New crystal and amorphous form of tryazol[4,5-d] pyrimidine

FIELD: medicine; pharmacology.

SUBSTANCE: this invention describes new crystal forms of tryazol[4,5-d]pyrimidine formula I , composition methods and based pharmaceutical formulations. Compounds develop high efficiency as antagonist P2T, can be applied for medical prevention and treatment of arterial thrombotic complication, as well as tumour growth and extension.

EFFECT: compounds show high metabolic stability and bioavailability.

22 cl, 5 ex, 6 dwg

 

The invention relates to forms of chemical compounds, in particular crystalline and amorphous forms, more specifically four crystalline forms and amorphous form. The invention further relates to methods of producing such forms, pharmaceutical compositions comprising the compound in crystalline and/or amorphous form and to therapeutic use of such forms.

In the preparation of pharmaceutical compositions, it is important that drug connection was in the form in which it would be convenient to handle and to process. This is important not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of the subsequent production of pharmaceutical compositions comprising an active connection. Chemical stability, stability in the solid state and shelf life active ingredients are also very important factors. Medicinal compound and compositions comprising it, must have ability to effectively stored for considerable periods of time, without showing significant changes in physico-chemical properties of the active component (e.g., its chemical composition, density, hygroscopicity and solubility). In addition, it also is important to present the drug in a form that is as can the cleaner. In this regard, amorphous compounds may pose significant problems. For example, such compounds are more difficult to apply and to include them in the dosage form compared to the crystal connection through dubious solubility, and it often turns out that they are unstable and chemically contaminated. The person skilled in the art it will be clear that if the drug can be easily obtained in a stable crystalline form, it is possible to solve the above problems. Thus, in the production of commercially viable and pharmaceutically acceptable pharmaceutical compositions it is desirable, where possible, to ensure the drug mainly in crystalline and stable form. It should be noted, however, that this goal is not always achievable. Indeed, it is usually impossible to predict based only on molecular structure, what will be the behavior of the compound in the crystallization, and usually that can only be established empirically.

Adhesion and aggregation of platelets are the initial events in the coronary arteries. Although the process of adhesion of platelets to subendothelial surfaces can play an important role in the repair of damaged blood vessels, platelet aggregation, which initiates the process, can cause acute tromboticescuu vital vessels, leading to pathology with high mortality, such as myocardial infarction and unstable angina. The success of the interventions used to prevent or alleviate these conditions, such as thrombosis and angioplasty, is also under threat mediated platelet occlusion and re-occlusion.

It was found that adenosine-5'-diphosphate (ADP) acts as a key mediator of thrombosis. ADP-induced platelet aggregation is mediated by a subtype of P2C-receptors located on the membrane of platelets. P2C-receptor (also known as P2YADPor P2TAC) mainly involved in mediating aggregation/activation of platelets and is paired with G-protein receptor that is not yet cloned. Described pharmacological properties of this receptor, for example, in the sources of Humphries et al., Br. J. Pharmacology (1994), 113, 1057-1063 and Fagura et al., Br. J. Pharmacology (1998), 124, 157-164. Recently, it was shown that antagonists at this receptor provide significant improvements with respect to other antithrombotic agents (see J. Med. Chem. (1999), 42, 213). In the application for international patent WO 9905143 disclosed in a common row group triazolo[4,5-d]pyrimidine compounds having activity as antagonists of P2C(P2YADPor P2TAC). The compound of formula (I) (below) is the total volume of requests for international patent WO 9905143, but specifically there is disclosed. This compound shows high effectiveness as an antagonist of P2C(P2YADPor P2TAC). It also has a surprisingly high metabolic stability and bioavailability.

Accordingly, the present invention relates to the compound of formula (I):

(I)

in essentially crystalline form.

The compound of formula (I) is usually called:

{1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-differenl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol.

The compound of formula (I) can be in four different, essentially crystalline, forms, called in the following polymorph I, polymorph II, polymorph III and polymorph IV. Polymorph is a specific crystalline form of the compound.

Various physical properties of polymorphic forms in relation to each other and relative to the amorphous state can have a significant impact on the chemical and pharmaceutical processing connections, especially when the connection receives or uses in an industrial scale.

In one aspect of the invention, the preferred crystalline form of the compound of formula (I) is the form of polymorph I, polymorph II, polymorph III or polymorph IV.

In ternatives aspect of the invention, the preferred crystalline form of the compound of formula (I) is polymorph I.

In another aspect of the invention, the preferred crystalline form of the compound of formula (I) is polymorph II.

In another aspect of the invention, the preferred crystalline form of the compound of formula (I) is polymorph III.

In an additional aspect of the invention, the preferred crystalline form of the compound of formula (I) is polymorph IV.

The following aspect of the invention the compound of formula (I) is in a substantially amorphous form. In amorphous form three-dimensional long-range order structure, which is present in crystalline form (e.g., polymorpha) is missing, and the position of the molecules with respect to each other in amorphous form mostly disordered (see B.C.Hancock and G.Zografi, J. Pharm. Sci. (1997) 86 1). The amorphous form of the compound of formula (I) is called the form α.

Applicants have identified a compound of formula (I) in crystalline and amorphous forms. These forms can be largely or substantially free from water (waterless). Therefore, in one aspect of the invention features anhydrous form of the compound of formula (I) in crystalline form or amorphous form. When using the term "substantially pure and in practically anhydrous form" applicants do not exclude the presence of some quantity of solvent, including water, crystalline resh is de or outside of the crystal lattice. The anhydrous form is less than 0.4 molecules of water per molecule of compound (gidratirovana less than 40%). Preferably, the anhydrous form contains less than 0.1 molecules of water per molecule of the compound.

Polymorphs I, II, III and IV can be distinguished by the beginning of melting, powder diffraction spectra of x-rays and/or x-ray single crystal.

Polymorph I has a melting point of beginning, which is within 146-152°With, for example, about 151°when it is largely clean and in a practically anhydrous form.

Polymorph II has a melting point of beginning, which is within 136-139°With, for example, about 137,5°when it is largely clean and in a practically anhydrous form.

Polymorph III has a melting point of beginning, which is within 127-132°With, for example, about 132°when it is largely clean and in a practically anhydrous form.

Polymorph IV has a melting point of beginning, which is usually 139°when it is largely clean and in a practically anhydrous form.

Form α usually undergoes a transition with subsequent crystallization into one of the above polymorphic forms, such as polymorph II, before melting.

The melting point was determined using differential is territorial scanning calorimetry (DSC), using equipment Perkin Elmer DSC7. The beginning of melting is defined as the point at which there is a significant change compared to the baseline, and it is determined using the software Perkin Elmer Pyris. It is clear that alternative data on the melting point can be obtained with other types of equipment or when using conditions different from those described here. Therefore, these figures should not be considered as absolute values. Specialists in this field it is clear that the exact value of the melting point will affect the purity of the compounds, the sample mass, heating rate and particle size.

Polymorph I, when it is largely clean and in a practically anhydrous form has a powder x-ray, including characteristic peaks of high intensity at 5,3° (±0,1°), 20,1° (±0,1), 20,7° (±0,1°), 21,0° (±0,1°) and 21.3° (±0,1°) 2θ. More preferably, substantially pure and almost waterless polymorph I has a powder x-ray, including characteristic peaks at 5,3° (±0,1°), 8,0° (±0,1°), 9,6° (±0,1°), 13,9° (±0,1°), 15,3° (±0,1°), 20,1° (±0,1°), 20,7° (±0,1°), 21,0° (±0,1°), 21,3° (±0,1°), 26,2° (±0,1°) and 27.5° (±0,1°) θ .

Polymorph II, when he is largely clean and in a practically anhydrous form has a powder x-ray, including characteristic peaks of high intensity at 5.5° (±0,1°), 13,5° (±0,1), 18,3° (±0,1°), 22,7° (±0,1°) and 24.3° (±0,1°) 2θ. More preferably, substantially pure and almost waterless polymorph II has a powder x-ray, including characteristic peaks at 5.5° (±0,1°), 6,8° (±0,1°), 10,6° (±0,1°), 13,5° (±0,1°), 14,9° (±0,1°), 18,3° (±0,1°), and 19.2° (±0,1°), 22,7° (±0,1°), 24,3° (±0,1°) and 27.1° (±0,1°) 2θ.

Polymorph III, when it is largely clean and in a practically anhydrous form has a powder x-ray, including characteristic peaks of high intensity at 14,0° (±0,1°), 17,4° (±0,1), 18,4° (±0,1°), 21,4° (±0,1°) and 24.1° (±0,1°) 2θ. More preferably, substantially pure and almost waterless polymorph III has a powder x-ray, including characteristic peaks at 5,6° (±0,1°), 12,5° (±0,1°), 14,0° (±0,1°), 17,4° (±0,1°), 18,4° (±0,1°), 21,4° (±0,1°), 22,2° (±0,1°), 22,9° (±0,1°), 24,1° (±0,1� ) and 24.5° (±0,1°) 2θ.

Polymorph IV, when he is largely clean and in a practically anhydrous form has a powder x-ray, including characteristic peaks of high intensity at a 4.9° (±0,1°), 9,2° (±0,1), 11,6° (±0,1°), 15,6° (±0,1°) and 16.4° (±0,1°) 2θ. More preferably, substantially pure and almost waterless polymorph IV has a powder x-ray, including characteristic peaks at 4,9° (±0,1°), 6,0° (±0,1°), 9,2° (±0,1°), 11,6° (±0,1°), 12,8° (±0,1°), 15,6° (±0,1°), and 16.4° (±0,1°), 17,2° (±0,1°) and 18.1° (±0,1°) 2θ.

Form αwhen it is largely clean and in a practically anhydrous form has a powder x-ray that does not contain sharp peaks.

Data on x-ray diffraction for polymorph II, polymorph III, polymorph IV and form α received using equipment Siemens D5000. Data on x-ray diffraction for polymorph I got on the Philips X'pert MPD. It is clear that other hardware and/or conditions can lead to several other data. Therefore, these figures should not be considered as absolute values.

In an alternative aspect of the invention MoE is et to form a solvated form, for example hydrated form ("hydrate"). Therefore, this aspect of the invention features a hydrate of the compound of formula (I) in crystalline form. The hydrate is 0.8 or more molecules of water per molecule of the compound (80% or more gidratirovana). The hemihydrate is from 0.4 to 0.8 molecules of water per molecule of compound (40-80% gidratirovana).

In an additional aspect, the invention features any mixture of crystalline and/or amorphous forms of the compounds of formula (I). Preferably the mixture is polymorph I, polymorph II, polymorph III, polymorph IV and/or form α. More preferably the invention provides any mixture of polymorph II and polymorph III.

In an additional aspect, the invention features a method of obtaining a crystalline form of the compound of formula (I) crystallization of the compounds of formula (I) from a suitable solvent. Preferably the solvent is selected from the group of ethanol, ethyl acetate, isopropanol, isooctane, acetonitrile, water or a mixture. More preferably the solvent is selected from the group of ethanol, ethyl acetate, isopropanol, isooctane, water or their mixture. Mainly the solvent is selected from the group: a mixture of methanol-water, ethanol, ethyl acetate, a mixture of ethanol-water mixture of isopropanol-water mixture ethyl acetate : isooctane and acetonitrile.

The compound of formula (I) can be obtained by methods similar to those, is written in WO 9905143.

For the onset of crystallization may be necessary to make the seed crystals of the compounds of formula (I). The introduction of seed crystals of the required polymorpha may be necessary to obtain the selected polymorpha. Crystallization of the compounds of formula (I) from the appropriate solvent system can achieve overload, for example, by cooling, evaporation of the solvent and/or by adding antibacterial (solvent in which the compounds of formula (I) laboratorii; examples of suitable antibacterial include heptane or isooctane). The temperature and time of crystallization will vary depending on the concentration of the compound in solution, the systems used solvents and acceptable method of crystallization.

The compound of formula (I) in crystalline form can be isolated from the above reaction mixture using methods well known to specialists in this field, for example, by decantation, filtration or centrifugation. Similarly, the compound of formula (I) in crystalline form can be dried using well known methods.

Optional phase and recrystallization can be carried out with the use of the same or other solvent system to further reduce the content of impurities such as amorphous substance, chemical note is C, or conversion of crystalline form from one polymorph in other polymorph or gidratirovannuyu or anhydrous form. In addition, you can spend the conditioning stage, subjecting the solid is exposed to high humidity for removal of amorphous material.

Preferably the crystallization was carried out directly from the reaction solution. Alternative crystallization was carried out subsequent solution.

In an additional aspect, the invention features a method of producing polymorph I, which includes obtaining multiple seed crystals polymorpha I due to the slow growth of crystals polymorpha I melt polymorph II and use them to make the seed crystals in the reaction mixture containing the compound of formula (I) and a suitable mixed solvent system such as methanol/water.

In an additional aspect, the invention features a method of producing polymorph II, which includes crystallization from a suitable solvent such as ethyl acetate.

In an additional aspect, the invention features a method of producing polymorph III, which includes crystallization from a suitable solvent, such as alcohol, for example ethanol or isopropyl alcohol (IPA), in the entry of the seed specific crystals polymorph III or suspendirovanie connection is of formula (I) in a suitable solvent, such as isopropyl alcohol.

In an additional aspect, the invention features a method of producing polymorph IV, which includes crystallization from a suitable solvent, such as acetonitrile, in the entry of the seed specific crystals polymorph IV or suspendirovanie the compounds of formula (I) in a suitable solvent, such as acetonitrile.

In an additional aspect, the invention features a method of producing polymorph III, mostly free from polymorph II, which includes, for example, the suspension of the compounds of formula (I) in the solvent system With1-6aliphatic alcohol/water (preferably isopropyl alcohol/water) at a temperature in the range 5-65°C for 1-10 days.

In an additional aspect of the invention proposes a method of obtaining compounds of formula (I) mainly in the amorphous form, which comprises drying by freezing or spray drying of a solution of the compounds of formula (I) using a suitable solvent system, for example a mixture of ethanol/water.

The term "mostly free" refers to the case content less than 10% of another polymorph, preferably less than 5%.

In an additional aspect of the invention proposes a connection, get one of the methods above.

The compound of formula (I) in crystalline and/or amorphous form acts as an antagonist of cocktail recipes. is s P 2C(P2YADPor P2TAC). Therefore, the compound of formula (I) in crystalline and/or amorphous form suitable for treatment, including combination therapy. In particular, the compound of formula (I) in crystalline form is shown for use in the treatment or prevention of arterial thrombotic complications in patients with coronary artery disease, cerebrovascular or peripheral vascular disease. Arterial thrombotic complications may include unstable angina, primary arterial thrombotic complications of atherosclerosis, such as thrombotic or embolic stroke, intermittent episodes of ischemia, peripheral vascular disease, myocardial infarction with thrombolism or without arterial complications as a result of interventions for atherosclerosis, such as angioplasty, including angioplasty of coronary artery (RTSA), endarterectomy, stent placement, transplant coronary and other vascular, thrombotic complications of surgical or mechanical damage such as tissue retention after accidental or surgical trauma, reconstructive surgery including skin and muscle flaps, state the presence of a component of a diffuse thrombotic/depletion of platelets, such as distributed the traveler intravascular coagulation, thromboembolitic thrombocytopenic purpura, hemolytic bladder syndrome, thrombotic complications of septicaemia, respiratory distress syndrome of adults, antiphospholipid syndrome, heparin-induced thrombocytopenia and pre-eclampsia/eclampsia, or venous thrombosis such as deep vein thrombosis, venoocclusive disease, hematological conditions such as myeloproliferative disease, including trombozitemia, sickle cell disease; or for the prevention of mechanically-induced platelet activation in vivo, such as extracorporeal circulation and extracorporeal membrane oxygenation (prevention of microchromosome), mechanically-induced platelet activation in vitro, such as use in the preservation of blood products such as platelet concentrates, or occlusions in the bypass, such as when kidney dialysis and plasmapheresis, thrombosis, secondary damage/inflammation of blood vessels, such as vasculitis, Takayasu, glomerulonephritis, inflammatory bowel disease and rejection in organ transplantation, conditions such as migraine, Raynaud's syndrome, conditions in which platelets contribute to the main inflammatory disease of the vessel wall, as, for example, education/progression and aromatase plaques stenosis/restenosis and other inflammatory conditions such as asthma, in which the platelets are derived from the platelet factors are involved in immunological disease. Additional indications include the treatment of disorders of the Central nervous system and preventing the growth and spread of tumors.

According to an additional aspect of the present invention features a compound of formula (I) in crystalline and/or amorphous form for use in therapeutic treatment of the human or animal.

According to an additional aspect of the present invention features a compound of formula (I) in crystalline and/or amorphous form for use as a medicinal product. Preferably the compound of formula (I) in crystalline and/or amorphous form is used as a medicine as a receptor antagonist P2C(P2YADPor P2TAC) in a warm-blooded animal such as man. More preferably the compound of formula (I) in crystalline and/or amorphous form is used as a drug for the treatment or prevention of arterial thrombotic complications in patients with coronary artery disease, cerebrovascular or peripheral vascular disease in a warm-blooded animal such as man.

According to image meniu further provides a use of compounds of formula (I) in crystalline and/or amorphous form in the manufacture of a medicinal product for use as a receptor antagonist P 2C(P2YADPor P2TAC). In particular further provides a use of compounds of formula (I) in crystalline and/or amorphous form in the manufacture of a medicinal product for the treatment or prevention of arterial thrombotic complications in patients with coronary artery disease, cerebrovascular and peripheral vascular disease.

The invention also provides a method of treatment or prevention of arterial thrombotic complications in patients with coronary artery disease, cerebrovascular or peripheral vascular disease, which includes the introduction of a person suffering from such disease or located towards him, a therapeutically effective amount of the compounds of formula (I) in crystalline and/or amorphous form.

The compound of formula (I) in crystalline and/or amorphous form can be entered locally in the lungs and/or Airways, in the form of solutions, suspensions, HFA aerosol and dry powder compositions; or systemically, e.g. by oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or parenterally in the form of sterile solutions or suspensions for parenteral administration, subcutaneous injection, or rectally in the form of suppositories or transdermal.

The compound of formula (I) in crystalline and/or Amorin the second form, you can enter by itself, or in pharmaceutical compositions comprising the compound of formula (I) in crystalline and/or amorphous form in combination with a pharmaceutically acceptable diluent, adjuvant and/or carrier. Therefore, it is suggested as an additional aspect of the invention the pharmaceutical composition comprising the compound of formula (I) in crystalline and/or amorphous form in combination with a pharmaceutically acceptable diluent, adjuvant and/or carrier. Particularly preferred are compositions that do not contain substances that can cause adverse reactions, such as adverse allergic reaction.

The dry powder composition and HFA-aerosol under pressure from the compounds of formula (I) in crystalline and/or amorphous form can be administered orally or by inhalation through the nose. For inhalation, the compound of formula (I) in crystalline and/or amorphous form, preferably finely chop. The compound of formula (I) in crystalline and/or amorphous form, you can enter it using a nebulizer for inhalation dry powders. The inhaler may be a nebulizer with one or many doses and can be inhaler for dry powders for inhalation.

One possibility is to mix the finely ground compound of formula (I) in crystalline and/or amorphous form, substance-carrier, for example mono-, di - or polysaccharide, alcohol - production is diversified sugar or other polyol. Suitable carrier materials include sugar and starch. Alternatively, a micronized compound of formula (I) in crystalline and/or amorphous form may be covered by another connection. Powdery mixture can be distributed in hard gelatin capsules, each containing the desired dose of the active compounds of formula (I) in crystalline and/or amorphous form.

Another possibility is to make fine powder in the balls, which are destroyed by inhalation. This veronicalovely powder can be placed in the reservoir for drug-parenteral multi-dose inhaler, for example, is known as the Turbuhaler®in which the metering device measures the desired dose, which is then inhaled by the patient. Using this system active compound of the formula (I) with a substance carrier and without it delivered to a patient. Pharmaceutical composition comprising a compound of formula (I) in crystalline and/or amorphous form may be such convenient forms such as tablets, pills, capsules, syrups, powders or granules for oral administration; sterile solutions for parenteral or subcutaneous injection; suspension for parenteral injection or suppositories for rectal administration.

For oral administration the compound of formula (I) in crystalline and/or amorphous Faure, the e can be mixed with an adjuvant or a carrier, for example lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, binders such as gelatin or polyvinylpyrrolidone, lubricating agents such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If you require coated tablets, cores, obtained as described above, can be coated with a concentrated sugar solution which may contain, for example, gum Arabic, gelatin, talc, titanium dioxide and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved or in a volatile organic solvent, or in aqueous solvent.

To obtain soft gelatin capsules of the compound of formula (I) in crystalline and/or amorphous form may be mixed, for example, with vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the connection using either of the above mentioned excipients for tablets, for example, lactose, saccharose, sorbitol, mannitol, starches, cellulose derivatives or gelatin. Liquid or semi-liquid composition of the drug product can be filled into hard gelatin capsules.

Liquid preparations for oral application is to be placed can be in the form of syrups or suspensions, for example, solutions containing the compound of formula (I) in crystalline and/or amorphous form, and the rest is sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to specialists in this field.

Fig. is the radiograph of polymorph I obtained with the use of the device Philips X'pert MPD θ-θ configuration within the scan from 1° to 40° 2θ when 2 or 5 sec exposure at an increment of 0.02° 2θ. X-rays were obtained using long copper tube operated at 40 kV and 50 mA. The wavelength of x-rays was equal 1,5406 Å.

Fig. is the radiograph of polymorph II, obtained using the instrument Siemens D5000 θ-θ configuration within the scan from 2° to 30° 2θ 4 sec exposure at an increment of 0.02° 2θ. X-rays were obtained using long copper tube operated at 45 kV and 40 mA. The wavelength of x-rays was equal 1,5406 Å. The holder was made of single crystal silicon, which has been cut along newimagename plane and then polished to an optically flat finish. X-rays, ageusia on this surface, undermined by extinction Bragg.

Fig. is the radiograph of polymorph III, obtained using the instrument Siemens D5000, as described above.

Fig. is the radiograph of polymorph IV, obtained using the instrument Siemens D5000, as described above.

Fig. represents the x-ray form αobtained with the use of the device Siemens D5000, as described above.

Figure 2 shows the DSC curves for polymorphs I, II, III and IV and form αobtained with the use of the instrument Perkin Elmer DSC 7. The Cup was aluminum with cap. The sample mass was 1-3 mg Procedure the measurements were carried out in an atmosphere of nitrogen gas (30 ml/min), and the investigated temperature range was between 30°and 325°at a constant rate of temperature increase of 10°With in minutes

It should be understood that the analysis of samples with grains larger than 30 microns and neurofisiologia ratio of the geometric dimensions can influence the relative intensity of the peaks. The person skilled in the art will also understand that the position of the reflection is influenced by the exact height, on which is placed the sample in the diffractometer, and the zero calibration of the diffractometer. The plane of the sample surface can also have a small effect. Consequently, presents data on the spectra of diffraction should not consider is regarded as absolute values.

The invention can be illustrated by the following non-limiting examples.

Example 1

{1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-differenl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol in the form of polymorph I

Part 1

The compound of formula (I) in the form of polymorph II (2 mg) were heated and cooled in the DSC as follows: from 35 to 143, 35, 148, 35, 148, 35°C. the annealing process resulted in crystallization of pure polymorph I according to the DSC.

Part 2

The solution containing the compound of formula (I), 5 ml/g of methanol and 7.3 ml/g of water and a small amount of seed crystals polymorpha I was led at 30°C. Data the powder x-ray and DSC confirmed that formed mostly clean polymorph I.

Example 2 (reference)

{1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-differenl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol in the form of polymorph II

Chloroform (150 ml) was added to 45 mg of the compounds of formula (I) and the mixture was heated to dissolve on the steam bath. The resulting solution was left to crystallize overnight, and dried in nitrogen atmosphere. Powder data of x-ray and DSC confirmed that formed mostly clean polymorph II.

Example 3

{1S-[1α,2α,3β(1S*,2R*),5β ]}-3-(7-{[2-(3,4-differenl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol in the form of polymorph III

Ethanol (200 ml) was added to 10 mg of the compounds of formula (I) and the mixture was heated to dissolve on the steam bath. The resulting solution was left to crystallize overnight. Powder data of x-ray and DSC confirmed that the formed mixture of polymorphs II and III. This substance is used to make the seed to get to a greater extent: 191 mg polymorph II suspended in 1 ml of 50% aqueous isopropanol. To this suspension was added 15 mg of seed crystals mixed polymorph II/III. After 2 days there was a complete transformation in polymorph III according to the powder x-ray.

Example 4

{1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-differenl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol in the form of polymorph IV

Acetonitrile (0,12 ml) was added to 10 mg of the compounds of formula (I) and the mixture was heated to dissolve on the steam bath. The warm solution was let to cool slowly in the water jacket with hot water. The obtained crystals were dried in nitrogen atmosphere. Powder data of x-ray and DSC showed that it was the other polymorph.

Example 5

{1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-differenl)cycloprop the l]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol mainly in the form α

The compound of formula (I) (218 mg) was dissolved in 50% aqueous ethanol (24 ml). To this solution was added dropwise more of 14.5 ml of water. Then, the resulting saturated solution was dried by freezing using the apparatus of Virtusa the following conditions (vacuum 2170 MT, cycle 20,2 h, condensing temperature -52°C, ambient temperature of 20.3°).

Reference example 1

{1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-differenl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol

The solution {3aR-[3aα,4α,6α(1R*,2S*),6aα]}-2-[6-({7-[2-(3,4-differenl)cyclopropyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl}tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-yl)oxy]ethanol (method A, of 0.59 g) in triperoxonane acid (15 ml) and water (15 ml) was stirred at room temperature for 30 minutes, the Reaction mixture was carefully added to a solution of sodium bicarbonate (21 g) in water (150 ml) and was stirred for 30 minutes the Mixture was extracted with ethyl acetate, which was dried and evaporated. The residue was purified (SiO2the ethyl acetate as eluent) to obtain specified in the connection header (0,44 g). MS (APCI) (chemical ionization at atmospheric pressure) 523 (M+N+, 100%); NMR: 8,95 (1H, d, J=3.3V), 7,39-7,21 (2H, m), 7,10-7,00 (1H, m), 5,12 (1H, d, J=6,4), of 5.05 (1H, d, J=3.6), and 4,96 (1H, q, J=9,0), 4,62-of 4.54 (2H, m), 3,95 (1H, Shir. C),3,79-to 3.73 (1H, m), 3,55-3,47 (4H, m), 3,20-3,13 (1H, m), 2,98-of 2.81 (2H, m), 2.63 in (1H, dt, J=13,6, 8,5), to 2.29-2.21 and 2,16-of 2.09 (1H, m), 2,07 is 2.00 (1H, m), 1,73-of 1.33 (4H, m), 0,99 (3H, t, J=7,4).

Obtaining input connections

The initial compounds are either industrially produced, or they are easy to get conventional methods from known compounds. For example, the subsequent reaction of the present illustration, but not limitation, some of the original compounds used in the above reactions.

Method And

{3aR-[3aα,4α,6α(1R*,2S*),6aα]}-2-[6-({7-[2-(3,4-differenl)cyclopropyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl}tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-yl)oxy]ethanol

DIBAL-H® (1.0 M solution in hexane, 5,15 ml) was added to a cooled on ice to a solution of methyl ester {3aR-[3aα,4α,6α(1R*,2S*),6aα]}-{[6-(7-[2-(3,4-differenl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl)tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-yl]oxy}acetic acid (method, 0,76 g) in THF (1 ml) and the solution was stirred at this temperature for 2 hours the Reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (75 ml). Was added a saturated aqueous solution of sodium tartrate, potassium (75 ml) and the mixture was vigorously stirred for 16 hours Organic fraction was collected and the aqueous fraction was extracted again with ethyl acetate (2×50 ml). Volume is yennie organic fraction was dried and concentrated, and the residue was purified (SiO2the mixture of isohexane:ethyl acetate 1:1 as eluent) to obtain specified in the connection header (0,63 g). MS (APCI) 563 (M+N+, 100%).

Method In

Methyl ester {3aR-[3aα,4α,6α(1R*,2S*),6aα]}-{[6-(7-{[2-(3,4-differenl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-yl]oxy}acetic acid

To a mixture of methyl ester [3aR-(3aα,4α,6α,6aα)]-({6-[7-bromo-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol}oxy)acetic acid (method D, to 0.80 g) and (1R-TRANS)-2-(3,4-differenl)cyclopropylamine, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (the way, and 0.61 g) in dichloromethane (25 ml) was added N,N-diisopropylethylamine of 0.85 ml). The resulting solution was stirred at room temperature for 16 h and then concentrated in vacuum. Cleanup (SiO2the mixture of isohexane:ethyl acetate 3:1 as eluent) gave specified in the title compound as a colourless foam (0,77 g). MS (APCI) 591 (M+N+, 100%).

Way

(1R-TRANS)-2-(3,4-differenl)cyclopropanation, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1)

Specified in the title compound can be obtained according to the method described in the application WO 9905143.

Method D

Methyl ester of [3aR-(3aα,4α,6α,6aα)]-({6-[7-bromo-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]t is trihydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol}oxy)acetic acid

Methyl ester of [3aR-(3aα,4α,6α,6aα)]-({6-[7-amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol}oxy)acetic acid (method E, 1.1 g) and isoenergetic (2.4 ml) in bromoform (30 ml) was heated at 80°C for 30 minutes the Cooled reaction mixture was purified (SiO2, a mixture of ethyl acetate:isohexane 1:4 as eluent) to obtain specified in the connection header (0,44 g). MS (APCI) 502/4 (M+N+), 504 (100%).

Method E

Methyl ester of [3aR-(3aα,4α,6α,6aα)]-({6-[7-amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol}oxy)acetic acid

To a solution of [3aR-(3aα,4α,6α,6aα)]-6-[7-amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol (method F, 0.50 g) in THF (25 ml) at 0°With added utility (of 0.62 ml of 2.5 n in hexane). After 20 min, the suspension was treated with a solution of the methyl ester triftoratsetilatsetonom acid (0.34 g) (obtained according to the method Biton, Tetrahedron, 1995, 51, 10513) in THF (10 ml). The resulting solution was allowed to warmed to room temperature, then concentrated and purified (SiO2, ethyl acetate:hexane 4:6 as eluent) to obtain the specified title compound (0.25 g). MS (APCI) 439 (M+N+, 100%).

Method F

[3aR-(3aα,4α,6α,6aα)-6-[7-amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol

[3aR-(3aα,4α,6α,6aα)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol (method G, 13,2 g) in THF (200 ml)containing 0.88 g of ammonia (5 ml)was stirred within 2 h, and then concentrated to dryness and the residue was distributed in water and ethyl acetate. The organic fraction was dried and then concentrated to obtain specified in the title compound (12.5 g). MS (APCI) 367 (M+N+, 100%).

Method G

[3aR-(3aα,4α,6α,6aα)]-6-[7-Chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol

Soliditet (1.1 ml) was added to a solution of [3aR-(3aα,4α,6α,6aα)]-6-{[5-amino-6-chloro-2-(propylthio)pyrimidine-4-yl]amino}tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol (method H, 2.0 g) in acetonitrile (100 ml) and the solution was heated at 70°C for 1 h the Cooled reaction mixture was concentrated and purified (SiO2, a mixture of ethyl acetate:isohexane 1:3 as eluent) to obtain the specified title compound (1.9 g). MS (APCI) 386 (M+N+, 100%).

Way N

[3aR-(3aα,4α,6α,6aα)]-6-{[5-amino-6-chloro-2-(propylthio)pyrimidine-4-yl]amino}tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol

Iron powder (3.0 g) was added to a stirred solution of [3aR-(3aα,4α,6α,6aα)]-6-{[6-chloro-5-nitro-2-(propylthio)pyrimidine-4-yl]amine is}tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol (method I, 2.7 g) in acetic acid (100 ml). The reaction mixture was stirred at room temperature for 2 h, concentrated to half volume, diluted with ethyl acetate and washed with water. The organic phase was dried and concentrated to obtain specified in the title compound (2.0 g). MS (APCI) 375 (M+N+, 100%).

The way I

[3aR-(3aα,4α,6α,6aα)]-6-{[6-chloro-5-nitro-2-(propylthio)pyrimidine-4-yl]amino}tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol

A solution of [3aR-(3aα,4α,6α,6aα)]-6-aminotetraline-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol hydrochloride (method J, 10.0 g) and N,N-diisopropylethylamine (35 ml) in THF (600 ml) was stirred for 1 h the Mixture was filtered and the solution was added over 1 h to a solution of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (WO 9703084, of 25.6 g) in THF (1000 ml) and stirred for 2 hours, the Volume of solvent was reduced in vacuo and added ethyl acetate (1000 ml). The mixture was washed with water and the organic layers were dried and purified (SiO2the mixture of isohexane-ethyl acetate as eluent) to obtain the specified title compound (14.2 g). MS (APCI) 405 (M+N+, 100%).

Method J

[3aR-(3aα,4α,6α,6aα)]-6-aminotetraline-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol hydrochloride

Bis(1,1-dimethylethylene)ether [1R-(1α,2β,3β,4α)]-2,3,4-trihydroxypyrimidine acid is (method K, of 17.4 g) in 6 M HCl (100 ml)/methanol (500 ml) was stirred for 18 hours the Mixture was evaporated and then spent azeotropic distillation with toluene (4×200 ml) to give colorless powder (8.7 g). This solid is suspended in acetone (250 ml)containing 2,2-dimethoxypropane (25 ml) and concentrated HCl (0.2 ml), and then boiled under reflux for 2 hours the Mixture was cooled, evaporated and carried out azeotropic distillation with toluene (3×200 ml). The residue was dissolved in 20% aqueous acetic acid and was stirred for 2 hours the Mixture was evaporated and carried out azeotropic distillation with toluene (4×200 ml) to obtain the specified title compound (10.1 g). MS (APCI) 174 (M+N+, 100%).

Method K

Bis(1,1-dimethylethylene)ether [1R-(1α,2β,3β,4α)]-2,3,4-trihydroxypyrimidine acid

To a solution of (1R-CIS)-bis(1,1-dimethylethyl)-4-hydroxy-2-cyclopentanecarbonyl (method L, 17.1 g) in THF (500 ml)/water (50 ml) was added N-methylmorpholine-N-oxide (9.4 g), then cityregional osmium (10 ml, 2.5% solution in tert-butanol). The mixture was stirred at room temperature for 4 days, then was treated with hydrosulfite sodium (6.0 g). The suspension was filtered through diatomaceous earth and the product was purified (SiO2, a mixture of ethyl acetate:hexane 1:1 as eluent) to obtain the specified title compound (19.1 g). NMR: 1,4 (18H, C)a 1.46-1,60 (1H, m), 1,97-2,05 (1H, m), 3,55-to 3.58 (1H, m), 3,66-to 3.73 (1H, m), 4,11-is 4.21 (2H, m), of 4.54 (1H, d, J=4,8), 4,56 (1H, d, J=5,9), 4,82 (1H, d, J=4,6).

Method L

(1R-CIS)-bis(1,1-dimethylethyl)-4-hydroxy-2-cyclopentanecarbonyl

To a suspension of ether, washed with sodium hydride (60% dispersion in oil; 0.31 g) in THF (30 ml)was added bis(1,1-dimethylethylene)ether iminodicarboxylic acid (1.84 g). The mixture was stirred at 40°C for 1 h and Then to the mixture at room temperature was added (1S-CIS)-4-acetoxy-2-cyclopenten-1-ol (0.5 g) and tetrakis(triphenylphosphine)palladium(0) (0.18 g). The reaction mixture was stirred for 24 h, and then purified (SiO2, a mixture of ethyl acetate:hexane 1:9 as eluent) to obtain the specified title compound as a colourless solid (0,90 g). NMR: USD 1.43 (18H, s)to 1.61 (1H, DDD, J=12,3, 7,7, 6,4), 2,54 (1H, dt, J=12,6, 7,4), 4,51-4,57 (1H, m), a 4.86 (1H, TCEs, J=8.0 a, 1,8), 4,91 (1H, d, J=5,4), 5,71 is 5.77 (2H, m).

Example 2

Subsequent shows a typical pharmaceutical dosage forms containing the compound of formula (I) in crystalline and/or amorphous form (below compound X), for therapeutic or prophylactic use in humans.

(a) Tablet Img/per pill
Compound X100
Lactose in Heb. Pharmacopoeia182,75
Sodium with the l croscarmellose to 12.0
Pasta corn starch (5% paste wt./about.)2,25
Magnesium stearate3,0
(b) Tablet IImg/per pill
Compound X50
Lactose in Heb. Pharmacopoeia223,75
Sodium salt croscarmellose6,0
Corn starch15,0
Polyvinylpyrrolidone (5% paste wt./about.)2,25
Magnesium stearate3,0
(C) Tablet IIImg tablet
Compound X1,0
Lactose in Heb. Pharmacopoeia93,25
Sodium salt croscarmellose4,0
Pasta corn starch (5% paste wt.,about.)0,75
Magnesium stearate1,0
(d) Capsulemg/capsule
Compound X10
Lactose in Heb. Pharmacopoeia488,5
Magnesium stearate1,5
(e) Injecting the solution I(50 mg/ml)
Compound X5,0% wt./about.
1 n solution of sodium hydroxide15,0%.about
of 0.1 n hydrochloric acid(to bring the pH to 7.6)
The polyethylene glycol 4004.5% wt./about.
Water for injectionup to 100%
(f) Injecting the solution II(10 mg/ml)
Compound X1.0% wt./about.
Sodium phosphate BP3,6% wt./about.
a 0.1 n solution of sodium hydroxide15,0%.about.
Water for injectionup to 100%
(g) Injecting the solution III(1 mg/ml
buffered to pH 6)
Compound X0.1% wt./about.
Sodium phosphate BP2.26 wt./about.
Citric acid0,38% wt./about.
The polyethylene glycol 400a 3.5% wt./about.
Water for injectionup to 100%

Note

The above composition can be obtained by conventional means, well known in the field of pharmacy. The tablets (a)-(C) can be covered intersolubility shell by conventional means, for example, by providing a shell of acetamidoacrylate.

NMR spectra were taken on the spectrometer Varian Unity Inova 300 or 400; NMR data are given in the form of Delta values for major diagnostic item is otons, presented in ppm (ppm) relative to tetramethylsilane was (TMS) as internal standard using predeterminado dimethyl sulfoxide (DMSO-δ6) as solvent unless otherwise indicated; for examples, showing the presence of rotamers in proton NMR spectra, the chemical shifts for the main rotamer; constant interaction (J) is represented in Hz.

Mass spectra (MS) were determined in the following way: EI-spectra (electron ionization) were obtained using the spectrophotometer VG 70-250S or Finnigan Mat Incos-XL, FAB spectra (fast atom bombardment) were obtained using the spectrophotometer VG 70-250SEQ, ESI (ionization electrofresh.com) and APCI spectra chemical ionization at atmospheric pressure) were obtained using the spectrometer Finnigan Mat SSQ7000 or Micromass Platform.

Preparative HPLC separation mainly was performed using a Novapak column®, Bondapak® or Hypersil®filled with reversed-phase silica BDSC-18.

Flash chromatography (indicated in examples like (SiO2)) was performed using silica Fisher Matrix, 35-70 μm.

Reduction

THF - tetrahydrofuran

Powder x - ray powder x-ray diffraction analysis of the

DSC - differential scanning calorimetry.

Data for biological studies

In this application, as well as in the application WO 99/05143 describe what I connection which act as antagonists of the receptor R2T. These compounds can be used as pharmaceutical agents for the inhibition of platelet aggregation.

In order to be used biologically active compound had low estimated dose for use in human beings among all factors significantly important are the following factors:

a) a good impact on the receptors of the person;

b) good metabolic stability in human body.

Therefore, increasing the metabolic stability of the affinity to the receptor R2Tallows the treatment to be effective at a lower settlement of the applied dose for a person.

"Good impact" is defined as the affinity to the receptor R2t. For this connection to test the binding of the ligand obtained the value of Ki is more than 8, as indicated in the following table pharmacological data.

As for metabolic stability, in the literature and confirmed by documents that measurements in vitro can be used to predict the metabolic stability of drugs in vivo. For example, this issue is discussed in the following sources:

1) A.D.Rodrigues, Biochem. Pharmacol, 1994,48, 2147;

2) .Mistry, J.B.Houston, Drug Metab. Dispo., 1987,15, 710;

3) J.B.Houston, Biochem. Pharmacol,47, 1469.

In vitro studies in human liver microsomes have shown that the compounds of the General structure described in the application WO 99/05143, are metabolized by oxidation and glucuronidation. The connection is illustrated by the examples in this patent application, show an unexpected advantage of the fact that they are metabolically more stable with respect to oxidation and glucuronidation. Because these compounds retain the affinity to the receptor R2Tthere is an advantage in the calculation of therapeutic dose for the inhibition of platelet aggregation in humans.

The rate of oxidation in microsomes of a man is measured by comparing the rate of oxidation of the test compounds with the oxidation rate of the standard connection of dextromethorphan, which is known that it is quickly broken down in the human body (Martindale, 23rdEdition, Pharmaceutical Press, 2002, p.1087). Thus, the higher this ratio, the more stable the test connection.

Speed glukuronidirovania measured by comparing the speed of glukuronidirovania test connection speed glukuronidirovania standard connections - silicone (zileuton), which is known that it is quickly broken down in the human body (W.M.Awni et al., Clin. Pharmacokinet., 1995,29(suppl. 2), 49). So the m way the higher this ratio, the more stable the test connection.

The present invention relates to polymorphs of the following connections:

Data biological/pharmacological testing of compounds according to the invention are presented in the table below.

ConnectionThe impact on the receptor R2C(Ki)Stability to oxidation in microsomes person, regarding the dextromethorphanTest in vitro with glucuronosyltransferases - stability glucuronidation regarding silicone
8,724Stable - glucuronide was not detected

The data presented in the table show that the compound of the present invention saves the impact on the receptor R2Tand, at the same time, shows a significantly higher metabolic stability compared to glucuronidation. Thus, the compounds of the present invention can be used in the treatment of diseases associated with platelet aggregation.

1. Polymorph (I) the compounds of formula (I):

essentially crystalline form, which which is characterized by a powder x-ray, containing characteristic peaks of high intensity at 5,3° (±0,1°), 20,1° (±0,1), 20,7° (±0,1°), 21,0° (±0,1°) and 21.3° (±0,1°) 2θ.

2. The compound of formula (I) according to claim 1, which is essentially anhydrous form.

3. The compound of formula (I) according to claim 1 or 2, characterized in that its x ray powder contains characteristic peaks at 5,3° (±0,1°), 8,0° (±0,1°), 9,6° (±0,1°), 13,9° (±0,1°), 15,3° (±0,1°), 20,1° (±0,1°), 20,7° (±0,1°), 21,0° (±0,1°), 21,3° (±0,1°), 26,2° (±0,1°) and 27.5° (±0,1°) 2θ.

4. The compound of formula (I) according to any one of claims 1, 2 or 3, characterized in that the curve of differential scanning calorimetry has a melting point of beginning, located within 146-152°C.

5. A method of obtaining a compound according to claim 1, in which the crystallization of the compounds of formula (I) from a solvent selected from the group of lower alkylphenol and water or their mixtures, when included in the reaction mixture of the seed crystals polymorph I.

6. The method according to claim 5, in which the solvent is a mixture of methanol and water.

7. A method of obtaining a compound according to claim 1 or 2, using seed crystals.

8. The method according to claim 7, in which the seed crystals are prepared by melting the compound according to claim 1 or 2.

9. Poly is Orff (III) the compounds of formula (I):

essentially in crystalline form characterized by a powder x-ray that contains characteristic peaks of high intensity at 14,0° (±0,1°), 17,4° (±0,1), 18,4° (±0,1°), 21,4° (±0,1°) and 24.1° (±0,1°) 2θ.

10. The compound of formula (I) according to claim 9, characterized in that its x ray powder contains characteristic peaks at 5,6° (±0,1°), 12,5° (±0,1°), 14,0° (±0,1°), 17,4° (±0,1°), 18,4° (±0,1°), 21,4° (±0,1°), 22,2° (±0,1°), 22,9° (±0,1°), 24,1° (±0,1°) and 24.5° (±0,1°) 2θ.

11. The compound of formula (I) according to claim 9 or 10, characterized in that the curve of differential scanning calorimetry has a melting point of beginning, located within 127-132°C.

12. A method of obtaining a compound according to claim 9 or 10, in which the crystallization of the compounds of formula (I) from a solvent which is an alcohol, when included in the reaction mixture a few seed crystals of polymorph III.

13. A method of obtaining a compound according to claim 9 or 10, which includes a suspension of the compounds of formula (I) in the solvent system IPA/water at a temperature in the range 5-65°C.

14. Polymorph (IV) the compounds of formula (I):

essentially in crystalline form characterized by a powder x-ray that contains characteristic peaks of high intensity at a 4.9° (±0,1°), 9,2° (±0,1), 11,6° (±0,1°), 15,6° (±0,1°) and 16.4° (±0,1°) 2θ.

15. The compound of formula (I) according to 14, characterized in that its x ray powder contains characteristic peaks at 4,9° (±0,1°), 6,0° (±0,1°), 9,2° (±0,1°), 11,6° (±0,1°), 12,8° (±0,1°), 15,6° (±0,1°), and 16.4° (±0,1°), 17,2° (±0,1°) and 18.1° (±0,1°) 2θ.

16. The compound of formula (I) according to 14 or 15, characterized in that the curve of differential scanning calorimetry has a melting point of beginning, situated at about 139°C.

17. The method of obtaining connection 14 or 15 in which the compound of formula (I) is crystallized from a solvent which is acetonitrile.

18. The compound according to any one of claims 1 to 4, 9-11 and 14-16 for use as a medicine.

19. The compound according to any one of claims 1 to 4, 9-11 and 14-16 for use in the manufacture of a medicinal product for use in the prevention of arterial thrombotic complications in patients with coronary artery disease, cerebrovascular disease or peripheral vascular Soboleva is eat.

20. The compound according to any one of claims 1 to 4, 9-11 and 14-16 for use in the manufacture of a medicinal product for use in preventing the growth and spread of tumors.

21. Pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 4, 9-11 and 14-16 in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the prevention of arterial thrombotic complications in patients with coronary artery disease, cerebrovascular disease or peripheral vascular disease.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, 9-11, 14-16, for use in preventing the growth and spread of tumors.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention refers to organic substances production and can be applied for production of herbicides and other bioactive compounds. Production of 2-sulphanilamine-1,2,4-triazolo[1,5-a]pyrimidine of general formula , where R1 is metal, phenylic, 4-methyl phenylic, 4-chlorophenylic group, R is phenylic, 4-methyl phenylic, 4-chlorophenylic, methoxyphenylic group, R is metal, phenylic, 4-methyl phenylic, 4-chlorophenylic group is sulphurization of 2-amino-4,7-dihydro-1,2,4-triazolo [1,5-a]pyrimidines (II) by sulphochlorides (III) in pyrimidine and oxidation of produced 2-sulphanilamine-4,7-dihydro-1,2,4-triazolo[1,5-a] pyrimidines (IV) by bromine in acetic acid with sodium acetate occurrence.

EFFECT: method allows to produce compounds using low-price and reasonable raw materials without any complicated processing steps applied.

1 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of heterocyclic compounds, which contain pyrrolo[1,2-а][1,4]diazepine fragment, annelated to aromatic and heteroaromatic ring. Method for preparation of derivatives of pyrrolo[1,2-а][1,4]diazepine of general formula I, where А =

, is described. The said derivatives may be of use as substances with potential CNS activity, or with analgesic, antimicrobial and antifungal effect. Method implies recyclization of furan ring of 5-methyl-furfurylamides of general formula 2, , where А stands for above shown groups, by exposure to temperature of 60-70°С in the mixture of glacial acetic acid and strong hydrochloric acid in volumetric ratio 1:0.15 for 10-15 minutes.

EFFECT: provides for simultaneous formation of pyrrole and diazepine rings and improves yield of end products due to less number of process steps.

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 represents (C1-C4)-alkyl with branched or linear chain; R2 represents hydrogen atom (H); R3 represents (C1-C4)-alkyl with branched or linear chain; R4 represents (C1-C4)-alkyl with branched or linear chain, (C2-C4)-alkenyl; R5 represents -SO2NR10R11; R8 represents (C1-C4)-alkyl with branched or linear chain; each R10 and R11 represents independently H or (C1-C12)-alkyl with branched or linear chain; or R10 and R11 in common with nitrogen atom to which they are bound form pyrrolinone group, piperidyl, morpholinyl, 4-N(R13)-piperazinyl that are substituted optionally with (C1-C4)-alkyl with branched or linear chain, -NR14R15, phenyl group substituted optionally with -OH or phenyl group bound in common with other substituted phenyl group by carbonyl group; R13 represents (C1-C4)-alkyl with branched or linear chain, (C2-C6)-alkyl with branched or linear chain and substituted with hydroxyl; (C2-C6)-alkyl with branched or linear chain substituted with phenyl; (C2-C6)-hydrocarbon with branched or linear chain substituted with -CO2R8; wherein each radical among R14 and R15 represents independently H; (C1-C4)-alkyl with branched or linear chain, or its pharmaceutically acceptable salt. The claimed compounds possess inhibitory effect on activity of phosphodiesterase-5 and can be used for production of drug for treatment or prophylaxis of diseases associated with phospholipase and its function. Also, invention relates to pharmaceutical composition, medicinal composition for veterinary science, and intermediate compounds IA-IG used for synthesis of compound of the formula (I).

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

8 cl, 2 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the general formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), -(CH2)3-, -(CH2)4-, -CH2-S-CH2-, -S-CH2-CH2-; R2 is chosen from group consisting of nitrogen (N), sulfur (S) atom; n = 0 or 1; Z is chosen from group consisting of (C2-C10)-alkyl; R3 is chosen from group consisting of H; m = 0-2; R4 is chosen from group consisting of oxygen atom (O), -CH2-; R5 is chosen from group consisting of the following groups:

wherein R6 is chosen from group consisting of H, alkyl-(C1-C5)-alkoxyl; W is chosen from group consisting of -NH wherein each "alkyl" can be linear or branched and can be also cyclic or linear, or branched and comprises such cyclic residues, and each "aryl" comprises monocyclic aromatic group comprising 5-12 carbon atoms bound with one or some heteroatoms chosen from N, O or S atoms, and to their salts and solvates. Also, invention relates to a pharmaceutical composition, to a method for their synthesis and using compounds by claims 1-6. Invention provides synthesis of novel active compounds and pharmaceutical compositions based on thereof that possess affinity to serotonin receptors of subtype 5-HT1A.

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

10 cl, 4 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the general formula (I): wherein R0 represents hydrogen atom; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be similar or different and each represents independently hydrogen atom, halogen atom, perhalogenalkyl, substituted or unsubstituted groups, such as linear or branched (C1-C12)-alkyl, (C3-C7)-cyclaoalkyl, (C1-C12)-alkoxy, cyclo-(C3-C7)-alkoxy group, hydroxyalkyl; R13 and R14 can be similar or different and each represents independently hydrogen atom, substituted or unsubstituted groups, such as linear or branched (C1-C4)-alkyl, (C3-C7)-cycloalkyl, optionally, R13 and R14 in common with nitrogen atom can form 5-6-membered heterocyclic ring wherein heterocycle can be substituted also, and it can comprise one, two or three double bonds or "additional heteroatoms" chosen from nitrogen atom (N); "n" means a whole number in the range 1-6, and pharmaceutical compositions based on its. Indicated compounds are ligands of 5-HT (serotonin) and can be used in treatment in cases if modulation of activity of 5-HT and melatonin is desirable.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

21 cl, 31 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to novel hydrogenated pyrrolo[4,3-b]indoles of the general formula (1): , their racemates, optical isomers, geometric isomers, pharmaceutically acceptable salts and/or hydrates that can be used, for example, in treatment and prophylaxis of different neurodegenerative diseases, such as Alzheimer's syndrome. In the general formula (1): a dotted line with accompanying unbroken line represents ordinary or double bond; R1 and R2 represent independently of one another substitutes of amino group chosen from hydrogen atom, possibly substituted (C1-C6)-alkyl substituted possibly with aryl, possibly substituted phenyl, possibly substituted carbonylamino or thiocarbonylamino group, substituted acyl, possibly substituted aryl sulfonate wherein substituted in indicated R1 and R2 are chosen from (C1-C6)-alkyl, halogen atoms, nitro, carboxy, alkoxy group, aryl; R1n represents one or some similar or different substituted of cyclic system chosen from hydrogen atom, alkyl, aryl, cyano group, halogen atom, 5-6-membered nitrogen-containing heteroaryl. Also, invention relates to methods for synthesis of these compounds, pharmaceutical compositions and their using, and to using compounds in libraries with their using.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved methods of synthesis.

20 cl, 2 tbl, 12 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to 1,4,5,6-tetrahydro-6-oxo-5-(2-piperazinoethyl)-4-phenyl-3-(4-chlorophenyl)pyrrolo[3.4]pyrazole dihydrochloride of the formula (I): . This compound is synthesized by interaction of 1-(2-piperazinoethyl)-5-phenyl-4-(4-chlorobenzoyl)-3-hydroxy-3-pyrrolin-2-one dihydrochloride with hydrazine hydrate. Synthesized compound can be used in medicine as agent decreasing arterial blood pressure and blood coagulation. Invention provides synthesis of a novel compound not described early that possesses hypotensive and anti-coagulant effect simultaneously.

EFFECT: valuable medicinal properties of compound.

3 tbl, 1 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel derivatives of 1,2,4-triazole of the general formula (I): wherein A and b can be taken separately or in common being when they are taken separately then A means (C1-C6)-alkyl or phenyl, and B means (C1-C6)-alkyl; A and B taken in common mean (C2-C5)-alkanediyl, and they form with C-atoms 3-6-membered cycle optionally substituted with (C1-C4)-alkylene, oxo, ethylenedioxy group, (C1-C4)-alkyl, 1-2 halogen atoms, (C1-C3)-alkoxy-(C1-C3)-alkoxy or hydroxy group; each R1 means independently hydrogen atom, -OH, halogen atom, (C3-C6)-cycloalkyl, (C1-C6)-alkyl optionally substituted with 1-3 halogen atoms; or two R1 groups near adjacent carbon atoms form 6-membered aryl cycle; R2 and R3 can be taken in common or separately, and when they are taken in common then they represent (C3-C8)-alkanediyl that forms condensed 5-10-membered nonaromatic cycle; when R2 and R3 are taken separately then R2 means (C1-C6)-alkyl possibly substituted with 1-3 halogen atoms or cyclopropyl, and R3 means cyclopropyl possibly substituted with (C1-C4)-alkyl, naphthyl, phenyl possibly substituted with halogen atom, -OH, (C1-C6)-alkyl wherein indicated (C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, -O-(C1-C6)-alkyl wherein indicated -O-(C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, phenyl or benzyloxy group, dihydrobenzofuranyl, benzothiadiazolyl or benzoimidazolyl possibly substituted with (C1-C6)-alkyl, their pharmaceutically acceptable salts or solvates, and pharmaceutical composition based on thereof. Proposed compounds are inhibitor of 11β-hydroxysteroid dehydrogenase I, and can be used in medicine in treatment of diabetes mellitus, obesity and dyslipidemia.

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

19 cl, 17 tbl, 4 ex

FIELD: organic chemistry, medicine, oncology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): or their pharmaceutically acceptable salts possessing the inhibitory effect on activity of tyrosine kinase. Proposed compounds can be used in treatment of proliferative disease, such as tumor. In the formula (I) each R1 and R2 means independently of one another hydrogen atom, methyl, ethyl, isopropyl, hydroxyethyl, piperidine-1-ylmethylcarbonyl, pyrrolidine-1-ylmethylcarbonyl, morpholine-4-ylmethylcarbonyl, 4-methylpiperazine-1-ylmethylcarbonyl, N,N-dimethylaminomethylcarbonyl, 4-ethylpiperazine-1-ylmethylcarbonyl, piperidine-1-ylethylcarbonyl, N,N-diethylaminoethylcarbonyl, N,N-dimethylaminopropylcarbonyl, 2-pyridylcarbonyl, tetrahydropyrane-4-yl, morpholine-4-ylethyl, N,N-diethylaminoethyl, tert.-butyl; or R1 and R2 in common with nitrogen atom to which they are bound form 4-ethylpiperazine-1-yl, pyrrolidine-1-yl, 4-methylpiperazine-1-yl, piperidine-1-yl, morpholine-4-yl, 3,5-dimethylpiperazine-1-yl; R3 is chosen from 3-chloro-4-fluorophenyl, phenyl, 4-benzyloxyphenyl, 3-hydroxy-4-methylphenyl, 3-hydroxy-4-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,5-dichlorophenyl, 3-methoxyphenyl, benzo[1,3]dioxol-5-yl, 6-methoxypyridine-3-yl, 2-methoxypyridine-4-yl, pyridine-2(1H)-one-5-yl, pyridine-2(1H)-one-4-yl, 3-methoxyphenyl, 3-methylphenyl, pyridine-2(1H)_one-4-yl; G means -CH2-; Q means -NH-; X absents or means -CH(CH3)-, -CH2- under condition that if X absents then R3 is bound by ring carbon atom. Also, invention relates to variants of methods for synthesis of compounds of the formula (I), preparing a pharmaceutical composition and using compounds proposed.

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

13 cl, 147 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): that are antagonists of CRF receptors and wherein Ar means optionally substituted phenyl or monocyclic 6-membered heteroaryl comprising one heteroatom chosen from nitrogen, oxygen or sulfur atoms; R1-R4 have values given in the invention claim, or to their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of indicated compounds and to pharmaceutical compositions containing these compounds that are useful for administration to a patient suffering from diseases that are relived in therapy using antagonists of CRF receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 10 tbl, 17 ex

FIELD: medicine; pharmacology.

SUBSTANCE: suggested use of 2-ethyl-6-methyl-3-oxypiridin succinate as treatment in combination with traditional therapy for faster physical rehabilitation of patients with chronic heart failure.

EFFECT: improved diastolic function of the left myocardial ventricle; higher tolerance to physical stress in patients with chronic cardiac failure of any origin.

2 cl, 2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: intravenous bolus dosing with 750000 U of streptokinase is administered to the patient. At the same time, the external counterpulsation is performed for 30 min, for this purpose, the compression cuffs are turned around calves, hips and buttocks, the cuffs are sequentially inflated, starting from the distal to proximal, at the beginning of diastole, and deflated simultaneously before systole.

EFFECT: efficiency and safety of thrombolytic therapy is increased, risk of hypotonic complications during and after re-perfusion thrombolytic therapy is decreased.

1 tbl

FIELD: medicine.

SUBSTANCE: subtype of stroke is determined based on the clinical, instrumenta; and biochemical tests, and the differentiated therapy is performed by use of one or few of following 4 treatments and taking in account the concomitant diseases, contraindications and stroke type: 1) antithrombotic therapy (AT), 2) hypotensive therapy (HtT), 3) hypolipidemic therapy (HlT), 4) surgery (S). The AT is used in life-long cardioembolic aterothrombotic ischemic stroke. The HtT is administered to all patients with stroke; HlT is used in patients without diabetes and after the low-cholesterol diet within 6 months, with plasma cholesterol more than 5.5 mmol/L or 220 mg/dL, or in patients with diabetes I or II with plasma cholesterol more than 3.2 mmol/L or 128 mg/dL, on agreement with endocrinologist. S is used in patients with 50-70% stenosis of head and neck blood vessels and in embologenic plaque, or if stenosis if more than 70%.

EFFECT: complex effect upon different pathogenetic levels of stroke is provided, and patient's individual characteristics are taken in account.

3 cl, 3 tbl, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: description is provided for the derivative of phenylalcan or phenyloxyalcan acids, formula (I), or their pharmaceutically acceptable salt or hydrolysable ester, where: R1 and R2 independently present the H or С1-3alkyl; X presents the O or (СН2)n where n is 0.1 or 2; R3 and R4 independently present the H, С1-3alkyl, -ОСН3, CF3, allyl or halogen; X1 presents О, S, SO2, SO or СН2; one of R5 and R6 independently presents hydrogen, and another - С1-6alkyl (including the ramified alkyl and, probably, the substituted С1-6alkoxy); R7 presents a phenyl or hexamerous heterocycle taken from pyridine, and each of specified phenyl or heterocycles is substituted by phenyl (probably, substituted by one ore more С1-3alkyl, CN, halogen or CF3). The pharmaceutical composition is also described.

EFFECT: compounds can be used in treatment of cardiovascular and endocrine diseases.

13 cl, 145 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 represents (C1-C4)-alkyl with branched or linear chain; R2 represents hydrogen atom (H); R3 represents (C1-C4)-alkyl with branched or linear chain; R4 represents (C1-C4)-alkyl with branched or linear chain, (C2-C4)-alkenyl; R5 represents -SO2NR10R11; R8 represents (C1-C4)-alkyl with branched or linear chain; each R10 and R11 represents independently H or (C1-C12)-alkyl with branched or linear chain; or R10 and R11 in common with nitrogen atom to which they are bound form pyrrolinone group, piperidyl, morpholinyl, 4-N(R13)-piperazinyl that are substituted optionally with (C1-C4)-alkyl with branched or linear chain, -NR14R15, phenyl group substituted optionally with -OH or phenyl group bound in common with other substituted phenyl group by carbonyl group; R13 represents (C1-C4)-alkyl with branched or linear chain, (C2-C6)-alkyl with branched or linear chain and substituted with hydroxyl; (C2-C6)-alkyl with branched or linear chain substituted with phenyl; (C2-C6)-hydrocarbon with branched or linear chain substituted with -CO2R8; wherein each radical among R14 and R15 represents independently H; (C1-C4)-alkyl with branched or linear chain, or its pharmaceutically acceptable salt. The claimed compounds possess inhibitory effect on activity of phosphodiesterase-5 and can be used for production of drug for treatment or prophylaxis of diseases associated with phospholipase and its function. Also, invention relates to pharmaceutical composition, medicinal composition for veterinary science, and intermediate compounds IA-IG used for synthesis of compound of the formula (I).

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

8 cl, 2 tbl, 4 ex

FIELD: chemical-pharmaceutical industry.

SUBSTANCE: invention proposes a butylphthalide-containing soft capsule consisting of capsule wall and oil containing a drug wherein indicated oil consists of mainly butylphthalide and vegetable oil taken in the ratio about 1:10, not above. Material of capsule wall consists of mainly a base, plasticizing agent and water taken in the ratio about = 1:(0.2-0.4):(0.8-1.3), respectively. Soft gel capsules masks strong and specific odor of butylphthalide and solve problems associated with preparing oily active agents for oral using.

EFFECT: improved and valuable properties of capsules.

15 cl, 4 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the general formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), -(CH2)3-, -(CH2)4-, -CH2-S-CH2-, -S-CH2-CH2-; R2 is chosen from group consisting of nitrogen (N), sulfur (S) atom; n = 0 or 1; Z is chosen from group consisting of (C2-C10)-alkyl; R3 is chosen from group consisting of H; m = 0-2; R4 is chosen from group consisting of oxygen atom (O), -CH2-; R5 is chosen from group consisting of the following groups:

wherein R6 is chosen from group consisting of H, alkyl-(C1-C5)-alkoxyl; W is chosen from group consisting of -NH wherein each "alkyl" can be linear or branched and can be also cyclic or linear, or branched and comprises such cyclic residues, and each "aryl" comprises monocyclic aromatic group comprising 5-12 carbon atoms bound with one or some heteroatoms chosen from N, O or S atoms, and to their salts and solvates. Also, invention relates to a pharmaceutical composition, to a method for their synthesis and using compounds by claims 1-6. Invention provides synthesis of novel active compounds and pharmaceutical compositions based on thereof that possess affinity to serotonin receptors of subtype 5-HT1A.

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

10 cl, 4 tbl, 26 ex

FIELD: medicine.

SUBSTANCE: the present innovation refers to isolated human antibodies against peptides being the derivatives of apolipoprotein B. It is necessary to apply isolated human antibody or antibody fragment indicated to, at least, one oxidized fragment of apolipoprotein B, in manufacturing pharmaceutical composition for either therapeutic or prophylactic treatment of atherosclerosis due to immunization. The advantage of the present innovation lies in the fact that passive immunization has been occurred with pre-developed antibodies indicated to the same peptides. Moreover, as the applied antibodies are being completely human ones, the risk of unfavorable immunological reaction during the process of their introducing to a patient is decreased.

EFFECT: higher efficiency.

72 cl, 18 dwg, 5 ex, 3 tbl

FIELD: medicine, cardiosurgery.

SUBSTANCE: in addition to conventional therapy it is necessary to introduce 5-oxymethyl uracil per 500 mg thrice daily for 5 d before operation and for 14 d after operation. The innovation provides efficient rehabilitation due to complex - antioxidizing, cardiotonic and antiphlogistic action of 5-oxymethyl uracil.

EFFECT: higher efficiency.

1 ex

FIELD: medicine, biotechnology, genetic engineering.

SUBSTANCE: invention proposes non-infectious for human adenovirus as a vector for substitution genetic therapy of angiogenesis disorders. This adenovirus is replicative-defect in mammalian cells (including humans) in region that is not essential for replication in avian cells and carries expression cassette consisting of cytomegalovirus promoter, human angiogenin gene cDNA and polyadenylation signal of bovine hormone growth, and provides induction of angiogenesis. Invention proposes a method for induction of angiogenesis and method for treatment of ischemic disease by using a composition comprising the proposed recombinant adenovirus. Invention can be used in medicine in treatment of cardiovascular diseases.

EFFECT: valuable medicinal properties of adenovirus and composition.

5 cl, 1 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: invention concerns glycoforms of VII factor and compositions of VII factor, characterized by modified configurations on basis of asparaginic oligosaccharide chains. In addition invention includes detection method applied for polypeptide glycoforms of VII factor, receiving method and disease treatment method as well.

EFFECT: identification of biologically active forms of recombinant VII factor.

53 cl, 5ex

Up!