid of the formula II, R1connection with X, HE, R2connection with X, HE, -O-(C1-C6)alkyl, -NH-(C2-C6)-alkyl-SO3N, -NH-(C1-C6)-alkyl-COOH, R1and R2at the same time does not mean the relationship with X, X -

l,m, n- 0,1; L - (C1-C6)-alkyl, AA1, AA2independently amino acid residue, may be one - or multi-substituted amino group

The invention relates to new effectors dipeptidylpeptidase IV - the dipeptide mimetics (I) formed from amino acids and thiazolidinone or pyrrolidino groups, namely: L-ALLO-isoleucyl-thiazolidine, L-ALLO-isoleucyl-pyrrolidino and their salts, salts of L-threo-isoleucyl-thiazolidine and L - threo-isoleucyl-pyrrolidine; a pharmaceutical composition having the ability to lower blood sugar, containing at least one of the above-mentioned compounds (1)

The invention relates to the field of medicine and relates to new N-pinakamaraming tryptophanase of dipeptides of the formula

C6H5-(CH2)n-CO-NH-(CH2)m-CO-X-Trp-R,

where n=1-5;

m=1-3;

X=L or D-configuration;

R=OH, OCH3OC2H5, NH2, NHCH3,

as well as pharmaceutical compositions containing them

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to means for inhibiting the adhesion or migration of cells, or inhibition of VLA-4 receptor, representing the heterocycles of General formula (I), where W means R1-A-C (R13), Y represents carbonyl, Z denotes N(R0), And means a divalent residue of phenylene, divalent (C1-C6)-alkalinity balance, means the divalent (C1-C6)-alkalinity residue which may be substituted (C1-C8)-alkyl, D is C(R2) (R3), E mean R10CO., R and R0independently of one another denote hydrogen, if necessary substituted (C6-C14)-aryl, if necessary substituted heteroaryl, if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl or, if necessary, substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl, R1means hydrogen, Gets the remainder R28N (R21)-C(O)-, R2means hydrogen, R3means CONHR4, R11NH, R4means (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from the range hydroxy (C6-C14)-aryl, R10means hydroxyl or (C1-C6)-alkoxy, R11means R12CO., R12means R15-O-, R13means (C1-C6)-alkyl, R15means R16-(C1-C6)-alkyl, R16means 7-12-membered bicyclic or tricyclic residue, a saturated or partially unsaturated and which may be substituted by one or more identical or different (C1-C4)-alkyl residues, R21means hydrogen, R28means R21, Het denotes a mono - or polycyclic, 4-14-membered, aromatic or non-aromatic cycle, which may contain 1, 2, 3 or 4 nitrogen atom, b, C, d and f independently of one another denote 0 or 1, but at the same time may not mean zero, e, g and h independently of one another denote 0, 1, 2, 3, 4, 5 or 6, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts

The invention relates to a simple, effective method of obtaining the N2-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-Proline (2), which includes the first stage of implementation of the alkaline hydrolysis of N2-(1(S)-alkoxycarbonyl-3-phenylpropyl)-N6-TRIFLUOROACETYL-L-lysyl-L-Proline (1) in a mixed solution consisting of water and a hydrophilic organic solvent using an inorganic base n number of molar equivalents (n3) per mole of the above compound (1), the second stage of neutralization of the hydrolysis product with the use of inorganic acid in an amount of (n-1) to n molar equivalents (n3) and remove inorganic salts, obtained at deposition from a solvent system suitable for reducing the solubility of the inorganic salt, and the third stage is crystallization of the compound (2) present in the mixture after removal of inorganic salts from the solvent at its isoelectric point and thereby removing the compound (2) in the form of crystals, salts containing salt of organic acid - derived triperoxonane acid remains dissolved in the mother

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms

The invention relates to a group of new compounds - heterocyclic derivatives of glycyl-beta-alanine General formula I

< / BR>
or pharmaceutically acceptable salt of this compound, where

< / BR>
is a 5-8-membered monocyclic heterocyclic, optionally unsaturated ring containing from 1 to 4 heteroatoms selected from the group comprising N and S, and1selected from the group comprising SN, SN2, N, NH, O and S, provided that

< / BR>
is not pyrrolidinium when V represents NH;

A represents a group of the formula

< / BR>
where Y1selected from the group comprising N-R2and R2means hydrogen; R2means hydrogen, R7when not with R2and R8mean hydrogen, alkyl, substituted alkoxy group, or R2together with R7form a 4 to 12-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted by one or more substituents selected from the group comprising hydroxy, C1-C10< / BR>
where R2together with R7form a 5-8-membered ring containing two nitrogen atom a heterocycle, R5means hydrogen, R8means alkyl, optionally substituted by alkoxygroup; or A signifies a group

< / BR>
where R2together with R7form a 5-8-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted hydroxy-group; R8- alkyl, substituted alkoxygroup; V means-N(R6)-; R6is hydrogen; Y and Z denote hydrogen, t = 0, n and R = 1, 2; R means X-R3where X is-O-; R3is hydrogen, alkyl; R1selected from the group including aryl, alkyl, optionally substituted one or more times by halogen, alkyl, HE; monocyclic heterocycle; haloalkyl; R11means hydrogen, or a pharmaceutically acceptable salt of the compounds; pharmaceutical compositions having properties antagonistV3-integrin, as well as to a method of treating diseases mediatedV3-integrin in a mammal

The invention relates to the field of molecular biology and genetic engineering and can be used in medicine

The invention relates to the field of biotechnology and biochemistry, and can be used in medicine

The invention relates to biotechnology, in particular to a technology for basic proteinase inhibitor from the bodies of cattle

The invention relates to medicine and is a pharmaceutical combination containing antagonist of P2C-receptor and other antithrombotic agent, and their use for the treatment and prevention of thrombosis

The invention relates to medicine, specifically to pharmacology, and relates to means influencing the rheology of blood and platelet aggregation

The invention relates to medicine, therapy, and can be used for prevention of thrombosis and embolism

The invention relates to experimental medicine, cardiology

The invention relates to chemical-pharmacological industry and relates to an inhibitor of the expression of integrin, comprising as active ingredient a compound sulfonamida formula IaIbthat means, containing an inhibitor of the expression of integrin formula IaIbfor the treatment of arteriosclerosis, psoriasis, osteoporosis, angiogenesis, retinal angiogenesis, diabetic retinopathy, inflammatory diseases, and how to prevent, treat or alleviate disease associated with increased expression of integrin

The invention relates to medicine, specifically to pharmacology, and relates to means having a hemorheological and antiplatelet properties
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