RU2393164C1 - α- OR β-CRYSTALLINE MODIFICATIONS OF 5'-DESOXY-N4-CARBOPENTYLOXY-5-FLUOROCYTIDINE, PREPARATION METHOD THEREOF AND PHARMACEUTICAL COMPOSITIONS BASED ON SAID COMPOUNDS - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: disclosed are α- and β-crystalline forms of 5'-desoxy-N⁴-carbopentyloxy-5-fluorocytidine of formula (III)

, their preparation method through crystallisation of the raw product from a suitable solvent and pharmaceutical compositions based on the said compounds, having anti-cancer activity. The solvent used when preparing the α-modification is an ester or a mixture of ester-containing solvents. The solvent used when preparing the β-modification is a mixture of water and alkanol or a mixture of tetrahydrofuran and diethyl ether or carbon tetrachloride.

EFFECT: obtaining compounds and pharmaceutical compositions based on the said compounds, having anticancer activity.

10 cl, 2 dwg, 7 ex

Description

The invention relates to biologically active compounds, in particular to α- and β-crystalline modifications of 5'-deoxy-N ⁴ -carbopentyloxy-5-fluorocytidine, the method for their preparation and pharmaceutical compositions based on them. These crystalline modifications can be used in the manufacture of drugs for the treatment of cancer of the colon, breast and ovary [Fischer, DS; Knobf, M.T .; Durivage, HJ; Beaulieu, NJ (2003). The Cancer Chemotherapy Handbook (6 th Ed.). Mosby.].

Derivatives of 5'-deoxy-5-fluorocytidine of the general formula are known

showing high anti-cancer activity [Jap. J. Cancer Res., 1990, 81, 188-195].

A representative of this group of compounds 5'-deoxy-N ⁴ -carbopentyloxy-5-fluorocytidine exhibits antitumor activity due to the release of 5-fluorouracil in the tumor cells, which is an antimetabolite of pyrimidine (an inhibitor of thymidylate synthase). The use of this biologically active substance in the form of an amorphous powder in the manufacture of medicines has a disadvantage associated with its ability to form dust during drying and packaging operations, as well as in the manufacture of a dosage form that leads to contamination of production facilities and poses a health hazard to personnel. The effect of drug dust on the body largely depends on its degree of dispersion. Characterizing medicinal dust from this point of view, it should be noted that most of its species are highly dispersed aerosols. At 96-98% they consist of dust particles smaller than 5 microns. As a result of this, almost all aerosols of drugs have high stability in the air and are able to penetrate deeply into the lungs. Getting on the skin, mucous membranes, in the respiratory system, an aerosol can have a specific adverse effect: toxic, irritating, allergic, etc. A number of medicinal substances can simultaneously have toxic and irritating or any other effect. For example, broad-spectrum antibiotics have a toxic, allergenic property and cause dysbiosis. Another disadvantage is caking and short shelf life.

The objective of the invention is to develop such forms of biologically active compounds, which along with high anticancer activity would have improved properties for further processing into drugs.

This problem is solved by the proposed α-crystalline form of the compounds of formula (III):

characterized by the following X-ray powder diffraction pattern, measured using a STOE Powder Diffraction System diffractometer with an operating frequency of K _1α 1.54060 Å (Cu), a Ge (111) monochromator, an emitter with an operating voltage of 40 kV at a current strength of 40 mA, and expressed in terms of interplanar distance d, angle 2θ, absolute and relative intensities (expressed as a percentage of the most intense reflex):

D, Å 2θ Absolute intensity,% The relative intensity,% 18.706518 4.7200 695 6.29 17.392509 5.0768 2019 18.26 8.349193 10.5873 1423 12.87 5.145699 17.2188 1816 16.42 4.984726 17.7793 1045 9.45 4.714762 18.8063 4601 41.61 4.589795 19.3232 2920 26.41 4.526295 19.5969 3998 36.15 4.415842 09/20/21 11057 100.00 4.248667 20.8914 1439 01/13 4.169528 21.2925 1089 9.85 4.041695 21.9742 1294 11.71 3.586609 24.8042 599 5.42 3.510801 25.3486 3100 04/28 3.495126 25.4642 1643 14.86 3.441927 25.8645 2445 11/22 3.360984 26.4986 1331 12.03 3.255179 27.3764 438 3.96 3.134357 28.4535 1197 10.83 3.060282 29.1573 312 2.82 3.002893 29.7272 374 3.38 2.867519 31.1654 355 3.21 2.783453 32.1317 480 4.34 2.702822 33.1175 963 8.71 2.676631 33.4510 1177 10.64 2.638055 33.9549 747 6.76 2.600138 34.4654 419 3.79 2.586441 34.6537 1078 9.75 2.483769 36.1345 507 4.59 2.453536 36.5954 619 5.60 2.373557 37.8746 436 3.95 2.360295 38.0956 436 3.94 2.277506 39.5370 742 6.71

The above problem is also solved by the β-crystalline form of the compounds of formula III:

characterized by the following X-ray powder diffraction pattern, measured using a STOE Powder Diffraction System diffractometer with an operating frequency of K _1α 1.54060 Å (Cu), a Ge (111) monochromator, an emitter with an operating voltage of 40 kV at a current strength of 40 mA and expressed as terms: interplanar distance d, angle 2θ, absolute and relative intensities (expressed as a percentage of the most intense reflex):

D, Å 2θ Absolute intensity,% The relative intensity,% 17.457664 5.0579 5943 100.00 8.355730 10.5790 851 14.33 5.148365 17.2098 1076 10/18 4.992127 17.7527 957 11/16 4.719445 18.7875 1646 27.70 4.590744 19.3192 1218 20.49 4.528882 19.5856 1317 22.16 4.417918 08.2026 2939 49.45 4.353234 20.3842 962 16.19 4.250788 20.8809 850 14.31 4.170886 21.2855 807 13.58 4.044059 21.9612 816 13.73 3.590448 24.7772 472 7.95 3.511590 25.3428 854 14.36 3.443123 25.8554 762 12.83 3.363979 26.4746 554 9.32 3.136288 28.4356 536 9.02 2.706745 33.0681 383 6.44 2.676772 33.4492 400 6.72 2.587544 34.6384 472 7.95

A method for obtaining crystalline forms of the compounds of formula (III):

by crystallization of the crude product from a suitable solvent.

A method in which, to obtain an α-crystalline form of a compound of formula (III), the product is crystallized from a solvent of the ester class or a mixture of solvents containing an ester, ethyl acetate being used as an ester.

A method in which to obtain a β-crystalline form of a compound of formula (III), the product is obtained by crystallization from a water-alkanol mixture, methanol being used as the alkanol.

A method in which to obtain a β-crystalline form of a compound of formula (III), the product is obtained by crystallization from a mixture of tetrahydrofuran-diethyl ether or from carbon tetrachloride.

Another object of the invention is a pharmaceutical composition comprising, as an active ingredient, an α-crystalline form of a compound of formula III in combination with one or more pharmaceutically acceptable, inert, non-toxic compounds.

A pharmaceutical composition is also provided comprising, as an active ingredient, a β-crystalline form of a compound of formula III in combination with one or more pharmaceutically acceptable, inert, non-toxic compounds.

5'-Deoxy-N ⁴ -carbopentyloxy-5-fluorocytidine (formula III) is obtained by selective deacylation of O ^{2 '} , O ^3' -diacetyl-5'-deoxy-N ⁴ -carbopentyloxy-5-fluorocytidine (formula II) under the action of a base :

O ^{2 '} , O ^3' -Diacetyl-5-deoxy-N ⁴ -carbopentyloxy-5-fluorocytidine (Formula II) is obtained by selective addition of n-pentyl chlorocarbonate to O ^{2 '} , O ^3' -diacetyl-5'-deoxy-5'-fluorocytidine (formula I) in the presence of organic bases:

Methods of obtaining the proposed crystalline modifications are illustrated by the following examples:

Example 1. O ^{2 '} O ^3' -Diacetyl-5'-deoxy-5-fluorocytidine (formula I)

(1с CHCl₃)+86.To a suspension of 2.6 kg (20 mol) of 5-fluorocytosine in 8 L of hexamethyldisilazane (hereinafter HMDS), 120-140 ml of trimethylchlorosilane are added with stirring. The mixture is boiled with stirring until the precipitate of 5-fluorocytosine is dissolved (3-5 hours), cooled, the volatiles are distilled off in vacuo. The residue was dissolved in 20 L of methylene chloride and transferred to a 100-liter thermostatic reactor equipped with a reflux condenser, a productive mechanical stirrer and a dropping funnel. 20 L of methylene chloride are added and 6 kg (21.6 mol) of 5-deoxy-1,2,3-tri-O-acetyl-β- (D) -ribofuranose are added. The reaction mixture is cooled to 0 ° C and 6.24 kg of anhydrous SnCl _{4 are} added dropwise with stirring over 30-40 minutes. The reaction mixture is stirred for 2 hours at room temperature, the reaction mixture is cooled to 0-10 ° C, 10 kg of dry drinking soda are sprinkled and 3.5 L of water are carefully added dropwise. The reaction mixture was stirred at room temperature overnight, filtered from a precipitate of inorganic salts, and the filter residue was washed with 7 L of methylene chloride, the combined filtrate was washed with 10 L of a 4% solution of baking soda, and the solvent was distilled off under vacuum at atmospheric pressure. 6 l of methyl tert-butyl ether (MTBE) was added to the residue with stirring, the precipitated crystalline product was filtered and dried in air to constant weight. Obtain 5.0-5.6 kg of a white or yellowish crystalline substance (formula I), so pl. 191-193 ° C.

(1s CHCl ₃ ) +86.

¹ H NMR (δ ppm CDCl ₃ ) 8.1 (1H, broad s), 7.39 (1H, 5.81 Hz), 5.99 (1H, 3.79 Hz), 5, 69 (1 H broad s), 5.32 (1 H t 4.95 Hz), 5.00 (1 H t 5.90 Hz), 4.24 (1 H t, 6.20 Hz), 2.11 (3H s.), 2.09 (3H s.), 1.46 (3H d. 6.57 Hz).

Example 2. O ^{2 '} , O ^3' -Diacetyl-5-deoxy-N ⁴ -carbopentyloxy-5-fluorocytidine (formula II)

A solution of 2.5 kg (7.6 mol) of 2 ', 3'-di-O-acetyl-5'-deoxy-5- is placed in a 20-liter temperature-controlled reactor equipped with a reflux condenser, a productive mechanical stirrer and a dropping funnel. fluorocytidine (Formula I) in 6 L of CH ₂ Cl ₂ and 1.23 L of pyridine, while cooling to -10 ° C, 1.513 L (1.6 kg, 10.6 mol) of n-pentyl chloroformate are added dropwise so that the reaction temperature the mixture was in the range from -10 ° C to -5 ° C. The reaction mixture was stirred for 30 minutes at room temperature. 60 ml of MeOH are added to bind the excess n-pentyl chloroformate, 3 L of water, the organic layer is separated, the aqueous layer is extracted with 2 L of methylene chloride and the combined organic layers are washed once with 4 L of water, the solvent is evaporated off under vacuum. The output is quantitative.

¹ H NMR (δ ppm CDCl ₃ ) 12.0 (1H broad s.), 7.4 (1H broad s.), 5.93 (1H d. 4.3 Hz), 5.27 (1H t. 5.4 Hz), 4.99 (1H t. 5.5 Hz), 4.23 (1H t. 5.8 Hz), 4.15 (2H t. 6.7 Hz), 2.09 (3H s), 2.07 (3H s), 1.69 (2H p. 7.2 Hz), 1.44 (3H d. 6.57 Hz), 1.37-1.29 (4H m.), 0.88 (3H, 6.95 Hz).

Example 3. 5'-Deoxy-N ⁴ -carbopentyloxy-5-fluorocytidine α-crystalline modification (formula IIIa) (see figure 1)

(с1 МеОН)+96-100. ЯМР ¹H (δ м.д. CDCl₃) РФА (формула IIIa):A solution of O ^{2 '} , O ^3' -diacetyl-5'-deoxy-N ^4- carbopentyloxy-5-fluorocytidine (formula II) is placed in a 20-liter temperature-controlled reactor equipped with a reflux condenser, a productive mechanical stirrer and a dropping funnel. 2) in 5.5 l of methanol, cooled to -20 ° C and add a dropwise solution of 1.262 kg of NaOH in 1.75 l of water at such a rate that the temperature of the reaction mixture was below -10 ° C. The reaction mixture was altered for another 5-10 minutes, then 2.63 L of 36% hydrochloric acid was added. The solvent was removed in vacuo, 3 L of water and 6 L of CH ₂ Cl _{2 were} added to the residue. The organic layer was separated, washed with water and the solvent was removed in vacuo. The resulting mass was heated to 60 ° C and 2 L of ethyl acetate was added. The reaction mixture was cooled to room temperature, and the α-crystalline 5'-deoxy-N ⁴ -carbopentyloxy-5-fluorocytidine precipitate (formula IIIa) was filtered. The product is washed with water and dried in vacuo. Yield 2.5 kg (80%,). Mp 119-121.

(c1 MeOH) + 96-100. ¹ H NMR (δ ppm CDCl ₃ ) XRD (formula IIIa):

D, Å 2θ The relative intensity,% Absolute intensity,% 18.706518 4.7200 6.29 695 17.392509 5.0768 18.26 2019 8.349193 10.5873 12.87 1423 5.145699 17.2188 16.42 1816 4.984726 17.7793 9.45 1045 4.714762 18.8063 41.61 4601 4.589795 19.3232 26.41 2920 4.526295 19.5969 36.15 3998 4.415842 09/20/21 100.00 11057 4.248667 20.8914 01/13 1439 4.169528 21.2925 9.85 1089 4.041695 21.9742 11.71 1294 3.586609 24.8042 5.42 599 3.510801 25.3486 04/28 3100 3.495126 25.4642 14.86 1643 3.441927 25.8645 11/22 2445 3.360984 26.4986 12.03 1331 3.255179 27.3764 3.96 438 3.134357 28.4535 10.83 1197 3.060282 29.1573 2.82 312 3.002893 29.7272 3.38 374 2.867519 31.1654 3.21 355 2.783453 32.1317 4.34 480 2.702822 33.1175 8.71 963 2.676631 33.4510 10.64 1177 2.638055 33.9549 6.76 747 2.600138 34.4654 3.79 419 2.586441 34.6537 9.75 1078 2.483769 36.1345 4.59 507 2.453536 36.5954 5.60 619 2.373557 37.8746 3.95 436 2.360295 38.0956 3.94 436 2.277506 39.5370 6.71 742

X-ray diffraction data were obtained using a STOE Powder Diffraction System diffractometer with an operating frequency of K _1α 1.54060 Å (Cu), a Ge (111) monochromator, an emitter with an operating voltage of 40 kV at a current strength of 40 mA and expressed in terms of: interplanar distance d, angle 2θ, absolute and relative intensities (expressed as a percentage of the most intense reflex).

Example 4. 5'-Deoxy-N ⁴ -carbopentyloxy-5-fluorocytidine β-crystalline modification (formula IIIb) (from methanol / water) (see figure 2)

A solution of O ^{2 '} , O ^3' -diacetyl-5'-deoxy-N ^4- carbopentyloxy-5-fluorocytidine (formula II) is placed in a 20-liter temperature-controlled reactor equipped with a reflux condenser, a productive mechanical stirrer and a dropping funnel. 2) in 5.5 l of methanol, cooled to -20 ° C and add a dropwise solution of 1.262 kg of NaOH in 1.75 l of water at such a rate that the temperature of the reaction mixture was below -10 ° C. The reaction mixture was altered for another 5-10 minutes, then 2.63 L of 36% hydrochloric acid was added. The solvent was removed in vacuo, 3 L of water and 6 L of CH ₂ Cl _{2 were} added to the residue. The organic layer was separated, washed with water and the solvent was removed in vacuo. The resulting mass is heated to 60 ° C and add 2 l of methanol. Gradually add water (approx. 4 l) until crystallization begins. The reaction mixture was cooled to room temperature and the precipitate of 5'-deoxy-N ⁴ -carbopentyloxy-5-fluorocytidine β-crystalline modification (formula IIIb) was filtered. The product is dried in vacuo.

Yield 2.0 kg (64%,). T. pl. 119-121. α ^D ₂₀ (s1 MeOH) + 96-100.

¹ H NMR (δ ppm CDCl ₃ )

XRD (formula IIIb)

D, Å 2θ The relative intensity,% Absolute intensity,% 17.457664 5.0579 100.00 5943 8.355730 10.5790 14.33 851 5.148365 17.2098 10/18 1076 4.992127 17.7527 11/16 957 4.719445 18.7875 27.70 1646 4.590744 19.3192 20.49 1218 4.528882 19.5856 22.16 1317 4.417918 08.2026 49.45 2939 4.353234 20.3842 16.19 962 4.250788 20.8809 14.31 850 4.170886 21.2855 13.58 807 4.044059 21.9612 13.73 816 3.590448 24.7772 7.95 472 3.511590 25.3428 14.36 854 3.443123 25.8554 12.83 762 3.363979 26.4746 9.32 554 3.136288 28.4356 9.02 536 2.706745 33.0681 6.44 383 2.676772 33.4492 6.72 400 2.587544 34.6384 7.95 472

X-ray diffraction data were obtained using a STOE Powder Diffraction System diffractometer with an operating frequency of K _1α 1.54060 Å (Cu), a Ge (111) monochromator, an emitter with an operating voltage of 40 kV at a current strength of 40 mA and expressed in terms of: interplanar distance d, angle 2θ, absolute and relative intensities (expressed as a percentage of the most intense reflex).

Example 5. 5'-Deoxy-N ⁴ -carbopentyloxy-5-fluorocytidine β-crystalline modification (formula IIIb) (from a mixture of tetrahydrofuran / diethyl ether)

A solution of O ^{2 '} , O ^3' -diacetyl-5'-deoxy-N ^4- carbopentyloxy-5-fluorocytidine (formula II) is placed in a 20-liter temperature-controlled reactor equipped with a reflux condenser, a productive mechanical stirrer and a dropping funnel. 2) in 5.5 l of methanol, cooled to -20 ° C and add a dropwise solution of 1.262 kg of NaOH in 1.75 l of water at such a rate that the temperature of the reaction mixture was below -10 ° C. The reaction mixture was altered for another 5-10 minutes, then 2.63 L of 36% hydrochloric acid was added. The solvent was removed in vacuo, 3 L of water and 6 L of CH ₂ Cl _{2 were} added to the residue. The organic layer was separated, washed with water and the solvent was removed in vacuo. The resulting mass is heated to 60 ° C and add 2 l of tetrahydrofuran. Diethyl ether (approx. 4 L) was added gradually until crystallization began. The reaction mixture was cooled to room temperature and the precipitate of 5'-deoxy-N ⁴ -carbopentyloxy-5-fluorocytidine β-crystalline modification (formula IIIb) was filtered. The product is dried in vacuo.

Yield 2.3 kg (73.6%,). Mp 119-121. α ^D ₂₀ (s1 MeOH) + 96-100.

¹ H NMR (δ ppm CDCl ₃ ).

XRD (formula IIIb) (see example 4).

Example 6. 5'-Deoxy-N ⁴ -carbopentyloxy-5-fluorocytidine β-crystalline modification (formula IIIb) (from a mixture of tetrahydrofuran / diethyl ether)

A solution of O ^{2 '} , O ^3' -diacetyl-5'-deoxy-N ^4- carbopentyloxy-5-fluorocytidine (formula II) is placed in a 20-liter temperature-controlled reactor equipped with a reflux condenser, a productive mechanical stirrer and a dropping funnel. 2) in 5.5 l of methanol, cooled to -20 ° C and add a dropwise solution of 1.262 kg of NaOH in 1.75 l of water at such a rate that the temperature of the reaction mixture was below -10 ° C. The reaction mixture was altered for another 5-10 minutes, then 2.63 L of 36% hydrochloric acid was added. The solvent was removed in vacuo, 3 L of water and 6 L of CH ₂ Cl _{2 were} added to the residue. The organic layer was separated, washed with water and the solvent was removed in vacuo. The resulting mass is heated to 60 ° C and add 20 l of carbon tetrachloride until complete dissolution of the precipitate. The reaction mixture was cooled to room temperature and the precipitate of 5'-deoxy-N ⁴ -carbopentyloxy-5-fluorocytidine β-crystalline modification (formula IIIb) was filtered. The product is washed with carbon tetrachloride and dried in vacuo. Yield 2.6 kg (83.2%,). T. pl. 119-121. α ^D ₂₀ (s1 MeOH) + 96-100.

¹ H NMR (δ ppm CDCl ₃ ).

XRD (formula IIIa) see example 4.

The following example illustrates the preparation of the proposed compositions.

An example of obtaining a composition

A coated tablet containing the following ingredients:

1) α- or β-crystalline form of capecitabine - 500.00 mg;

2) anhydrous lactose - 142.88 mg;

3) hypromellose - 14.28 mg;

4) crospovidone - 150.0 mg;

5) mannitol - 92.84 mg;

6) microcrystalline cellulose - 187.28 mg;

7) magnesium stearate - 32.88 mg;

8) aspartame - 62.16 mg;

9) shell - 32.03 mg;

Total weight - 1214.35;

The method of obtaining tablets

1) mix the α- or β-crystalline form of capecitabine with anhydrous lactose and part of crospovidone;

2) dissolve hypromellose in purified water;

3) mix the mixture according to claim 1 and the solution according to claim 2;

4) conduct wet grinding of the mixture according to claim 3;

5) dry and grind the granulate according to claim 4;

6) mix the granulate according to claim 5 with the remainder of crospovidone, mannitol, microcrystalline cellulose and aspartame;

7) sift the magnesium stearate through a sieve, add to the mixture according to claim 6 and mix;

8) compress the tablets from the mixture according to claim 7;

9) to prepare a suspension from a mixture for a film membrane and purified water;

10) apply a film coating to the tablets using the suspension prepared according to claim 9.

The proposed crystalline modifications have the same level of the above biological activity, but are more convenient in processing into a medicinal product. In addition, crystalline forms of capecitabine are less prone to caking during storage, and dosage forms based on them have higher stability, which ensures the preservation of their therapeutic properties for a longer time.

Claims (7)

1. The α-crystalline form of the compounds of formula (III)

characterized by the following X-ray powder diffraction pattern, measured using a STOE Powder Diffraction System diffractometer with an operating frequency of K _1a 1.54060 Å (Cu), a Ge (111) monochromator, an emitter with an operating voltage of 40 kV at a current strength of 40 mA and expressed in terms: interplanar distance d, angle 2θ, absolute and relative intensities (expressed as a percentage of the most intense reflex):
D, Å 2θ Absolute intensity,% The relative intensity,% 18.706518 4.7200 695 6.29 17.392509 5.0768 2019 18.26 8.349193 10.5873 1423 12.87 5.145699 17.2188 1816 16.42 4.984726 17.7793 1045 9.45 4.714762 18.8063 4601 41.61 4.589795 19.3232 2920 26.41 4.526295 19.5969 3998 36.15 4.415842 09/20/21 11057 100.00 4.248667 20.8914 1439 01/13 4.169528 21.2925 1089 9.85 4.041695 21.9742 1294 11.71 3.586609 24.8042 599 5.42 3.510801 25.3486 3100 04/28 3.495126 25.4642 1643 14.86 3.441927 25.8645 2445 11/22 3.360984 26.4986 1331 12.03 3.255179 27.3764 438 3.96 3.134357 28.4535 1197 10.83 3.060282 29.1573 312 2.82 3.002893 29.7272 374 3.38 2.867519 31.1654 355 3.21 2.783453 32.1317 480 4.34 2.702822 33.1175 963 8.71 2.676631 33.4510 1177 10.64 2.638055 33.9549 747 6.76 2.600138 34.4654 419 3.79 2.586441 34.6537 1078 9.75 2.483769 36.1345 507 4.59 2.453536 36.5954 619 5.60 2.373557 37.8746 436 3.95 2.360295 38.0956 436 3.94 2.277506 39.5370 742 6.71 2. The β-crystalline form of the compound of formula (III)

characterized by the following X-ray powder diffraction pattern, measured using a STOE Powder Diffraction System diffractometer with an operating frequency of K _1a 1.54060 Å (Cu), a Ge (111) monochromator, an emitter with an operating voltage of 40 kV at a current strength of 40 mA and expressed as terms: interplanar distance d, angle 2θ, absolute and relative intensities (expressed as a percentage of the most intense reflex):
D, Å 2θ Absolute intensity Relative intensity% 17.457664 5.0579 5943 100.00 8.355730 10.5790 851 14.33 5.148365 17.2098 1076 10/18 4.992127 17.7527 957 11/16 4.719445 18.7875 1646 27.70 4.590744 19.3192 1218 20.49 4.528882 19.5856 1317 22.16 4.417918 08.2026 2939 49.45 4.353234 20.3842 962 16.19 4.250788 20.8809 850 14.31 4.170886 21.2855 807 13.58 4.044059 21.9612 816 13.73 3.590448 24.7772 472 7.95 3.511590 25.3428 854 14.36 3.443123 25.8554 762 12.83 3.363979 26.4746 554 9.32 3.136288 28.4356 536 9.02 2.706745 33.0681 383 6.44 2.676772 33.4492 400 6.72 2.587544 34.6384 472 7.95 3. The method of obtaining crystalline forms of the compound according to claim 1 or 2 of the formula (III)

by crystallization of the crude product from a suitable solvent - to obtain the α-crystalline form of the compound according to claim 1, the product is crystallized from a solvent belonging to the class of esters, or a mixture of solvents containing an ester, and to obtain a β-crystalline form of the compound according to p. 2, the product is crystallized from a solvent belonging to a water-alkanol mixture or a mixture of tetrahydrofuran-diethyl ether or carbon tetrachloride. 4. The method according to claim 3, characterized in that ethyl acetate is used as the ester. 5. The method according to claim 3, characterized in that methanol is used as alkanol. 6. A pharmaceutical composition exhibiting anticancer activity, comprising as an active ingredient the α-crystalline form according to claim 1, in combination with one or more pharmaceutically acceptable, inert, non-toxic compounds. 7. A pharmaceutical composition exhibiting anticancer activity, comprising as an active ingredient a β-crystalline form according to claim 2, in combination with one or more pharmaceutically acceptable, inert, non-toxic compounds.

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