40-o-(2-hydroxy)ethylrapamycin in crystalline nonsolvated form, pharmaceutical composition comprising such macrolide as active substance and method for its preparing
FIELD: organic chemistry, antibiotics, pharmacy.
SUBSTANCE: invention relates to a new crystalline nonsolvated form of 40-O-(2-hydroxy)-ethylrapamycin that shows crystalline lattice with the following parameters: a = 14.37Å; b = 11.24Å; c = 18.31 Å, and volume value is 2805Å. Also, invention relates to a method for preparing this crystalline form that involves crystallization of 40-O-(2-hydroxy)ethylrapamycin from a solvent with mixture with aliphatic hydrocarbon of the formula CnH2n+2 wherein n = 5, 6 or 7. Also, invention relates to a pharmaceutical composition based on thereof and its using in preparing medicinal agents used in treatment or prophylaxis of organ or tissue transplant rejection, autoimmune, inflammatory states, asthma, proliferative disorders, tumor or hyperproliferative vascular diseases. Invention provides preparing the novel crystalline nonsolvated form of 40-O-(2-hydroxy)ethylrapamycin possessing immunosuppressive properties.
EFFECT: improved preparing method, improved and valuable medicinal properties of compound and composition.
7 cl, 2 ex
The invention relates to the stabilization of the pharmaceutical active ingredient sensitive to oxidation, such as the macrolide polyene, preferably a polyene macrolide with immunosuppressive properties, primarily rapamycin.
Processing and storage, especially for bulk storage, pharmaceutical active substances sensitive to oxidation, are difficult. In this case it is necessary to apply special processing methods, and are often sensitive to oxidation ingredient store in an airtight container in a protective gas atmosphere. In the preparation of compositions based on such pharmaceutical active substances add significant amounts of stabilizers.
Polyene macrolides possess satisfactory stability characteristics. However, if an invention it was found that their stability against oxygen can be greatly improved by adding a stabilizer such as antioxidant, at the time of their selection.
The object of the invention is
1. The method of stabilization of the macrolide polyene, providing for the addition of antioxidant to the purified a macrolide, preferably in the early stages of its release.
The method can be used primarily for stable polien the first of the macrolide without packaging. The amount of antioxidant can typically up to 1%, more preferably from 0.01 to 0.5% (calculated on the weight of the macrolide). Hereinafter in this description of such a small number is called catalytic amount.
In addition, an object of the present invention is also:
2. The mixture such as a mixture without packaging containing polyene macrolide and antioxidant, preferably in a catalytic amount, preferably in solid form.
The mixture can be in the form of separate particles, for example, in crystalline or amorphous form. It can be sterile or substantially sterile condition, for example in a condition suitable for pharmaceutical applications.
3. Use of mixture specified in paragraph 2, for the preparation of pharmaceutical compositions.
Examples of polyene macrolides are, for example, molecules containing double bonds, preferably conjugated double bonds, for example, compounds with antibiotic and/or immunosuppressive properties, such as macrolides containing laktamovogo or lactoovo communication, and their derivatives, for example, compounds with biological activity, qualitatively similar to the activity of naturally occurring macrolides, for example, substituted by chemical macrolides. Relevant if the apostrophes are for example, rapamycin and accomapny. The preferred polyene macrolide is a macrolide containing at least 2 conjugated double bonds, for example 3 conjugated double bonds.
Rapamycin is a known laktamovogo macrolide, which is produced by, for example, Streptomyces hvgroscopicus. The structure of rapamycin are described in N. Kessler and others, Helv. Chim. Acta, 76: 117, 1993. Rapamycin has antibiotic and immunosuppressive properties. Known derivatives of rapamycin, for example, 16-O-substituted rapamycin, for example, described in WO 94/01136 and WO 96/41807, 40-O-substituted rapamycin, for example, described in WO 94/09010, WO 92/05179, WO 95/14023, WO 94/01136, WO 94/02385 and WO 96/13273, all documents included in the present description by reference. Preferred derivatives of rapamycin are, for example, rapamycin, in which the hydroxy-group in position 40 of the formula As shown on page 1 WO 94/01010 substituted by a group-OR, where R denotes hydroxyalkyl, hydroxyalkoxy, acylaminoalkyl or aminoalkyl, for example, 40-O-(2-hydroxy)tyramine, 40-O-(3-hydroxy)properposition and 40-O-[2-(2-hydroxy)ethoxy]tyramine.
Ascomycin, among which the most famous are the FK-506 and ascomycin, represent another class lactamase macrolides, many of which have a pronounced immunosuppressive and anti-inflammatory activity. FK-506 presented yet a laktamovogo macrolide, produced by Streptomyces tsukubaensis. The structure of FK-506 in the Annex to the Merck Index, 11th ed. (1989) in paragraph A5. Ascomycin described, for example, in USP 3244592. Ascomycin, FK-506 and other naturally occurring macrolides having similar biological activity, and their derivatives, such as synthetic analogs, and derivatives, generally referred to as "ascomycin". Examples of synthetic analogues or derivatives are, for example, halogenated ascomycin, for example, 33-epichloro-33-desoxycortisol described in EP-A 427680, tetrahydropyrane derivatives, which, for example, described in EP-A 626385.
The most preferred macrolides are rapamycin and 40-O-(2-hydroxy) tyramine.
Preferred antioxidants include, for example, 2,6-di-tert-butyl-4-METHYLPHENOL (hereinafter in the present description called BHT), vitamin E or C, most preferred is EIT.
The most preferred mixture according to the invention is a mixture of rapamycin and 40-O-(2-hydroxy)tyramine and 0.2% (calculated on the weight of the macrolide) of an antioxidant, preferably EIT.
The antioxidant may be added to the polyene macrolide in the early stages of selection, preferably at the final stage of selection, more preferably immediately before the final stage of deposition. Macrolide preferably is in the untreated condition. It can be dissolved in an inert solvent, and to the resulting solution add an antioxidant, followed by a stage of stable deposition of the macrolide, for example, in amorphous form or in the form of crystals. Preferably the mixture according to the invention is in amorphous form.
The obtained stable macrolide unexpectedly has a high stability to oxidation, and its handling and storage, for example in the form without packaging, prior to its further processing, for example, to get galenical compositions become much easier. This is the most important for macrolides in amorphous form.
Macrolide stabilized according to the invention, can be used in unmodified form for the preparation of the required galenical composition. Such compositions can be prepared according to known in the field methods, including adding one or more pharmaceutically acceptable diluents or carriers, including, if necessary, add additional stabilizer.
Accordingly another object of the invention is:
4. Pharmaceutical composition comprising as active ingredient the above-described stabilized mixture in combination with one or more pharmaceutically acceptable diluents or carrier is I.
The composition according to the invention may be adapted for oral, parenteral, local (e.g., skin), ocular, nasal injection or administration by inhalation (e.g., light). The preferred composition is a composition for oral administration, preferably anhydrous composition in which the active substance is leckonby of macrolides.
The pharmaceutical compositions according to the invention may include other excipients, for example, sizing, baking powder, surface-active substance, carrier, diluent, power of smell, etc. of the Composition can be in liquid form, for example, in the form of solutions, suspensions or emulsions, such as microemulsions, for example, described in USP 5536729, or in solid form, for example in the form of capsules, tablets, pills, powders (including finely ground or otherwise reduced particles), solid dispersions, granules, etc., for example, described in WO 97/03654, the contents of both documents are included in the present description by reference, or in semisolid forms such as ointments, gels, creams and pastes. Preferably they are produced in a form suitable for oral administration. Preferably they are in solid form. The pharmaceutical compositions according to the invention can be obtained according to known methods potenzmitte the macrolide, stabilized according to the invention, with additional ingredients; ingredients can be ground or crushed and optionally compressed, for example, into tablets.
The present invention most preferably relates containing rapamycin compositions in liquid or solid form. The most preferred composition is a solid dispersion, for example, containing stable rapamycin according to the invention and a carrier, for example water-soluble polymer, such as hypromellose, for example as described in WO 97/03654.
The composition of the invention can be applied to evidence known to the macrolides, which they contain, for example, in known doses. For example, if the macrolides has immunosuppressive properties, for example, is a rapamycin or a derivative of rapamycin, the composition can be used, for example, for treating or preventing acute or chronic rejection of ALLO - or xenograft organ or tissue, autoimmune diseases or inflammatory conditions, asthma, proliferative diseases, for example, tumors, or hyperproliferative vascular diseases, preferably for the prevention or treatment of transplant rejection.
The amount of the macrolide and composition, you want to use, dependence is from numerous factors, for example, the applied active substance conditions to be treated, duration of treatment, etc. for Example, rapamycin and 40-O-(2-hydroxy)tyramine suitable daily dose for oral administration is from 0.1 to 10 mg, and it can be administered once or in divided doses.
Another object of the present invention is 40-O-(2-hydroxy)tyramine in crystalline form, especially in practically pure form. Preferably, the crystalline form is characterized by the absence or near absence of any components of the solvent; it is resolutional form.
Crystalline form 40-O-(2-hydroxy)tyramine refers to monocyclic system. The resulting crystals have tPL146-147°mainly 146,5°C. To identify new crystalline form of the analysis was performed using the diffraction of x-rays. The conditions under which received these data were as follows:
|the dimensions of the unit cell|
|density (calculated)||1,134 g/cm3|
|the absorption coefficient||0,659 mm-1|
|the crystal size||0,59×0,11×0.03 mm|
|range θ collection data||from 2,55 57,20 to°|
|the number of recorded reflections||4182|
|the number of independent reflections||4037 [R(int)=0,0341]|
|the decrease in the intensity||32%|
|method of refining||The method of least squares|
|using full matrix|
|the quality of fit of the curve F2||1,055|
|final R indices [I > 2 Sigma (I)]||R1=0,0574, wR2=0,1456|
|the maximum diffraction peak and hole||0,340 and -0,184 e/Å3|
40-O-(2-hydroxy)tyramine in cristalli eskay form can be obtained by dissolving the amorphous compound in the solvent, for example, in ethyl acetate, and adding an aliphatic hydrocarbon WithnH2n+2(n=5, 6 or 7). After adding the hydrocarbon resulting mixture can be heated, for example, to a temperature of 25-50°With, for example, up to 30-35°C. Maintaining the mixture formed is usually produced at a low temperature, e.g. below 25°C, preferably from 0 to 25°C. the Crystals are filtered and dried. As the aliphatic hydrocarbon is preferably used heptane. If necessary, the formation of centers of crystallization can be initiated, for example, by exposure to ultrasound, or by seed.
The present invention also relates to a method of cleaning 40-O-(2-hydroxy)tyramine, including crystallization of 40-O-(2-hydroxy)tyramine of the environment for crystallization, for example, from the above-described environment, and highlight the thus obtained crystals. Environment for crystallization may include one or more components in addition to those listed above. It was found that the most suitable environment for crystallization is the environment containing approximately 2 parts of ethyl acetate and about 5 parts of aliphatic hydrocarbon, such as heptane.
It was found that 40-O-(2-hydroxy)tyramine in the crystalline form has an in vitro and in vivo immunosuppressive Akti the activities comparable with the activity of the amorphous form. In localized GvHD maximum inhibition (70-80%) swelling of lymph nodes is achieved by using a dose of 3 mg 40-O-(2-hydroxy)tyramine in crystalline form.
40-O-(2-hydroxy)tyramine can be used for the same indications, which are known for amorphous compounds, for example, for the prevention or treatment of acute or chronic rejection of ALLO - or xenograft, autoimmune diseases or inflammatory conditions, asthma, proliferative diseases such as tumors, or hyperproliferative disease, for example as described in WO 94/09010 or in WO 97/35575, the contents of which are incorporated into this description by reference. In General, satisfactory results are obtained when administered orally in doses of from about 0.05 to 5 or 20 mg/kg/day, for example, from about 0.1 to 2 or up to 7.5 mg/kg/day administered as a single dose or in divided doses 2-4 times a day. Thus, suitable daily dosages for patients are up to about 10 mg, for example from 0.1 to 10 mg.
40-O-(2-hydroxy)tyramine in crystalline form may be administered by any suitable route, e.g. orally, e.g. in the form of tablets or capsules, or nasal or to the lungs (by inhalation). It can be entered in quality is TBE sole active ingredient or together with other medicines for example, immunosuppressants and/or immunomodulators and/or anti-inflammatory agents, for example as described in WO 94/09010.
In accordance with the foregoing objects of the present invention are:
5. The method of prevention or treatment of acute or chronic rejection of ALLO - or xenograft, autoimmune diseases or inflammatory conditions, asthma, proliferative diseases, or hyperproliferative vascular disease in a patient in need of such treatment, introducing the indicated patient a therapeutically effective amount of 40-O-(2-hydroxy)tyramine in crystalline form.
6. 40-O-(2-hydroxy)tyramine in crystalline form, intended for use as a pharmaceutical, for example, according to the above method.
7. Pharmaceutical composition comprising 40-O-(2-hydroxy)tyramine in crystalline form together with a pharmaceutically acceptable diluent or carrier.
8. The kit or package, intended for use in order immunosuppression or provide anti-inflammatory actions, including the above-described pharmaceutical composition, the pharmaceutical composition comprising an immunosuppressant or immunomodulator or anti-inflammatory agent.
Carried away the following examples serve to illustrate the invention, without limiting its scope.
Example 1. Crystallization
0.5 g of amorphous 40-O-(2-hydroxy)tyramine dissolved in 2.0 ml of ethyl acetate at 40°C. Add 5.0 ml of heptane, after which the solution becomes cloudy. After heating up to 30°With the solution again becomes transparent. After cooling to 0°and pokropivny from solution stands out oil. Experienced tube closed and stored over night at 10°C. Then the resulting solid substance was filtered and washed with 0.5 ml of a mixture of ethyl acetate/hexane (1:2.5), and the resulting crystals are dried at 40°at a pressure of 5 mbar for 16 hours So get 40-O-(2-hydroxy)tyramine in crystalline form, with tPL146,5°C.
Large-scale crystallization can be carried out as follows.
250 g of amorphous 40-O-(2-hydroxy)tyramine dissolved with slow stirring in 1.0 l of ethyl acetate in an argon atmosphere. The solution is incubated at 30°and then for 45 min added dropwise to 1.5 l of heptane. In the same conditions add portions 0.25 g of the seed crystals obtained as described above. The mixture was stirred at 30°C for 2 h and the mixture for crystallization is cooled to 25°C for 1 h, and then up to 10°C for 30 min and filtered. The crystals are washed with 100 ml of a mixture of ethyl acetate/hexane (2:3). Follow the second drying is carried out at 50° C and a pressure of about 5 mbar. TPL14 6,5°
IR (KBR): 3452, 2931, 1746, 1717, 1617, 1453, 1376, 1241, 1191, 1163, 1094, 1072, 1010, 985, 896 cm-1
Elementary structure, obtained by x-rays, with the corresponding coordinates is presented below in figure 1-3.
Example 2. Obtaining a stable 40-O-(2-hydroxy)tyramine
100 g of 40-O-(2-hydroxy)tyramine dissolved in 600 l of absolute ethanol. After adding 0.2 g of BHT the resulting solution is added dropwise under stirring for 1 h, added to 3.0 l of water. The resulting suspension is stirred for another 30 minutes After filtration, followed by washing (3×200 ml of a mixture of water/ethanol in a ratio of 5:1 (vol./about.)) get wet white product which is then dried under vacuum (1 mbar) at 30°C for 48 hours Resulting dried product contains 0.2 wt.% EIT.
The resulting product has improved stability during storage. The amount of by-products and decomposition products in % after storage for 1 week is:
|Connection||50°in an open flask|
|the compound from example 2 (0,2% EIT)||1,49|
The process described above in the example can be repeated using the m rapamycin as an active ingredient.
1. 40-O-(2-hydroxyethyl)rapamycin in crystalline resolutional form.
2. 40-O-(2-hydroxyethyl)rapamycin according to claim 1, having a crystal lattice with the following parameters: a=14,37 Åb=11,24 Åc=18,31 Å, volume 2805 Å3.
3. Pharmaceutical composition having immunosuppressive properties, comprising as an active ingredient 40-O-(2-hydroxyethyl)rapamycin according to claim 1 or 2, together with one or more pharmaceutically acceptable, diluent(s) or carrier(s).
4. The composition according to claim 3 for the treatment or prevention of transplant rejection of an organ or tissue, autoimmune diseases, inflammatory conditions, asthma, proliferative disorders, tumors, hyperproliferative vascular diseases.
5. The use of crystalline resolutional form 40-O-(2-hydroxyethyl)rapamycin according to claim 1 or 2 to obtain drugs for treatment or prevention of transplant rejection of an organ or tissue, autoimmune diseases, inflammatory conditions, asthma, proliferative disorders, tumors, hyperproliferative vascular diseases.
6. The method of obtaining crystalline form 40-O-(2-hydroxyethyl)rapamycin according to claim 1, consisting in the crystallization of the 40-O-(2-hydroxyethyl)rapamycin from the solvent with a mixture of aliphatic hydrocarbons With H2n+2where n is 5, 6 or 7, followed by separation of the thus obtained crystals.
7. The method according to claim 6, where the solvent is ethyl acetate.
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention relates to a method for separation of high-molecular lactone-containing compound. Invention describes a method for separation of lactone-containing compounds wherein mixture of lactone-containing compound showing the main chemical structure as 1,14-dihydroxy-12-[2-(4-hydroxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacoz-18-ene-2,3,10,16-tetraone and at least one among (C2-C6)-alkenyl group and (C1-C6)-alkoxy-group as a side chain and similar compounds is subjected for one or both the following stages in any order: stage (A) of the mixture adsorption on non-ionic adsorbing resin and elution with an aqueous solvent containing silver ions; and stage (B) of the mixture absorption on basic aluminum oxide and elution with organic solvent for separation of each compound. Invention provides the development of effective method for separation of high-molecular compounds being without their chemical structure.
EFFECT: improved method for separation.
14 cl, 2 dwg, 2 tbl, 3 ex
SUBSTANCE: invention discloses pharmaceutical compositions containing substance effective as modulators of biological activity "induced by activation of lymphocytic immunomodulating molecule (AILIM)" (known also as "induced common stimulator (ICOS)"), in particular modulating transduction of AILIM-mediated signal.
EFFECT: achieved suppression, treatment, or prevention of rejection of transplant arising in case of transplantation of organ, a part thereof or tissue.
11 cl, 7 dwg
FIELD: organic chemistry, pharmacy, biochemistry.
SUBSTANCE: invention relates to new substituted 2H-pyrano[2,3-c] of the general formula (1) eliciting ability to inhibit activity of protein kinase. In the general formula (1) X represents oxygen atom or group NR3; R1 represents group -C(O)R4, optionally substituted and optionally condensed azaheterocycle; R2 represents optionally substituted hydroxyl group or optionally substituted amino-group; R3 represents hydrogen atom or inert substitute meaning optionally substituted low- or non-reactive radical including such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, (C2-C12)-alkoxyalkyl, (C2-C10)-alkylsulfinyl, (C2-C10)-alkylsulfonyl, -(CH2)-O-(C1-C7-alkyl), -(CH2)m-N(C1-C7-alkyl)n, aryloxyalkyl, heterocyclyl wherein m and n have value from 1 to 7; R4 represents optionally substituted amino-group or hydrogenated optionally substituted azaheterocycle. Also, invention relates to combinatory and focused libraries consisting of compounds of the present invention and designated for the search of compound-hits and compound-leaders prepared by screening of these libraries for using in preparing medicinal agents.
EFFECT: valuable medicinal properties of compounds.
8 cl, 2 tbl, 6 ex
FIELD: organic chemistry, vitamins, medicine, pharmacy.
SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.
EFFECT: valuable medicinal properties of compounds.
13 cl, 3 sch, 3 tbl, 6 ex
FIELD: medicine, transplantology.
SUBSTANCE: method involves applying (R)-ibuprofen methanesulfonamide and its nontoxic salts for preparing medicinal agents used for prophylaxis or treatment of ischemic, reprefusion and functional damages of transplanted organs. Invention provides prophylaxis such complications as delayed function of transplant arising in transplantation of organs.
EFFECT: valuable medicinal properties of medicinal agent.
5 cl, 5 tbl, 1 dwg, 2 ex
FIELD: medicine, infectious diseases.
SUBSTANCE: invention relates to a method for preparing capsule antigen of meliodosis pathogen eliciting anti-phagocytic activity. Method involves culturing the strain B. pseudomallei, inactivation, isolation of glycoprotein by gel-filtration and ion-exchange chromatography methods resulting to preparing glycoprotein with molecular mass 200 kDA consisting of 90% of carbohydrates, 10% of proteins and comprising 2.17% of nitrogen, 46.4% of carbon and 8.09% of hydrogen. Advantage of method involves preparing the purified glycoprotein eliciting anti-phagocytic activity.
EFFECT: improved method for preparing, valuable properties of antigen.
2 dwg, 5 ex
FIELD: medicine, therapy.
SUBSTANCE: invention relates to treatment of vasculitis and erythematosus lupus. Method involves administration of 15-deoxyspergualine or its analogous by two or more courses with break for 4 days to 5 weeks. Period between successive injections of preparation within the treatment course is up to 48 h and the treatment course is at least 5-7 days. Method provides high treatment effect and reducing the total dose of 15-deoxyspergualine or its analogous.
EFFECT: enhanced effectiveness of treatment.
25 cl, 2 dwg, 3 ex
FIELD: drugs, medicine.
SUBSTANCE: invention relates to application of 1-methylindolyl-3-thioacetic acid tris-(2-hydroxyethyl)ammonia salt, which is known hypolipidemic agent, as immunosuppressor. Present invention ales it possible to produce pharmaceuticals for transplanted organ and tissue rejection prophylaxis or treatment of various immune-associated diseases.
EFFECT: new drug for transplant rejection prophylaxis or treatment of immune-associated diseases.
3 tbl, 3 ex
SUBSTANCE: the present innovation deals with cyclosporin-containing and practically oil-free compositions being of immunosuppressive action. The composition contains a hydrophilic surface-active substance, a lipophilic component, a lipophilic surface-active substance and ethanol. As a hydrophilic surface-active substance this composition contains ether of fatty acid and polyoxyethylene sorbitane and product of either natural or hydrogenised castor oil and ethylenoxide; as a lipophilic component and lipophilic surface-active substance it contains ether of fatty acid and sorbitane. The suggested composition has been designed as a gelatinous capsule with solid covering. The present innovation solves the problem dealing with stability of galena compositions with cyclosporin: at treating with water the composition develops practically stable microemulsion.
EFFECT: higher efficiency of application.
11 cl, 2 ex
FIELD: antibiotics, pharmacy.
SUBSTANCE: invention relates to stabilization of rapamycin or rapamycin derivative with immunosuppressive properties and sensitive to oxidation. Method for stabilization involves addition of antioxidant to the purified rapamycin in small concentrations - below 1% as recalculated for rapamycin mass. Also, invention relates to a solid mixture containing rapamycin and antioxidant taken in the catalytic amount. Antioxidant represent preferably 2,6-di-tert.-butyl-4-methylphenol. The stabilized rapamycin shows high stability against oxidation, it can be stored as formulation without package before it's the following treatment and can be used in an unmodified form for preparing the required galenic composition.
EFFECT: improved stabilizing method.
14 cl, 3 dwg, 2 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to a pharmaceutical composition used in prophylaxis or treatment of diseases caused by thrombosis or thromboembolism. As active components the composition comprises 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or its pharmaceutically acceptable salt and aspirin. Also, invention relates to a set used in prophylaxis or treatment of diseases caused by thrombosis or thromboembolism that comprises 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or its pharmaceutically acceptable salt and aspirin for simultaneous or successive administration, to using 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or its pharmaceutically acceptable salt and aspirin in preparing a medicinal agent used in prophylaxis or treatment of diseases caused by thrombosis or thromboembolism, to a method for prophylaxis or treatment of diseases caused by thrombosis or thromboembolism. Method involves administration the indicated pharmaceutical composition in pharmacologically active doses in warm-blooded animals and to a method for prophylaxis or treatment of diseases caused by thrombosis or thromboembolism involving the simultaneous or successive administration of this composition in warm-blooded animals. Invention provides effective inhibition of thrombosis due to potentiation of effects and enhanced effectiveness in treatment of diseases caused by thrombosis and thromboembolism.
EFFECT: valuable medicinal properties of compositions.
20 cl, 2 tbl, 1 dwg, 2 ex