Anhydrous crystalline vinflunine salts, method for preparing and using them as drug, and method for purifying vinflunine

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to anhydrous crystalline vinflunine salts of general formula (I) prepared with 1 or 2 equivalents of a pharmaceutically acceptable inorganic or organic acid. . In formula (I) [The acid] represents hydrobromic, lactic or fumaric acid for a group of water-soluble crystalline salts, as well as para-toluenesulphonic, benzoic, mandelic and para-hydroxybenzoic acid for a group of relatively water-insoluble crystalline salts.

EFFECT: preparing the anhydrous crystalline vinflunine salts.

8 cl, 8 ex, 9 dwg

 

The present invention relates to a new salt and crystalline forms vinflunine, methods of producing such forms and to their use in therapy.

Vinflunine is an indole derivative compounds vinblastine and vincristine

These compounds, extracts of Catharanthus roseus, are antimitoticescoy alkaloids and for several years was used for cancer chemotherapy. The difficulties associated with obtaining these derivatives by extraction from plants, has led to the fact that several research groups received a similar new connections that have the same properties, and has developed methods for their synthesis. Thus were obtained and presented to the market vindesine and vinorelbine (Navelbine) for the treatment of cancer. The principal characteristic of the chemical structure of these compounds is a combination of two monomers-alkaloids - catharanthine and vindoline.

In the framework of developing new ways of receiving vinorelbine reactivity of this compound in a strongly acidic environment led to the discovery of new molecules 20',20'-debtor-3',4'-dihydroquinoline, or vinflunine (WO 95/03312). During the same work were tested therapeutic benefits of this connection.

Various methods1H NMR and1 With NMR spectroscopy was studied exact conformation vinflunine (Magn. Reson. Chem., 2001, 39, p.43-48). This study was conducted on ditartrate vinflunine in solution. However, this salt is hygroscopic, which reduces its stability in the solid state, and thus is an impediment to its industrial production. Currently ditartrate vinflunine allocated in the form of an amorphous solid powder which should be stored at subzero temperatures below -15°C and in an atmosphere of inert gas, for example nitrogen or argon. So far, it was impossible to obtain anhydrous crystalline form ditartrate, although was obtained hydrated crystalline form ditartrate by crystallization in water-alcohol solvent (patent application FR 0512942).

The storage of this substance and handling, thus, require caution. Therefore, any form, which will improve its physical stability in the solid state, simplify production, storage and packaging.

Typically, the crystallization of the amorphous material is very difficult and getting the first crystals is very problematic. However, this type of solid substance allows to overcome several shortcomings of the amorphous form. Of course, it holds less moisture, and its stability, improving over time, the region is gchat production process thanks in particular, less tendency to agglomerate and the best yield. This allows us to produce more kinds of dosage forms to facilitate their production and storage.

Typically, the filterability of the crystal suspension significantly increases in comparison with an amorphous solid.

The inventors have shown that it is possible to obtain the crystalline form using other salts, giving the anhydrous crystalline form in a suitable solvent system. The use of the tested acids selected from pharmaceutically acceptable inorganic and organic acids, led to crystalline salts, where the molar ratio of acid to vinflunine is 1/1 or 2/1 in accordance with the used acid. Most acids gives salts, which are deposited the same with 1 or 2 molar equivalents based on the number of the used acid. The present invention relates to salts in crystalline form, essentially contains no water molecules in the structure, crystallization or water solvation. These salts are referred to in this description of "anhydrous crystalline salt vinflunine".

Fumaric acid to give the salt which is deposited preferably in a molar ratio of fumaric acid to vinflunine 1/1, regardless of the number of keys used is the notes.

Obtaining crystalline salt also opens the way to methods of purification by crystallization, which represent a significant advantage, taking into account the difficulties encountered in the production vinflunine high quality.

Anhydrous crystalline salt vinflunine obtained by the above method, can be divided into two categories:

- salts of inorganic acids or organic aliphatic acids that make up the group that has the preferred solubility in water for pharmaceutical use

salts of organic aromatic acids having lower solubility in water, however, their crystallinity is an advantage for cleaning vinflunine by crystallization.

Of course, it might be considered one recrystallization from these more or less soluble salts to improve the purity of raw vinflunine. These salts can be treated with base, such as, for example, sodium bicarbonate, Quaternary amine or, preferably ammonia, to obtain the base vinflunine best quality, which is then transferred to salt using one of the pharmaceutically acceptable acids to produce water-soluble salts, which can be used as medicine.

Such purification by crystallization can be carried out on the hypoxia stages of the production process, for example during final cleaning, to obtain batches of high purity, or at the stage of preliminary purification of the party before executing another purification method, for example, by preparative chromatography.

The inventors have shown that such anhydrous crystalline salts have better stability over time, as shown by comparative tests of amorphous ditartrate vinflunine and crystalline fumarata vinflunine that described in the application.

Thus, the present invention relates to anhydrous crystalline salts vinflunine with pharmaceutically acceptable inorganic and organic acids, such as (but not exclusively) salt, Hydrobromic, sulfuric, lactic and fumaric acids, which are classified as water-soluble crystalline salts, and salts of para-toluensulfonate, benzoic, almond, para-hydroxybenzoic acids, which belong to the category of relatively water-insoluble crystalline salts. All of these salts can be represented by the General formula (I):

where [Acid] is a Hydrobromic, sulfuric, lactic and / or fumaric acid to a group of water-soluble crystalline salts, and a pair of toluensulfonate, benzoic, almond or para-hydroxybenzoic acid group is otnositelno water-insoluble crystalline salts.

Preferred, in particular, is fumarate. This salt be obtained relatively easily, it is abundantly crystallizes, tends to always have a stoichiometry of 1 molar equivalent of fumaric acid to 1 molar equivalent vinflunine, which represents a significant advantage from the standpoint of reproducibility, production and mass ratio of the active product to the mass of salt.

This advantage is important for obtaining oral forms such as tablets, gel caps or capsules, the composition of which requires large quantities of the active ingredient, if necessary, to avoid an increase in volume, which makes oral administration is inconvenient. Accordingly, crystalline forms that are more compact form of the material, amorphous salts, also have an advantage.

Anhydrous crystalline state salt forms vinflunine according to the invention is demonstrated by methods known to experts in this field, for example by x-ray powder diffraction and infrared spectrometry, and can be verified by simple microscopy. For comparison purposes figure 1 shows the powder diffraction pattern of amorphous ditartrate vinflunine (having characteristic spectral lines).

The invention thus also relates to sposobnostey crystalline salts vinflunine, which include the following stages:

- dissolution of the Foundation vinflunine in a suitable solvent;

- add acid in proportions of 1 or 2 molar equivalent, in solution in a suitable solvent or solution;

the evaporation of solvent mixtures;

the agitation of the liquid or mixture of liquids, herstories or weak solvent, at room or low temperature during the period of time required for deposition;

filtering and highlighting formed crystals or amorphous solids;

- keeping under stirring amorphous solids in a liquid or mixture of liquids, herstories or weak solvent, at room or low temperature during the period of time required for crystallization,

filtering and highlighting formed crystals,

- washing using liquid or mixture of liquids, herstories or weak solvent, and drying the crystals in vacuum.

Preferably the solvents used for dissolving the base vinflunine, are acetone, ethyl acetate and toluene. Can also be used dichloromethane or alcohols, such as, for example, ethanol, methanol, 1 - and 2-propanol.

Preferably the solvents used for dissolving acids, are particularly the water, acetone, ethyl acetate and toluene. Can also be used dichloromethane or alcohols, such as, for example, ethanol, methanol, 1 - and 2-propanol.

Preferably liquid, which nerastvorim or weak solvent used for the deposition of salts, are ethyl ether, isopropyl ether, ethyl acetate, acetone and toluene. Can also be used tert-isobutyl ether, hexane, heptane or petroleum ether.

Preferably liquid, which nerastvorim or weak solvents used for keeping amorphous salts are (but not limited, for example, ethyl ether and isopropyl ether, ethyl acetate, acetone and toluene. Can also be used tert-isobutyl ether, hexane, heptane or petroleum ether.

Preferably liquid, which nerastvorim or weak solvent used for washing the crystals represent ethyl ether and isopropyl ether. Can also be used tert-isobutyl ether, hexane, heptane or petroleum ether.

As indicated above, the temperature of the deposition or curing can be controlled to optimize the time required for crystallization or for its quality. Thus, it is preferable to choose a temperature below 50°C, more FAV is preferably between 4°C and 25°C.

The amount of solvent is determined by the specialist and is preferably between 1 and 20 volume parts (ml) relative mass (g) vinflunine.

On the basis of what is already shown therapeutic benefit vinflunine and its derivatives, especially salts vinflunine, the present invention also relates to a medicinal product, including one of the crystalline salts vinflunine according to the invention. In the private aspect of the invention relates to the use of crystalline salts vinflunine for the manufacture of drugs for the treatment of cancer pathology. In particular, as non-restrictive examples, breast cancer, bladder, non-small cell lung cancer and prostate cancer.

The invention also relates to pharmaceutical compositions containing an effective amount of a crystalline salt vinflunine according to the invention in a physiologically acceptable medium.

In particular, as examples of pharmaceutical compositions for oral, parenteral, intravenous or subcutaneous injection, more preferably for oral administration in the form of tablets, capsules or gel capsules.

Doses depend on sex, age and weight of the patient and on the route of administration.

The following examples illustrate the invention without limiting its scope.

ravnitelnaya stability of amorphous ditartrate and crystalline fumarata:

1. Raw materials:

Party ARV: amorphous ditartrate vinflunine.

Batch JLM4008400: crystalline fumarate vinflunine.

2. Conditions stability:

The stability tests were conducted using the powder form in the absence of light under the following conditions:

- Closed bottle: 50°C,

- Open the bottle: 40°C, relative humidity (RH) of 75%.

The measurements were carried out at a temperature T0and T0+14 days.

3. Condition analysis:

The HPLC system:

Column: Sunfire C18, 5 μm, 4.6×250 mm (Waters), temperature of 35°C.

Eluent: CH3CN/Meon/H2O/KH2PO4400/150/450/6 .8 (ml/ml/ml/g), pH 7 (brought with KOH).

Flow rate: 1 ml/min

Detection: 269 nm

4. Results

Party. Natural salt vinflunineThe analysis timeConditions of stability analysisThe HPLC analysisWater content
ORV Amorphous ditartrateT0-99,28%6,27%
T0+14 days50°C97,18%-
40°C, 75% RHbeing equal to 98.21 per%10,18%
JLM4008400 Crystalline fumarateT0-99,52%1,33%
T0+14 days50°C99,56%-
40°C, 75% RH99,38%4,18%

Connection amorphous ditartrate vinflunine was destroyed in powder form to 2.1% at 50°C (closed bottle) and to 1.07% in the presence of moisture (40°C, 75% RH), while the crystalline fumarate vinflunine under the same conditions remained stable (destruction less than 0.2%).

Description of figures:

FIGURE 1: powder diffraction pattern of amorphous ditartrate vinflunine.

FIGURE 2: powder diffraction pattern hydrobromide

FIGURE 3: powder diffraction pattern of sulfate

FIGURE 4: powder diffraction pattern of lactate

FIGURE 5: powder diffraction pattern fumarata

6: powder diffraction pattern para-toluensulfonate

FIG.7: powder diffraction pattern of benzoate

FIG: powder diffraction pattern of mandelate

FIG.9: powder diffraction pattern of a para-hydroxybenzoate

Crystallization of salts vinflunine

Example 1: the hydrobromide

Dissolve the test sample 4,56 g base vinflunine in a minimum quantity of acetone and add 2 equivalents of an aqueous solution of Hydrobromic acid (0,53 ml of 62% solution). Salt slowly precipitates. Throw a small amount of ethyl ether and left to stand overnight. Filtered and washed with ether. Dried 20 hours in vacuum at 70°C in the absence of light. Get 4,43 g of crystalline salt.

1H NMR (400 MHz, Meon) δ ppm (ppm) 0.72 (t, J=7.33 Hz, 3 H) 1.37-1.46 (m, 1 H) 1.47-1.55 (m, 1 H) 1.60-1.97 (m, 4 H) 1.72 (t, J=19.00 Hz, 3 H), 2.04 (s, 3 H), 2.12-2.22 (m, 1 H), 2.65-2.77 (m, 2 H) 2.75 (s, 3 H) 2.81-3.20 (m, 4 H) 3.33-3.44 (m, 2 H) 3.54-3.65 (m, 3 H) 3.64 (s, 1 H) 3.77 (s, 7 H) 3.87 (s, 3 H) 4.87 (s, 2 H), 4.93 (d, J=15.16 Hz, 1 H), 5.07 (d, J=15.16 Hz, 1 H), 5.31 (s, 1 H), 5.42 (d, J=10.11 Hz, 1 H) 5.87 (dd, J=10.11, 4.55 Hz, 1 H), 6.38 (s, 2 H) 7.13-7.22 (m, 2 H) 7.38 (d, J=7.07 Hz, 1 H) 7.72 (d, J=7.07 Hz, 1 H), 10.25 (br. s., 1 (H)

Example 2: sulfate

Dissolve the test sample 4,29 g base vinflunine in a mixture of acetone and ethanol and add 2 equivalents of an aqueous solution of 3 M sulfuric acid (3.5 ml). Evaporated and place the residue in acetone, add ethyl ether and left to stand overnight. Filtered and washed with ether. Get 4.77 g of an amorphous powder.

The resulting powder was stirred for 24 hours in acetone at room temperature, then add a little isopropyl ether, filtered and washed with isopropyl ether. Dried for 20 hours in a vacuum of n and 70°C in the absence of light. Get a 4.53 g of crystalline product.

1H NMR (400 MHz, Meon) δ ppm 0.73 (t, J=7.33 Hz, 3 H) 1.44-1.56 (m, 2 H) 1.63-1.83 (m, 2 H) 1.71 (t, J=19.45 Hz, 3 H), 1.89 (d, J=13.00 Hz, 1 H) 1.99-2.09 (m, 1 H) 2.07 (s, 3 H) 2.26-2.36 (m, 1 H) 2.67 (dd, J=15.66, 6.06 Hz, 1 H) 2.79 (s, 3 H) 2.97 (dd, J=14.40, 2.78 Hz, 1 H), 3.12 (t, J=14.40 Hz, 1 H), 3.30-3.35 (m, 3 H) 3.34 (s, 1 H), 3.40-3.51 (m, 2 H) 3.71-3.82 (m, 1 H) 3.72 (s, 1 H) 3.76 (s, 3 H) 3.81 (s, 3 H) 3.85-3.94 (m, 2 H) 3.88 (s, 3 H) 4.88 (s, 5H) 4.94 (d, J=15.00 Hz, 1 H), 5.05 (d, J=15.00 Hz, 1 H), 5.31 (s, 1 H), 5.64 (d, J=10.11 Hz, 1 H), 5.92 (dd, J=10.11, 4.55 Hz, 1 H), 6.42 (s, 1 H), 6.59 (s, 1 H) 7.12 (dd, J=7.33 Hz, 1 H) 7.15 (dd, J=7.33 Hz, 1 H) 7.37 (d, J=7.58 Hz, 1 H) 7.73 (d, J=7.58 Hz, 1 H), 10.41 (s, 1 H)

Example 3: lactate

Dissolve the test sample 4.59 g base vinflunine in a minimum quantity of acetone and add 2 equivalent to L(+) lactic acid (1.01 g) in the form of a solution in acetone. Evaporate the acetone and the precipitate is ground into powder in isopropyl ether and left to stand overnight. Filtered and washed with isopropyl ether. Dried 20 hours in vacuum at 70°C in the absence of light. Get 3,81 g of crystalline product.

1H NMR (400 MHz, Meon) δ ppm 0.70 (t, J=7.33 Hz, 3 H) 1.33 (d, J=7.07 Hz, 3 H) 1.36-1.49 (m, 2 H) 1.60-1.81 (m, 2 H) 1.70 (t, J=19.00 Hz, 3 H) 1.84-1.94 (m, 1 H) 1.99-2.12 (m, 1 H), 2.02 (s, 3 H) 2.27-2.40 (m, 1 H) 2.61-2.83 (m, 4 H), 2.72 (s, 3 H) 3.06-3.27 (m, 6 H), 3.47-3.56 (m, 1 H) 3.59 (s, 1 H) 3.66-3.73 (m, 1H) 3.76 (s, 6 H) 3.85 (s, 3 H) 4.09 (q, J=7.00 Hz, 1 H), 4.87 (s, 4 H), 4.92-5.03 (m, 2H) 5.25-5.35 (m, 2 H) 5.84 (dd, J=10.11, 4.55 Hz, 1 H), 6.28 (s, 1 H), 6.35 (s, 1 H), 7.13-7.23 (m, 2 H) 7.36 (d, J=7.58 Hz, 1 H) 7.70 (d, J=7.58 Hz, 1 H)

Example 4: fumarate

Dissolve the test sample 4,58 g base vinflunine in a minimal amount of Aceto the a and add 1 equivalent of fumaric acid (0.65 g) in the form of a solution in methanol. Evaporated the solvent and the residue ground to powder in acetone, filtered and washed with ether. Dried 20 hours in vacuum at 70°C in the absence of light. Get of 3.54 g of crystalline salt.

1H NMR (400 MHz, Meon) δ ppm 0.71 (t, J=7.33 Hz, 3 H) 1.31-1.41 (m, 1 H) 1.41-1.50 (m, 1 H) 1.60-1.84 (m, 3 H) 1.70 (t, J=19.20 Hz, 3 H), 1.89 (d, J=14.00 Hz, 1 H), 1.99-2.12 (m, 1 H) 2.02 (s, 3 H) 2.37-2.47 (m, 1 H) 2.69-2.75 (m, 6 H) 2.80 (dd, J=13.89, 2.27 Hz, 1 H), 3.11 (t, J=14.40 Hz, 1 H) 3.17-3.39 (m, 4 H), 3.55 (d, J=14.65 Hz, 1 H) 3.59 (s, 1 H), 3.71 (d, J=13.14 Hz, 1 H) 3.76 (s, 6 H) 3.86 (s, 3 H) 4.87 (s, 5 H), 5.00 (d, J=13.00 Hz, 1 H), 5.27-5.35 (m, 2 H), 5.84 (dd, J=10.11, 4.04 Hz, 1 H), 6.32 (s, 1 H), 6.35 (s, 1 H), 6.66 (s, 2 H) 7.10-7.20 (m, 2 H) 7.35 (d, J=7.58 Hz, 1 H) 7.70 (d, J=7.58 Hz, 1 H)

Example 5: pair-toluensulfonate

Dissolve the test sample 1.8 g base vinflunine in a minimum quantity of acetone and add 2 equivalents of para-toluenesulfonic acid (0,76 g) in the form of a solution in ethyl acetate. Add isopropyl ether and left to stand overnight. Filtered and washed with isopropyl ether. Dried 20 hours in vacuum at 70°C in the absence of light. Obtain 2.5 g of an amorphous powder.

The resulting powder was stirred for 24 hours in toluene at room temperature, filtered and washed with isopropyl ether. Dried 20 hours in vacuum at 70°C in the absence of light. Get 1.5 g of crystalline product.

1H NMR (400 MHz, Meon) δ ppm 0.67 (t, J=7.33 Hz, 3 H), 1.45-1.55 (m, 2 H) 1.58-1.83 (m, 2 H) 1.71 (t, J=19.00 Hz, 3 H), 1.89 (d, J=14.00 Hz, 1 H), 2.02 (s, 1 H) 2.05 (s, 3 H) 2.19-2.30 (m, 1 H), 2.35 (s, 6 H), 2.67 (dd, J=15.66, 6.06 Hz, 1 H) 2.78 (s, 3 H) 2.92 (dd, J=1415, 2.53 Hz, 1 H) 3.03-3.44 (m, 5 H), 3.54-3.64 (m, 1 H) 3.59 (s, 1 H) 3.68 (s, 1 H), 3.72-3.82 (m, 3 H) 3.76 (s, 3 H), 3.79 (s, 3 H) 3.87 (s, 3 H) 4.87 (s, 2 H), 4.93 (d, J=15.16 Hz, 1 H), 5.05 (d, J=15.16 Hz, 1 H), 5.29 (s, 1 H), 5.55 (d, J=10.61 Hz, 1 H), 5.83 (dd, J=10.11, 4.55 Hz, 1 H), 6.40 (s, 1 H), 6.62 (s, 1 H) 7.05 (dd, J=7.33 Hz, 1 H) 7.18 (dd, J=7.33 Hz, 1 H) 7.18 (d, J=8.08 Hz, 4 H), 7.39 (d, J=8.08 Hz, 1 H) 7.57 (d, J=8.08 Hz, 4 H) 7.63 (d, J=8.08 Hz, 1 H), 10.43 (s, 1 H)

Example 6: benzoate

Dissolve the test sample 1.8 g base vinflunine in a minimum amount of ethyl acetate and add 2 equivalents of benzoic acid (0.54 g) in the form of a solution in ethyl acetate. Evaporate the ethyl acetate and the precipitate is ground into powder in isopropyl ether, filtered and washed the residue with isopropyl ether. Dried 20 hours in vacuum at 70°C in the absence of light. Obtain 2.1 g of a crystalline salt.

1H NMR (400 MHz, Meon) δ ppm 0.70 (t, J=7.07 Hz, 3 H) 1.30-1.40 (m, 2 H) 1.54-1.92 (m, 4 H) 1.68 (t, J=20.00 Hz, 3 H), 2.02 (s, 3 H), 2.03-2.11 (m, 1 H) 2.28-2.37 (m, 1 H) 2.65 (d, J=16.00 Hz, 2 H) 2.64 (s, 1 H), 2.71 (s, 3 H) 3.02-3.29 (m, 6 H) 3.50 (d, J=14.15 Hz, 1 H), 3.57 (s, 1 H), 3.62 (d, J=12.63 Hz, 1 H) 3.75 (s, 6 H) 3.85 (s, 3 H), 4.78 (d, J=14.00 Hz, 1 H), 4.88 (d, J=14.00 Hz, 1 H), 4.87 (br. s., 2 H), 5.28 (d, J=10.50 Hz, 1 H), 5.30 (s, 1 H), 5.82 (dd, J=10.11, 4.04 Hz, 1 H), 6.32 (s, 1 H), 6.34 (s, 1 H) 7.07 (dd, J=7.33 Hz, 1 H) 7.14 (dd, J=7.33 Hz, 1 H) 7.31-7.36 (m, 2H) 7.38 (d, J=7.58 Hz, 1 H), 7.45-7.47 (m, J=7.4 Hz, 1H) 7.70 (d, J=7.58 Hz, 1 H) 7.92 (d, J=7.4 Hz, 2 H)

Example 7: Mandela

Dissolve the test sample 1.3 g base vinflunine in a minimum quantity of acetone and add 1 equivalent of R(-) almond acid (0.24 g) in the form of a solution in acetone. Evaporate the acetone in vacuo and the residue triturated to powder is isopropyl ether. Leave to stand overnight at room temperature, filtered and washed the residue with isopropyl ether. Dried 20 hours in vacuum at 70°C in the absence of light. Obtain 1.3 g of a crystalline salt.

1H NMR (400 MHz, Meon) δ ppm 0.70 (t, J=7.07 Hz, 3 H) 1.32-1.44 (m, 2 H) 1.55-1.92 (m, 3 H) 1.68 (t, J=19.00 Hz, 3 H), 1.98-2.08 (m, 1 H) 2.01 (s, 3 H) 2.28-2.42 (m, 1 H), 2.55-2.87 (m, 3 H) 2.67 (s, 1 H), 2.72 (s, 3 H) 3.00-3.29 (m, 6 H), 3.60 (s, 2 H) 3.57 (s, 1 H) 3.75 (s, 6 H) 3.85 (s, 3 H) 4.89 (s, 3 H) 4.88 (s, 4 H), 5.28 (d, J=10.00 Hz, 1 H), 5.29 (s, 1 H), 5.82 (dd, J=9.60, 4.04 Hz, 1 H), 6.33 (s, 2 H) 7.09 (t, J=7.58 Hz, 1 H) 7.16 (t, J=7.58 Hz, 1 H) 7.20-7.30 (m, 3 H) 7.34 (d, J=8.08 Hz, 1 H) 7.43 (d, J=7.07 Hz, 2 H) 7.67 (d, J=8.08 Hz, 1H)

Example 8: pair-hydroxybenzoate

Dissolve the test sample 1.3 g base vinflunine in a minimum quantity of acetone and add 1 equivalent of para-hydroxybenzoic acid (0,22 g) in the form of a solution in acetone. Evaporate the acetone in vacuo and the residue ground to powder in isopropyl ether. Leave to stand overnight at room temperature, filtered and washed the residue with isopropyl ether. Dried 20 hours in vacuum at 70°C in the absence of light. Obtain 1.3 g of a crystalline salt.

1H NMR (400 MHz, Meon) δ ppm 0.71 (t, J=7.07 Hz, 3 H), 1.29-1.40 (m, 2 H) 1.56-1.92 (m, 3 H) 1.67 (t, J=19.20 Hz, 3 H), 1.98-2.08 (m, 1 H) 2.01 (s, 3 H) 2.28-2.38 (m, 1 H) 2.53-2.76 (m, 2 H) 2.65 (s, 1 H), 2.71 (s, 3 H) 3.00-3.28 (m, 7 H), 3.49 (d, J=13.64 Hz, 1 H) 3.58 (d, J=10.00 Hz, 1 H), 3.57 (s, 1 H) 3.75 (s, 6 H) 3.84 (s, 3 H), 4.76 (d, J=14.00 Hz, 1 H), 4.84 (d, J=15.00 Hz, 1 H), 4.89 (s, 4 H), 5.28 (d, J=14.00 Hz, 1 H), 5.30 (s,, 1 H), 5.82 (dd, J=9.60, 4.04 Hz, 1 H), 6.34 (s, 2 H) 6.74 (d, J=8.59 Hz, 2 H) 7.06 (dd, J=7.33 Hz, 1 H) 7.12 (dd, J=7.33 Hz, 1 H)7.31 (d, J=8.08 Hz, 1 H) 7.70 (d, J=7.58 Hz, 1 H) 7.79 (d, J=8.08 Hz, 2H)

Nuclear magnetic resonance.

Range1H NMR were recorded at normal 400 MHz spectrometer Bruker Avance DPX 400 with a broadband inverse probe and z-gradient. Before registering NMR spectrum of the product dissolved in deuterated methanol (Euriso-top, paragraph (D 324-B, party A-3561) at an approximate concentration of 0.4% (wt./vol.). Chemical shifts are expressed in ppm (ppm)as internal standard tetramethylsilane was used (TMS). Constant interaction is expressed in Hertz.

Nuclear magnetic resonance is used to confirm the structural integrity of the salt molecule vinflunine after crystallization and to determine the molar ratio of acid used to vinflunine. This ratio is 1/1 or 2/1 in accordance with the acid used.

Diffraction of x-rays:

Samples were analyzed on a diffractometer Bruker AXS D8 Advance with copper anti-cathode (λ=1,A)operating at 30 kV and 53 mA, equipped with a unit receiving slit of variable width and a Vantec detector.

Analyses were performed between 2 and 40°2θ with a step 0,007°2θ and a counting 40 sec. The samples were placed in a sample holder with zero reflection (S-A-V Bruker AXS).

1. Anhydrous crystalline salt vinflunine obtained with 1 or 2 equivalents of a pharmaceutically acceptable neola is practical or organic acid, selected from fumarata, hydrobromide, lactate, para-toluensulfonate, benzoate, mandelate and para-hydroxybenzoate with powder diffraction pattern, as shown in figures 2-9.

2. A method of obtaining a crystalline salt vinflunine, comprising the following stages:
- dissolution of the Foundation vinflunine in a solvent or mixture of solvents selected from acetone, ethyl acetate, mixtures of acetone with ethanol, mixtures of acetone with methanol, mixtures of acetone with ethyl acetate;
- adding inorganic or organic acids;
the deposition of salt;
filtering and highlighting the formed salt;
- maintaining and crystallization of salt in the solvent or herstorical selected from ethyl ether or isopropyl ether;
filtering, washing and drying of the crystals in vacuum.

3. The method of claim 2 where the acid is selected from pharmaceutically acceptable inorganic or organic acids, such as fumaric, Hydrobromic, lactic, para-toluensulfonate, benzoic, almond and para-hydroxybenzoic acid.

4. The method of claim 2 where the acid is used at a ratio of 1 or 2 molar equivalent per 1 molar equivalent vinflunine.

5. The method of claim 2 where the acid is dissolved in water or a suitable organic solvent selected from acetone, ethyl acetate, ethanol, methanol.

6. The method according to claim 2, where Sardinia salt is carried out in the environment, or in a solvent or mixture of solvent and herstories, such as acetone, ethyl acetate, ethyl ether, isopropyl ether.

7. The method according to claim 2, where the curing is carried out in a solvent or mixture of solvent and herstories, such as acetone, ethyl acetate, ethyl ether, isopropyl ether.

8. Anhydrous crystalline salt vinflunine according to claim 1 or obtained by the method according to claim 2, used as medicine.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of vinflunine ditartrate, production method thereof and use thereof in therapy, especially for cancer pathology treatment.

EFFECT: high stability and wide variety of galenic forms.

8 cl, 3 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (l) and their pharmaceutically acceptable salts wherein X represents CH or N; one of R1 and R2 represents H and the other one is specified in OR6, SR6, Me, Et and SOR8; R3 is specified in tert-butylmethyl, sec-butyl, tert-butyl, cyclopentyl and cyclohexyl; R4 cyclopentyl C1-8alkyl optionally substituted by one C1-6alkoxy group; or C3-8cycloalkyl optionally substituted by one C1-6alkoxy group; R6 represents C1-8alkyl; and R8 represents C1-8alkyl, as well as to based pharmaceutical compositions and applying them as cathepsin K inhibitors and for analysing the cathepsin K inhibitors specified above.

EFFECT: there are presented new biologically active compounds and using them in medicine and pharmaceutics.

12 cl, 79 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing compounds of formula I The method is realised via cyclisation of a compound of formula (IV) with an intermediate compound Int4 at room temperature to obtain a compound of formula (III), reducing the nitro group in the compound of formula (III) to obtain a compound of formula (II). Further, by bonding the compound of formula (II) to a compound of formula Int5 in an aprotic solvent, a compound of formula (I) is obtained (structural formulae of compounds (II), (III), (IV), Int4, Int5 are given in the claim).

EFFECT: improved method of producing compounds of formula (I).

25 cl, 3 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new crystalline η-modification of 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]-phenyl]benzamide methanesulphonate (having the international nonproprietary name imanitib mesylate), to a method for preparing it and a based pharmaceutical composition. The new modification may be used in pharmaceutical industry and medicine as an antileukemic cytostatic preparation for therapy of cancer. The new crystalline η-modification of imanitib mesylate is characterized by an individual unique set of planar distances (d, Ǻ) and related intensities (l, %) specified in the patent claim; as well as an endothermic melting effect equal to - (29.9±0.4) J/g at temperature (218.6±0.5)°C and IR-spectra within the ranges 450 to 4000 cm-1 and 5300 to 14000 cm-1. The method for preparing the η-modification of imanitib mesylate consists in the fact that an aqueous solution of imanitib mesylate is frozen in a liquid nitrogen medium at rate min. 80 degrees/min that is followed by sublimation dehydration for 22-27 hours.

EFFECT: preparing the new antileukemic cytostatic preparation for therapy of cancer.

3 cl, 8 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

FIELD: chemistry; pharmaceutics.

SUBSTANCE: invention concerns novel compounds of formula: where R1 denotes - OH; R2, R3 and R4 denote H; X denotes a pharmaceutically acceptable anion such as Br; Y denote a group of formula VIa: where the dotted line together with the nitrogen atom form an unsubstituted 6-member heteroaryl; X is as defined above; the compounds can be used in a pharmaceutical composition which inhibits tumour growth and intensifies immune response. Described is a method of producing a compound I, which further contains R1 -ORa, where Ra denotes an unsubstituted C1-8alkyl; R2 denotes -(O=)C-O-Ra, where Ra denotes an unsubstituted C1-8alkyl alkyl; described also are intermediate compounds and use thereof in producing compound I.

EFFECT: obtaining novel compounds.

18 cl, 11 dwg, 29 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds selected from a group, structural formulae and values of radicals as given in paragraph 1 and paragraph 9 of the claim, as well as a method of treating a cell proliferation-associated disease, involving administration of said compounds to a subject.

EFFECT: novel compounds which exhibit considerable activity as Jak2/STAT3 pathway and subsequent target inhibitors and inhibit growth and survival of tumour cell lines are obtained and described.

52 cl, 3 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chelated mercury complexes with cysteine of formula C6H13O4N2S2HgCl or methionine of formula C10H21O4N2S2HgCl which show anticancer, antiviral, antiparasitic and immunomodulating action. The invention also concerns a method for preparing the complexes specified above which involves conducting a reaction of mercury dichloride and an aqueous solution of cysteine or methionine, keeping the mixture at temperature 35-40°C for 60-90 min, cooling the reaction mixture to 18-20°C and setting at this temperature for one day. The invention also refers to a drug preparation that is an apoptosis modulator of showing anticancer, antiviral, immunomodulating and antiparasitic action which contains the chelated mercury complex with cysteine or methionine 0.38-0.52 wt % and distilled water.

EFFECT: invention provides preparing the new chelated mercury complexes showing anticancer, antiviral, antiparasitic and immunomodulating action, and also the simplified method for preparing them at lower temperatures.

6 cl, 8 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, possessing properties of inhibiting activity of receptor of kinase insertion domain (KDR), or their pharmaceutically acceptable salts. In formula (1): each of X and Y independently represent O, NR, where R represents H; Z represents CR', where R' represents H or halogen; V, U and T together represent or each of R1, R2, R3, R4 and R6 independently represent H, halogen, cyano, C1-10alkyl; R5 values are given in the invention formula; R7 represents C1-10alkyl.

EFFECT: invention also relates to method of treating angiogenesis-associated disorder such as cancer or age-related macular degeneration.

16 cl, 318 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and deals with method of inducing apoptotic death of skin melanoma cells, which includes application of ligand TsPO PK11 195 and inhibitor of MEK kinase UO126, characterised by the fact that by means of method of RFLP analysis presence of mutation in gene BRAF V600E is determined in patient with skin melanoma by method of RFLP analysis and in case of its presence in order to induce apoptosis inhibitor of MEK kinase UO126 is additionally used together with PK11 195 in concentration: PK11 195 10 nmol/L, UO126 10 umol/L.

EFFECT: invention ensures effective impact on processes of apoptosis and cell proliferation of skin melanoma, which influences therapy in general.

1 cl, 1 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of neuroleptic haloperidol as means able to prevent development of abnormalities in lung tissue, caused by introduction of cytostatics. Reduction in development of inflammatory response due to reduction of development of connective tissue (pneumofibrosis) in lungs at the background of bleomicin introduction is shown.

EFFECT: invention can be applied for pharmacological correction of abnormalities in lung tissue developing with administration of anti-tumour medications.

1 dwg, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, namely to oncology, and deals with method of combined treatment of non-small cell lung cancer of II and III stage. Method includes 2 courses of neoadjuvant chemotherapy with application of carboplatin and further radical surgery. Neoadjuvant therapy is carried out by intravenous introduction of vinorelbine in dose 25 mg/ m2 on 1 and 8 days of cycle, on the second day, 20 hours after introduction of vinorelbine carboplatin is introduced intravenously by drop infusion in dose by AUG 6, interval between courses of chemotherapy constitutes 20 days. After that in post-operative period on 14 day additionally carried out is adjuvant chemotherapy in the same regimen, with number of course being 3-4.

EFFECT: invention ensures increased efficiency of treatment of non-small cell lung cancer of II and III stage due to reduction of complications and increase of patients' survival.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly a composition containing a lyophilised salt of vinflunine or vinorelbine stable at room temperature. A pharmaceutical composition containing a water-soluble salt of vinflunine or vinorelbine stable at room temperature where said salt is presented in the lyophilised form prepared in the presence at least of one carbohydrate of specific pH and relation of the water-soluble salt of vinflunine or vinorelbine and carbohydrate.

EFFECT: composition is stable.

9 cl, 2 dwg, 6 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combination containing the mTOR inhibitor everolimus and vinorelbine applicable for simultaneous, combined, separate or successive introduction.

EFFECT: invention refers to a method for preventing or treating a proliferative disease.

8 cl, 6 dwg, 2 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to traumatology and orthopedics and can be applied in complex treatment of posttraumatic, dystrophic, neurological, degenerative and scar-adhesion processes in joint area, deforming osteoarthrosis of large joints and osteochondrosis. Method of treatment includes introduction of drug mixture by ultraphonoresis for 5 minutes on a field, daily. To obtain said mixture applied are ointment "Indomethacyne", "Chondroxyde", gel "Essaven" in proportion 1:1:1, in dose, expressed in form of 3-10 cm long stripe of each ointment. These components are mixed with 50 mg of medication Karipasim, dissolved in 5 ml of physiological solution and 5 ml 2% solution of Trental. Treatment course includes 15-20 procedures.

EFFECT: method ensures fast achievement of antihydrophic and analgetic effect, reduction of total terms of patients' rehabilitation, increase of disease remission periods.

3 ex, 1 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of vinflunine ditartrate, production method thereof and use thereof in therapy, especially for cancer pathology treatment.

EFFECT: high stability and wide variety of galenic forms.

8 cl, 3 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmacology and medicine and represents pharmaceutical composition, which contains conjugate or its pharmaceutically acceptable salt, where said conjugate includes: polypeptide, which contains amino acidsequence, at least, by 80% identical to sequence Angiopep-2 (SEQ ID NO.:97); and at least, one molecule of taxol, conjugated with said polypeptide; and Solutol® HS-15.

EFFECT: invention insures increasing action of anticancer medications.

23 cl, 14 ex, 7 tbl, 28 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to oncohematology and can be used for treatment of diffuse large B-cell lymphosarcomas (DLBCL) of lymphoid organs in adults. The method involves pre-phase chemotherapy of sequential 6-fold block radical chemotherapy A-B-A-B-C-A or A-B-A-B-A-B. The block A is performed by the intravenous introduction of: methotrexate 1500 mg/m2 and vincristine 2 mg on the 1st day, doxorubicine 25 mg/m2 on the 1st and 2nd days, vepezide 100 mg/m2 and cytosar 150 mg/m2 on the 4th and 5th days only, and iphosphamide 800 mg/m2 intravenously, dexamethasone 20 mg in tablets on the 1-5th days. Further, the block B follows by the intravenous introduction of: methotrexate 1500 mg/m2 and vincristine 2 mg on the 1st day, doxorubicine 25 mg/m2 on the 4th and 5th days only, cyclophosphan 200 mg/m2 and dexamethasone 20 mg in tablets on the 1-5th days, then another 2 blocks A and B follow. In the presence of a complete remission, another 2 blocks A-B are required, and in the absence thereof, the block C is performed by the intravenous introduction: methotrexate 1500 mg/m2 and vinblastine 10 mg on the 1st day, cytosar 2000 mg/m2 2 times a day on the 2nd and 3rd days, vepezide 150 mg/m2 on the 3rd, 4th and 5th days, dexamethasone 20 mg in tablets on the 1-5th days, and then in the presence of the complete remission, the block A is performed. The therapeutic course is 4.5-5 months, every 21 days.

EFFECT: method allows higher clinical effectiveness in DLBCL, reduced recurrent cases, higher survival rate.

2 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new capmtotecin derivatives of a following structure of formula (I) where R1 represents H, C1-C4alkyl, branched C1-C4alkyl or vinyl, as well as to a pharmaceutical composition exhibiting antineoplastic activity and based on the given compounds, and to application thereof for making a drug for treating tumours.

EFFECT: there are produced and described new compounds which exhibit high antineoplastic activities and have good water-solubility; they can be applied for creating new drugs.

7 cl, 3 ex, 3 tbl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology and medicine. Substance of the invention consists that an immunocorrective drug exhibiting an intense specific antiviral activity for treating diseases of viral aetiology contains human recombinant interferon alpha and/or beta, and/or gamma, an antioxidant complex of tocopherol acetate or its derivative, including water-soluble ones, and ascorbic acid salts, calcium pantothenate, antiviral ingredients, as well as pharmaceutical aids and excipients in certain ratios in 1 g of the drug. As antiviral ingredients, the drug contains arbidol and its derivatives, remantadin, oseltamivir, ribavirin, inosine pranobex (isoprinosine), glycyrrhizic acid and its derivatives, nucleosides of a group - famvir, valacyclovir, ganciclovir, valganciclovir, foscarnet, cidofovir, lobucavir, sorivudine, brivudine, antiretroviral - lamivudine, zidovudine, lopinavir, stavudine. The agent is presented in rectal and vaginal suppositories, gel, ointment, liquid.

EFFECT: invention provides higher therapeutic effect and high bioavailability for treating the diseases of viral aetiology.

5 cl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention describes an amide of formula:

where A and B are independently selected from CH or N; D is H; Z is selected from hydrogen, unsubstituted C1-8alkyl, each L is independently selected from -CraRb-, -CRa=, -CO-, -O- or -NRa-; k, m, n, q, x and w are integers independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, provided that k+m+n+q+x+w equals at least 4; R1-R6 are independently selected from hydrogen, CN or halogen; Ra and Rb are independently selected from hydrogen, unsubstituted C1-8alkyl, or its pharmaceutically acceptable salt. The invention describes a pharmaceutical composition, use of the compounds to treat AChE-mediated diseases, a treatment method, as well as an amide synthesis method and use of the formula (I) amide as a chemical agent for inhibiting acetylcholinesterase in biological research.

EFFECT: compounds have high acetylcholinesterase or butyrylcholinesterase inhibiting activity.

24 cl, 27 ex, 1 tbl

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