Crystalline forms of derivative of pyrimidine nucleoside (variants), pharmaceutical composition, method for prophylaxis and treatment of tumor disease and applying crystalline form

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new stable crystalline forms of derivative of pyrimidine nucleoside of the formula (I) eliciting the excellent anti-tumor activity. Also, invention relates to pharmaceutical composition eliciting an anti-tumor effect, applying crystalline form for preparing medicinal agent and to a method for prophylaxis or treatment of tumor diseases.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of derivative.

10 cl, 2 tbl, 4 dwg, 9 ex

 

The technical field

This invention relates to crystalline forms of the derivative of pyrimidine nucleoside, which has excellent antitumor activity, to pharmaceutical compositions preferably antitumor agents containing the specified crystalline form as the active ingredient; the use of specified crystalline form when receiving the said pharmaceutical compositions; and to a method for prevention or treatment of diseases (preferably, a tumor), which includes the introduction of a warm-blooded animal (preferably, a human, in need of such prevention or treatment, a pharmacologically effective quantity of a specified crystalline form.

Background of the invention

A derivative of pyrimidine nucleoside of the formula (I), (hereinafter designated as compound (I)described in Japan patent No. 2569251. The compound (I) has an excellent antitumor activity and is regarded as the agent for the treatment or prevention of tumors. To obtain the compound (I), more adapted for use as a drug, need better stability during storage, great ease of handling and so on.

Description of the invention

The authors of this invention have studied the stability and other similar t the VA compound (I) and succeeded in obtaining crystals of compound (I). These crystals have a much better stability during storage and ease of handling compared to the powder of the compound (I)obtained in example 1, presented in the description to the Japan patent No. 2569251. These crystals show excellent pharmacokinetic profile, such as oral absorption and similar properties, and, therefore, are applicable in practice drugs.

In accordance with this invention is invited to:

(1) the crystalline form of the compound of formula (I)

(2) the crystalline form (1)where the compound of formula (I) is a hydrate,

(3) the crystalline form according to (1) or (2)where the specified crystal form has main peaks at distances of the crystal lattice 19,53, 13,03, 9,75, 4,17, 4,00, 3,82, 3,68 and to 3.41 Å, determined by x-ray powder method using copper rays Kα (wavelength λ=1,54 E)

(4) the crystalline form according to (1) or (2)where the specified crystal form has main peaks at distances of the crystal lattice 19,36, 12,87, 9,63, 4,70, 4,64, 4,28, 4,10, 3,92, 3,77 and of 3.48 Å, determined by x-ray powder method using copper rays Kα (wavelength λ=1,54 E)

(5) the crystalline form according to (1) or (2)where the specified crystal form has main peaks at distances crystalline resh the TCI 19,62, 13,06, 9,82, 4,72, 4,63, 4,56, 4,15, 3,98, 3,93, 3,82, 3,45 and 3.40 Å, determined by x-ray powder method using copper rays Kα (wavelength λ=1,54 E)

(6) crystal form (1) or (2)where the specified crystal form has main peaks at distances of the crystal lattice 22,52, 5,17, 4,60, 4,28 and a 3.87 E defined by x-ray powder method using copper rays Kα (wavelength λ=1,54 E)

(7) a pharmaceutical composition comprising the crystalline form according to any one of (1)to(6) as the active ingredient,

(8) the pharmaceutical composition according to (7) for the prevention or treatment of tumors,

(9) the use of a crystalline form according to any one of (1)to(6) to obtain a pharmaceutical composition

(10) using (9), where the pharmaceutical composition is intended for the prevention or treatment of tumors,

(11) a method of prevention or treatment of diseases involving the introduction of a pharmacologically effective amount of a crystalline form according to any one of (1)to(6) warm-blooded animal in need of such prevention or treatment,

(12) the method according to (11), in which the disease is a tumor,

(13) the method according to (11) or (12), in which a warm-blooded animal is a human.

Crystalline form of compound (I) in accordance with this invention is a solid substance, to the which has a regular repeating arrangement of atoms (or groups of atoms) in the three-dimensional structure. Crystal differs from amorphous solids so that the latter does not have the correct arrangement of atoms in three-dimensional structure.

In General, depending on the conditions of crystallization can be obtained from multiple different crystalline forms (polymorphism) of the same connection. These different crystalline forms have different three-dimensional patterns and have different physico-chemical properties.

This invention covers a crystalline form and a mixture of two or more of these crystalline forms.

Crystalline forms of compound (I) include, for example, a crystal having main peaks at distances of the lattice d=19,53, 13,03, 9,75, 4,17, 4,00, 3,82, 3,68 and to 3.41 Å, determined by x-ray powder method using copper rays Kα (wavelength λ=1,54 E), where the main peaks are the relative intensity of diffraction more than 36 with respect to the relative intensity 100 peak on the lattice distance d=9.75 E;

(in addition, the lattice distance d can be calculated from equation 2dsinθ=nλ (n=1)),

crystal, having main peaks at distances of the lattice d=19,36, 12,87, 9,63, 4,70, 4,64, 4,28, 4,10, 3,92, 3,77 and of 3.48 Å, determined by x-ray powder method using copper rays Kα (wavelength λ=1,54 E), where the main peaks have otnositel the second diffraction intensity more than 53 with respect to the relative intensity 100 peak on the lattice distance d=3,92 E;

crystal, having main peaks at distances of the lattice d=19,62, 13,06, 9,82, 4,72, 4,63, 4,56, 4,15, 3,98, 3,93, 3,82, 3,45 and 3.40 Å, determined by x-ray powder method using copper rays Kα (wavelength λ=1,54 E), where the main peaks are the relative intensity of diffraction of more than 30 with respect to the relative intensity 100 peak on the lattice distance d=4,56 E; and

crystal, having main peaks at distances of the lattice d=22,52, 5,17, 4,60, 4,28 and a 3.87 E defined by x-ray powder method using copper rays Kα (wavelength λ=1,54 E), where the main peaks are the relative intensity of diffraction more than 36 with respect to the relative intensity 100 peak on the lattice distance d=22,52 E.

When the crystalline forms of compound (I) can withstand such a way that they are open to atmospheric effects or mixed with water or solvent, they can absorb water or solvent with the formation of a hydrate or of MES. This invention covers such a hydrate and a solvate.

The compound (I) can be obtained by the method similar to that described in Japan patent No. 2569251.

Crystalline forms of compound (I) can be obtained from a supersaturated solution. A supersaturated solution can be obtained by dissolving compound (I) in a suitable solvent, bringing the pH at asanoha solution, the concentration of the specified solution, cooling the specified solution by adding a solvent in which the compound (I) is dissolved slightly, to a solution of compound (I) in a solvent in which the compound (I) dissolved easily, or similar actions.

A suspension of crystalline or amorphous solids of the compound (I) in a suitable solvent transform into mist, and then stirred for converting alternating crystal (solvent mediated transformation).

In addition, the deposition of crystals in the reaction vessel occurs spontaneously or it can be initiated or accelerated by adding a crystal nucleating, mechanical stimulation, such as the use of ultrasonic waves or tension within the reaction vessel.

The temperature for crystallization of the compound (I) or its pharmacologically acceptable salt is usually from 0 to 60°S, preferably from 5 to 45°C.

Precipitated crystals can be collected by filtration, centrifugation or decantation. Selected crystals can be washed with a suitable solvent. The washing solvent may include, for example, water; an alcohol, such as ethanol, isopropanol; a ketone such as acetone; esters, such as methylformate, ethyl formate, methyl acetate, ethyl acetate; aromatic ug is avodart, such as toluene, xylene; NITRILES such as acetonitrile; a simple ether, such as diethyl ether, tetrahydrofuran or a mixture thereof. Preferably apply acetate, which contains water or waterless.

Selected crystals can be dried at a temperature of from 10 to 100°C, preferably from 30 to 50°up until the weight of these crystals are not permanent, if necessary, in the presence of a desiccant such as silica gel or calcium chloride and under reduced pressure.

The dried crystals can absorb water at a relative humidity from 20 to 90% and at a temperature of from 10 to 30°C, preferably at a relative humidity of from 50 to 80% and a temperature of 20 to 30°With, before, until the weight of these crystals are not permanent.

Thus obtained crystals can be further purified by recrystallization or purification of the suspension.

The recrystallization is conducted by methods known to experts in the art, such as (1) cooling method: compound (I) or its pharmacologically acceptable salt is dissolved in a hot solvent and then the resulting solution is cooled, (2) the method of concentration: a solution of compound (I) or its pharmacologically acceptable salt concentrate, (3) deposition method: solvent in which the compound (I) or its headlight is Ekologicheskie acceptable salt dissolves slightly, added to a solution of compound (I) or its pharmacologically acceptable salt in a solvent in which the compound (I) or its pharmacologically acceptable salt dissolves easily.

Clearing of the suspension includes the collection of crystals, which is obtained by mixing a suspension of a specific compound in a suitable solvent.

The solvent used in the cleaning method of a suspension of compound (I)includes, for example, a ketone such as acetone, methyl ethyl ketone; esters such as methyl acetate, ethyl acetate; a nitrile such as acetonitrile; halogenated hydrocarbons, such as methylene chloride, chloroform; aromatic hydrocarbons such as toluene, xylene; an alcohol, such as ethanol, isopropanol; a simple ether, such as diethyl ether, tetrahydrofuran; amide such as N,N-dimethylformamide; water; aliphatic hydrocarbons such as hexane; simple ether, such as diisopropyl ether, diethyl ether; or the like, and mixtures thereof. Preferably, use a ketone, such as acetone, methyl ethyl ketone; esters, such as methylformate, ethyl formate, methyl acetate, ethyl acetate; a nitrile such as acetonitrile; an alcohol, such as ethanol, isopropanol, and the solvents containing water, and more preferably, methyl acetate, water-containing or anhydrous.

The crystals obtained by recrystallization and purification of the Uspenie, there are also methods similar to those as described above.

If crystalline forms of compound (I) used as a drug, preferably as an agent for treatment or prevention of tumors, these crystal forms may be administered alone or as a mixture of these crystal forms with suitable pharmacologically acceptable excipient(s) and/or diluent(s). Compositions in accordance with this invention can be a single dosage form such as tablets, capsules, granules, powders, syrups, injections, ointments, solutions, suspensions, aerosols, tablets or similar forms for oral or parenteral administration.

The pharmaceutical compositions can be obtained by known methods using additives such as excipients, binders, disintegrant, lubricating agents, stabilizing agents, corrigentov, suspendresume agents, thinners and solvents.

Examples of excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethoxy starch; cellulose derivatives such as crystalline cellulose, hydroxypropylcellulose of low substitution is, the hypromellose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose with internal cross-stitching; Arabian gum; dextran; pullulan; silicate derivatives such as light silicic acid anhydride, synthetic aluminum silicate, metasilicate aluminate magnesium; phosphate derivatives such as calcium phosphate, derivatives of carbonate, such as calcium carbonate; sulfate derivatives such as calcium sulfate; or similar.

Examples of binding agents include the above-described excipients; gelatin; polyvinylpyrrolidone; macrogol; or similar.

Examples of disintegrants include the above-described excipients, chemically modified starch or cellulose derivatives, such as sodium cross-carmellose, sodium carboximetilkrahmal, cross-linked polyvinylpyrrolidone or the like.

Examples of lubricating agents include talc; stearic acid; derivatives of metal stearate such as calcium stearate and magnesium stearate; colloidal silica; Wigan; waxes, such as beeswax or spermaceti; boric acid; glycol; carboxylic acid derivative, such as fumaric acid, adipic acid; carboxylate sodium, such as sodium benzoate; a sulfate such as sodium sulfate; leucine; lauryl, such as Lau is rsultat or sodium lauryl magnesium; derivatives of silicic acids such as silicic acid anhydride, silicic acid hydrate; and starch derivatives, such as described above as excipient; or similar.

Examples of the stabilizing agent include derivatives of the ester of para-hydroxybenzoic acid, such as methylparaben, propylparaben, derivatives of alcohol, such as chlorobutanol, benzyl alcohol, finitely alcohol; benzalkonium chloride;

derivatives of phenol such as phenol, cresol; thimerosal; acetic anhydride; and sorbic acid; or the like.

Examples corrigentov include sweeteners, podnikatel and flavorings or the like, which is usually used.

Examples of solvents include water, ethanol, glycerin or the like.

The dose of the crystalline forms of compound (I) depends on factors such as the symptoms, body weight and age of the patient. A suitable dose is 0.1 mg (preferably 1 mg) per day up to 100 mg (preferably 50 mg) per day. The crystalline form of the compound of formula (I) may be given either as a single unit dose, or if desired, the dose may be divided into convenient subunits, administered one to several times per day, depending on the patient's symptoms.

The preferred implementation of this invention

The invention is further described with the aid of the completion of the examples.

The test examples and examples, preparative forms

Example 1

Crystal

(a) To 2'-cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine (30 g), which is the compound described in example 1 (Id) Japan patent No. 2569251 add the acetate containing water in an amount of 2.5% vol. (300 ml)and the resulting mixture is heated to a temperature of approximately 55°obtaining a transparent solution. Next, the solution is cooled to a temperature of 5°at the rate of approximately 0.5°in a minute. When cooled to about 45°during cooling from the solution are highlighted lamellar crystals. After further stirring at a temperature of 5°C for 20 min selected crystals are collected by filtration and washed with methyl acetate containing water in an amount of 2.5% vol. (30 ml) to give the desired crystals (28,78 g, purity 97,9%) 96,0% [N/N] output.

(b) To 2' -cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine (8,7 kg), which is the compound described in example 1 (Id) Japan patent No. 2569251 add the acetate containing water in an amount of 1.9%. (80 l)and the resulting mixture is stirred at a temperature of approximately 23°C for 1.5 hours. Selected crystals are collected by filtration and washed with methyl acetate containing water in an amount of 1.9%. (20 l) and dried with receipt the m desired crystals In (7,7 kg the purity of 97.3%) 90.1% of [N/N] output.

Example 2

Crystal

(a) To 2'-cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine (30 g), which is the compound described in example 1 (Id) Japan patent No. 2569251 add the acetate containing water in the amount of 4% vol. (600 ml)and the resulting mixture is heated to a temperature of approximately 50°obtaining a transparent solution. Next, the solution is cooled to a temperature of 40°at the rate of approximately 0.5°min and stirred. In the process of mixing the first solution produce crystals, which are then gradually transformed into needle-like crystals. After further stirring at a temperature of 40°C for 60 min, the solution is cooled to a temperature of 25°at the rate of approximately 0.5°in a minute. After stirring at a temperature of 25°C for 60 min selected crystals are collected by filtration and washed with methyl acetate containing water in the amount of 4% vol. (30 ml) to give the desired crystals (23,74 g, purity of 98.5%) with 79,7% [N/N] output.

(b) To 2'-cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine (60 g), which is the compound described in example 1 (Id) Japan patent No. 2569251 add the acetate containing water in an amount of 2.5% vol. (600 ml)and the resulting mixture is stirred at a temperature of approx the flax 23° C for 2 hours and then cooled to a temperature of 12°at the rate of approximately 0.5°in a minute. After stirring at a temperature of 12°C for 1 hour allocated crystals are collected by filtration and washed with methyl acetate containing water in an amount of 2.5% vol. (180 ml) and dried to obtain the desired crystals (55,1 g, purity of 94.5%) with 89,6% [N/N] output.

Example 3

Crystal With(I)

1) the Dried crystals was incubated for about 20 min in the atmosphere moistened to a moisture content of more than 45% with obtaining the desired crystals(I).

2) To the dried crystals To add water in an amount which corresponds to about 33 wt.%. the used crystals, and the resulting mixture stirred for 3 min to obtain the desired crystals(I).

Example 4

Crystal D

(a) To 2'-cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine (10.0 g), which is the compound described in example 1 (Id) Japan patent No. 2569251 add anhydrous methyl acetate (400 ml)and the resulting mixture is heated to a temperature of about 60°obtaining a transparent solution. Next, the solution is cooled to a temperature of 25°at the rate of approximately 0.5°in a minute. When cooled to about 43°during cooling from the solution are highlighted with crystals. After cooling to a temperature of 25°highlighted the haunted crystals are collected by filtration to obtain the desired crystal D (8.8 g, 88.4% of the output).

(b) To 2'-cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine (50 g), which is the compound described in example 1 (Id) Japan patent No. 2569251 add the acetate (1500 ml)and the resulting mixture is heated to a temperature of approximately 50°C and stirred at a temperature of about 50°C for 1 hour. Next, the solution is cooled to a temperature of 40°at the rate of approximately 0.5°in a minute. After stirring at 40°C for 30 min selected crystals are collected by filtration and dried to obtain the desired crystal D (37,0 g, purity of 99.2%) from 74.2% [N/N] output.

Example test 1.

Testing sustainability

When testing the stability of the crystals b, C and D in accordance with this invention obtained in examples 1, 2 and 4, respectively, and amorphous powder (amorphous) compounds of General formula (I)described in example 1 (1d) Japan patent No. 2569251, used as a control. These compounds separately placed in closed tubes vessels and stored at a temperature of 60°C in nitrogen atmosphere for 17 days, and the contents of these compounds are tested for 5, 10 and 17 days after the beginning of storage.

The content of these compounds determine quantitative high performance liquid chromatography (HPLC), and the remaining compounds (%) is calculated from sod is Rania compounds (I), defined in each moment of selection of the sample, on the basis of the initial concentration (100%), determined immediately before storage.

Conditions for HPLC following:

Column: L-column ODS (4.6 mm H 250 mm) (Chemicals Inspection and Testing Institute)

Mobile phase: acetonitrile:water:acetic acid = 750:250:1

Flow rate: 1.0 ml/min

Wavelength definition: 249 nm

The column temperature: 40°

Table 1

The stability of each compound at a temperature of 60°C in an atmosphere of nitrogen (residual content)
ConnectionDays after the beginning of the test resistance
5 days10 days17 days
Amorphous Andof 92.7%78,6%62,5%
The crystal obtained in example 1101,0%100,3%100,4%
The crystal obtained in example 2101,0%100,4%100,1%
Crystal D obtained in example 499,9%98,3%98,4%

Based on the results presented in table 1, the stability of the amorphous powder (amorphous) of the compound (I) at a temperature of 60°and in the atmosphere of nitrogen is very low, and the residual content is reduced to 62.5% after storage for 17 days. On the contrary, the residual quantity of crystals b and C obtained in examples 1 and 2, respectively, under the same conditions of storage is 100% for each connection and the residual quantity of crystals of D obtained in example 4 is 98.4 per cent, which suggests that the stability of crystals in accordance with this invention is very high.

Example formulation 1. Solution 1

Get the solution containing the compound obtained in example 1 (10% (wt./wt.)), the benzalkonium chloride (0,04% (wt./wt.)), finitely alcohol (0,04% (wt./wt.)) and purified water (89,56% (wt./wt.)).

Example formulation 2. Solution 2

Get the solution containing the compound obtained in example 1 (10% (wt./wt.)), the benzalkonium chloride (0,04% (wt./wt.)), propylene glycol (30% (wt./wt.)) and purified water (39,96% (wt./wt.)).

Example formulation 3. Powder

Get a powder containing the compound obtained in example 1 (40% (wt./wt.)) and lactose (60% (wt./wt.)).

The preparative example form 4. Aerosol

Get an aerosol containing the compound obtained in example 1 (10% (wt./wt.)), lecithin (0.5 percent (wt./wt.)), foulon 11 (34,5% (wt./wt.)) and foulon 12 (55% (wt./wt.)).

Industrial applicability

The crystalline form in accordance with this invention have a C is acetelyne better stability during storage and ease of use compared with the amorphous powder of the compound (I). These crystalline forms demonstrate excellent metabolic distribution, such as oral absorption and the like, and, therefore, are useful drugs (preferably, as agents for the treatment or prevention of tumors).

Description of the drawings

The figure 1 shows the powder x-ray crystalline product obtained in example 1, obtained by irradiation of the crystalline product copper Kα rays (wavelength λ=1,54 E).

The figure 2 shows the powder x-ray crystalline product obtained in example 2, obtained by irradiation of the crystalline product copper Kα rays (wavelength λ=1,54 E).

The figure 3 shows the powder x-ray crystalline product obtained in example 3, obtained by irradiation of the crystalline product copper Kα rays (wavelength λ=1,54 E).

The figure 4 shows a powder x-ray crystalline product obtained in example 4, obtained by irradiation of the crystalline product copper Kα rays (wavelength λ=1,54 E).

In addition, in these figures the vertical axis of each powder x-ray shows the diffraction intensity in counts/second (SDR) and the horizontal axis shows the diffraction angle CA is set to 2θ .

Application

Obtaining crystalline 2'-cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine in the form G

2'-cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine in crystalline form In (5 g) dissolved in a mixture of methyl acetate:N2O 93:7 (about./about.) (50 ml) at 45°C. a Clear solution is cooled to 35°C for 50 min, and then cooled to 20-25°within 10 minutes After stirring at the same temperature for 15 min, the crystals mentioned in the header, allocate filtering.

Obtaining crystalline 2'-cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine in form To a

2'-cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine in crystalline form In (7.2 g) are added to 1,4-dioxane (20 ml) and ethylcyclohexane (150 ml), the mixture is heated to 40°C. Add methanol (10 ml) and the mixture vigorously stirred at 40°within 20 minutes After addition of methanol crystalline form of form moved in K. the Obtained suspension is cooled to 20-25°C for 20 min, stirred at the same temperature for additional 10 min, the crystals mentioned in the title, is collected by filtration.

Obtaining crystalline 2'-cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine in the form L

2'-cyano-2'-deoxy-N4palm is toil-1-β -D-arabinofuranosylcytosine in amorphous form (5 g) dissolved in a mixture of 1,4-dioxane:H2About 20:1 (vol./about.) (52,5 ml) at 60°C. Add ethylcyclohexane (50 ml), the resulting solution was concentrated until, until crystallization. The crystals mentioned in the header is separated from the solvent with a spatula.

Obtaining crystalline 2'-cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine in the form M

2'-cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine in amorphous form (5 g) are added to a methanol (100 ml). The suspension is stirred for 10 min and then subjected to ultrasonic agitation for 5 minutes After the mixture was incubated for 20 min, the crystals mentioned in the header, allocate filtering.

Obtaining crystalline 2'-cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine in the form Q

2'-cyano-2'-deoxy-N4-Palmitoyl-1-β-D-arabinofuranosylcytosine in amorphous form (10 g) is added to a mixture of methyl acetate:N2O 100:1 (vol./about.) (104 ml) at 15°C, the resulting suspension is stirred at the same temperature for about 4 hours. To add an additional suspension of the mixture of methyl acetate:N2O 100:1 (vol./about.) (5 ml). After stirring at 15-23°C for 45 hours, the crystals mentioned in the title, indicating filtratio and dried under reduced pressure.

Table 2

The resistance of each connection at 60°C in an atmosphere of nitrogen (residual content)
ConnectionDays after the beginning of the test resistance
5 days10 days17 days
Amorphous form And93%79%63%
The crystal obtained in example 1101%100%100%
The crystal obtained in example 2101%100%100%
Crystal D obtained in example 4100%98%98%
Crystal G92%-81%
Crystal91%-86%
Crystal L100%-85%
Crystal M [compound of example 1(d) D2]92%-84%
Crystal Q85%-70%

The testing method is the same as in the example test 1 of this application.

1. The crystalline form of the compound of formula (I) or its hydrate/p>

where specified crystal form has main peaks at distances of the lattice 19,53, 13,03, 9,75, 4,17, 4,00, 3,82, 3,68 and 3.41 Angstrom determined by x-ray powder method using copper rays Kα (wavelength λ=1,54 Å).

2. The crystalline form of the compound of formula (I)

where specified crystal form has main peaks at distances of the lattice 19,36, 12,87, 9,63, 4,70, 4,64, 4,28, 4,10, 3,92, 3,77 and 3,48 Angstrom determined by x-ray powder method using copper rays Kα (wavelength λ=1,54 Å).

3. The crystalline form of the compound of formula (I)

where specified crystal form has main peaks at distances of the lattice 19,62, 13,06, 9,82, 4,72, 4,63, 4,56, 4,15, 3,98, 3,93, 3,82, 3,45 and 3.40 angstroms, determined by x-ray powder method using copper rays Kα (wavelength λ=1,54 Å ).

4. The crystalline form of the compound of formula (I)

where specified crystal form has peaks at distances of the lattice 22,52, 5,17, 4,60, 4,28 and a 3.87 angstroms, determined by x-ray powder method using copper rays Kα (wavelength λ=1,54 Å).

5. The pharmacy is practical composition, with antitumor activity that contains crystalline form according to any one of claims 1 to 4 as an active ingredient.

6. The pharmaceutical composition according to claim 5 for the prevention or treatment of tumors.

7. The use of a crystalline form according to any one of claims 1 to 4 in the manufacture of a medicinal product for preventing or treating tumors in warm-blooded animals.

8. The use according to claim 7, where the specified warm-blooded animal is a human.

Cab prevention or treatment of neoplastic diseases, including the introduction of a warm-blooded animal in need of such prevention or treatment a pharmacologically effective amount of a crystalline form according to any one of claims 1 to 4.

10. The method according to claim 9, in which a warm-blooded animal is a human.



 

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where R1represents a methyl group, R2represents a methyl group, R4represents a hydroxy-group and X represents a methylene group; R1represents a methyl group, R2represents a hydrogen atom, R4represents a hydroxy-group and X represents a methylene group; R1represents a methyl group, R2represents a methyl group, R4represents a hydrogen atom and X represents a methylene group; R1represents a hydrogen atom, R2represents a hydrogen atom, R4represents a hydroxy-group and X represents a methylene group; or R1represents a methyl group, R2represents a methyl group, R4represents a hydroxy-group and X represents a sulfur atom

The invention relates to substituted ammonium salts of 5'-H-phosphonate 3'-azido-3'-deoxythymidine General formula (1), where RR'R N are L-alanine, ethanolamine, triethanolamine, 6-aminocaproic acid, pyridoxine or dimethylaminoethanol, which are selective inhibitors of the production of human immunodeficiency virus HIV-1 and HIV-2

The invention relates to a method for producing 5'-deoxy-5-ptoluidine formula I, including (a) the interaction of 2',3'-O-isopropylidene-5-ptoluidine formula II with a functional derivative of a sulfonic acids R-SO3H, where R is a (C1-C4)alkyl, triptorelin, unsubstituted, mono-, di - or tizamidine phenyl group, (b) interaction of a derivative of formula IV with iodide of alkaline or alkaline earth metal, (C) hydrolysis of a derivative of formula V in an acidic environment, and (d) recovering a derivative of formula VI with hydrogen or a hydrogen donor

The invention relates to certain nucleoside derivative, which was found to possess valuable properties for the treatment of tumors

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: color-forming compositions and recording material.

SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.

EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.

21 cl, 14 tbl, 153 ex

The invention relates to a method for producing a condensed 2-getreleasedate General formula

using the diamine of General formula

where A=

R=2-furyl, 2-thienyl, 2-(1-methyl)pyrrolyl, 3-(1-methyl)indolyl, and aldehydes in the presence of acetate or copper sulfate, characterized in that the interaction takes place by boiling in 50% acetic acid, followed by decomposition of the copper salt, the effect on its suspension in 50% acetic acid sodium thiosulfate in 100With

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to 1-methyl-5-alkylsulfonyl-, 1-methyl-5-alkylsulfonyl - 1-methyl-5-alkylthiomethyl pyrazolylborate and herbicide tool based on them

The invention relates to tricyclic condensed heterocyclic compounds of the formula I, X is, for example, CH, CH2, СНR (where R means a lower alkyl group or a substituted lower alkyl group) or CRR' (where R and R' have the values specified above for R); Y means, for example, CH, CH2or C=O; z means, for example, S, S=O=; U denotes C; R1-R4independent means, for example, a hydrogen atom, SR (where R has the above values), phenyl group, substituted phenyl group, follow group, thienyl group, benzofuran or benzothiazyl at least one element of R5and R8means, for example, HE and the rest of the elements of R5and R8independent means, for example, a hydrogen atom; and their optical isomers, conjugates, and pharmaceutically acceptable salts

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I) or its pharmaceutically acceptable salt or solvate wherein X represents CH or nitrogen atom (N); Z represents CH; R1 represents hydrogen atom; R2 and R3 can be similar or different and represent (C1-C6)-alkoxy-group that is optionally substituted with halogen atom, hydroxyl, (C1-C4)-alkoxycarbonyl, amino-group wherein one or two hydrogen atom are optionally replaced for (C1-C4)-alkyl that is optionally substituted with hydroxyl or (C1-C4)-alkoxy-group, the group R12R13N-C(=O)-O- wherein R12 and R13 can be similar or different and represent hydrogen atom or (C1-C4)-alkyl substituted optionally with (C1-C4)-alkoxy-group or the group R14-(S)m- wherein R14 represents phenyl or saturated or unsaturated 5-7-membered heterocyclic group substituted optionally with (C1-C4)-alkyl; m = 0 or 1; R4 represents hydrogen atom; R5, R6, R7 and R8 can be similar or different and represent hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or nitro-group under condition that R5, R6, R7 and R don't represent hydrogen atom simultaneously; R9 represents hydrogen atom, (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl wherein alkyl fragment of indicated (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl is optionally substituted with (C1-C4)-alkoxy-group; R10 represents hydrogen atom or (C1-C6)-alkyl; R11 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl (wherein each (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl is substituted optionally with halogen atom or (C1-C6)-alkoxy-group), or R15-(CH2)n- wherein n is a whole number from 0 to 3; R15 represents naphthyl or 6-membered saturated or unsaturated carbocyclic or saturated or unsaturated 5-7-membered heterocyclic group that are substituted optionally with halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group. Also, invention relates to variants of compounds of the formula (I). Compounds elicit antitumor activity and don't effect on cytomorphosis. Also, invention relates to pharmaceutical composition based on above described compounds, to a method for treatment of such diseases as malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, and to a method for inhibition of vascular vessels angiogenesis.

EFFECT: valuable medicinal properties of compounds and composition.

22 cl, 4 tbl, 186 ex

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