Crystals

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes crystals of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulphonyl)acetamide ("compound A"), as a form I of the compound A crystal, which shows diffraction peaks at 9.4 degrees, 9.8 degrees, 17.2 degrees and 19.4 degrees in its power X-ray diffraction spectrum, as a form II of the compound A crystal, which shows diffraction peaks at 9.0 degrees, 12.9 degrees, 20.7 degrees and 22.6 degrees in its power X-ray diffraction spectrum, as a form III of the compound A crystal, which shows diffraction peaks at 9.3 degrees, 9.7 degrees, 16.8 degrees, 20.6 degrees and 23.5 degrees in its power X-ray diffraction spectrum. There are also described methods for producing the forms I, II and III of the compound A crystal, based pharmaceutical composition and PGI2 receptor agonist agent, an accelerating agent for angiogenic therapy, gene engineering or autoimmune bone marrow transplantation, and an accelerating agent for angiogenesis for peripheral artery recovery or angiogenic therapy on the basis thereof; there are also described a preventive or therapeutic agent for a wide range of diseases and conditions.

EFFECT: preparing the new therapeutic agent for the wide range of diseases and conditions.

11 cl, 6 dwg, 6 tbl, 5 ex

 

[Technical field]

The present invention relates to crystalline 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]bucalossi}-N-(methyl-sulfonyl)acetamide (hereinafter designated as "compound a").

[Formula 1]

[Prior art]

Compound a has a very strong agonistic effect on prostacyclin PGI2 and exhibits an inhibitory effect on platelet aggregation, vasodilating effect, bronchodilatory effect, the effect of inhibiting the deposition of lipids, the effect of inhibiting the activation of leukocytes, etc. (see, for example, patent reference 1).

Namely, the compound And are useful as preventive or therapeutic agents in the case of transient ischemic attack (TIA), diabetic neuropathy, diabetic gangrene, peripheral circulatory disorders (e.g., chronic obstruction of the arteries, intermittent claudication, obstruction of peripheral blood vessels, vibration syndrome, Raynaud's disease), connective tissue diseases (eg, systemic lupus erythematous, scleroderma, mixed connective tissue disease, the syndrome of inflammation of blood vessels), occlusion/restenosis after percutaneous transluminal coronary angioplasty (RTSA), arteriosclerosis, thrombosis (e.g.�, the acute phase of thrombosis of cerebral vessels, pulmonary embolism), high blood pressure, pulmonary hypertension, ishemicheskogo disease (e.g., cerebral infarction, myocardial infarction), angina pectoris (e.g. stable angina, unstable angina), glomerulonephritis, diabetic nephropathy, chronic renal failure, allergic reactions, asthma, ulcers, pressure ulcers (bedsores), restenosis after coronary angioplasty, such as atherectomy and stent implantation, thrombocytopenia due to dialysis, in the case of diseases that cause fibrosis of organs or tissues [e.g., renal failure (e.g., tubulointerstitial nephritis), respiratory diseases (e.g., interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease), diseases of the digestive tract (e.g., liver cirrhosis, viral hepatitis, chronic pancreatitis, scirrhous malignant tumor of the stomach), diseases of the cardiovascular system (e.g. myocardial fibrosis), diseases of bones and joints (e.g., bone marrow fibrosis and rheumatoid arthritis), skin diseases (e.g., surgical scar, burn scar, keloid and hypertrophic scar), post-Natal illness (e.g. hysteromyoma), zābol�ing the urinary tract (for example, prostatic hypertrophy), other diseases (e.g., Alzheimer's disease, sclerodermia peritonitis, type I diabetes and postoperative spike bodies)], in the case of erectile dysfunction (for example, diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after intrapelvic surgery removal of prostate and vascular erectile dysfunction associated with aging and atherosclerosis), inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease, intestinal tuberculosis, ischemic colitis and intestinal ulcer associated with Behcet's disease)in case of gastritis, gastric ulcer, ischemic ophthalmopathy (e.g., occlusion of retinal artery, occlusion of retinal vein, ischemic optic neuropathy) sudden hearing loss, avascular bone necrosis, gastrointestinal lesions induced by administration of nonsteroidal anti-inflammatory drugs (such as diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, Ketoprofen, naproxen, celecoxib) (there is no specific limitation gastrointestinal lesions, since this defeat, peavley�ease in the duodenum, the small intestine and the large intestine, and examples include mucous membranes, such as erosion and ulcer arising in the duodenum, the small intestine and the large intestine), and in the case of symptoms associated with spinal stenosis of lumbar region (for example, paralysis, weak activity sensory perception, pain, numbness, reduced movement capability, etc., associated with stenosis cervical spinal stenosis thoracic spinal stenosis of the lumbar spinal canal, with undifferentiated spinal stenosis or sacral stenosis) and others (see, for example, in patent references 1 through 6). In addition, compound a is used as the accelerating means in angiogenic therapy, such as gene therapy or autologous bone marrow transplantation, as a means for accelerating angiogenesis during recovery of peripheral artery or angiogenic therapy, etc. (see, for example, in the patent reference 1).

As noted above, despite the fact that the usefulness of the compounds As therapeutic agents in the above-mentioned diseases known, there is no link where it is described or suggested about the possibility of the existence of crystals of compound A.

[Links to previous liquid crystal�ü machinery]

[Patent references]

[Patent reference 1] WO2002/088084

[Patent reference 2] WO2009/157396

[Patent reference 3] WO2009/107736

[Patent reference 4] WO2009/154246

[Patent reference 5] WO2009/157397

[Patent reference 6] WO2009/157398

[The invention]

[Problem solved by the invention]

The main objective of the present invention is to provide a new crystalline form of compound A. in addition, the present invention is the provision of a method for producing crystal and pharmaceutical composition containing the crystal as the active ingredient.

[Means of solution]

It is hoped that the contents of the drug is an object of high quality, constant exposure to which can always be demonstrated, and is a form, which is easy to work in industry. The present inventors serious approach to the study of this aspect. As a result the present inventors have discovered a new crystalline form of the compound, and completed the present invention.

The present invention includes, for example, the following paragraphs(1)-(4).

(1) the Form-I crystal of compound A, which shows diffraction peaks in the spectrum of the powder x-ray diffraction of compound A (hereinafter in this document abbreviated as "Shape-I Christa�La of the invention") for the following values of angles of diffraction 2θ: 9.4°, 9.8 degrees, 17.2 degrees and 19.4 degrees, the range of x-ray powder diffraction obtained using Cu α radiation (λ=1,54 Å),

(2) Form-II crystal of compound A, which shows diffraction peaks in the spectrum of the powder x-ray diffraction of compound A (hereinafter in this document abbreviated as "Form-II crystal of the invention") for the following values of angles of diffraction 2θ: 9.0 degrees, 12.9 degrees, 20.7 degrees and 22.6 degrees, the range of x-ray powder diffraction obtained using Cu α radiation (λ=1,54 Å),

(3) Form-III crystal of compound A, which shows diffraction peaks in the spectrum of the powder x-ray diffraction of compound A (hereinafter in this document abbreviated as "Form-III crystal of the invention") for the following values of angles of diffraction 2θ: 9.3°, 9.7°, 16.8°, 20.6 degrees and 23.5 degrees, the range of x-ray powder diffraction obtained using Cu α radiation (λ=1,54 Å),

(4) a Pharmaceutical composition comprising the crystal, one of the above (1) to (3), as an active ingredient (hereinafter in this document referred to as "pharmaceutical composition of the invention").

In the case where indicates the diffraction angle 2 theta (2θ) of the peak in the examples of the invention and in the claims, it should be understood that Yes�tion value is interpreted as the interval from the value equal to minus 0.2°, to the value equal to + 0.2°, and preferably of a value equal to minus 0.1°, to the value equal to a plus of 0.1°.

[Brief description of the drawings]

[Fig.1] shows the spectrum of x-ray powder diffraction of Form-I crystal of the invention. The vertical axis indicates the peak intensity (cps), and the horizontal axis indicates a diffraction angle (2θ [°]).

[Fig.2] shows the spectrum of x-ray powder diffraction of Form-II crystal of the invention. The vertical axis indicates the peak intensity (cps), and the horizontal axis indicates a diffraction angle (2θ [°]).

[Fig.3] shows the spectrum of x-ray powder diffraction of Form-III crystal of the invention. The vertical axis indicates the peak intensity (cps), and the horizontal axis indicates a diffraction angle (2θ [°]).

[Fig.4] shows a scanning electron micrograph of the Form-I crystal of the invention.

[Fig.5] shows a scanning electron micrograph of the Form-II crystal of the invention.

[Fig.6] shows a scanning electron micrograph of the Form-III crystal of the invention.

[Mode for carrying out the invention]

Form-I crystal of the invention is characterized in that it shows diffraction peaks at 9.4 degrees, 9.8 degrees, 17.2 degrees and 19.4 �of Ragusa in the spectrum of the powder x-ray diffraction of compound A.

Form-II crystal of the invention is characterized in that it shows diffraction peaks at a high of 9.0 degrees, 12.9 degrees, 20.7 degrees and 22.6 degrees in the spectrum of the powder x-ray diffraction of compound A.

Form-III crystal of the invention is characterized in that it shows diffraction peaks at 9.3°, 9.7°, 16.8°, 20.6 degrees and 23.5 degrees in the spectrum of the powder x-ray diffraction of compound A.

A. Obtaining the compounds A

Compound a can be obtained, for example, the method described in the patent reference 1, and it can also be obtained according to the following method of producing.

[Formula 2]

Stage 1:

6-iodo-2,W-diphenylpyrazine can be obtained from 6-chloro-2,3-diphenylpyrazine through its reaction with sodium iodide. The reaction is conducted in the presence of acid in an organic solvent (e.g., ethyl acetate, acetonitrile, acetone, methyl ethyl ketone or in a solvent obtained by mixing them). Used acid represents, for example, acetic acid, sulfuric acid or the acid obtained by mixing them. The used amount of sodium iodide is usually a value in the range from 1 to 10 moles that are multiples relative to 6-chloro-2,3-diphenylpyrazine, preferably in the range from 2 to 3 molar times with�relationships. Reaction temperature varies depending on the nature of the substances used and the used acid, but typically may be in the range from 60°C to 90°C. the reaction Time varies depending on the nature of the substances used and the type of acid, and the reaction temperature, but generally may be in the range from 9 hours to 15 hours.

Stage 2:

5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine can be obtained from 6-iodo-2,3-diphenylpyrazine through its reaction with 4-hydroxybutyl(isopropyl)amine. The reaction is conducted in the presence of base in an organic solvent (e.g., sulfolane, N-methylpyrrolidone, N,N-dimethylimidazolidine, dimethylsulfoxide, or in solvent obtained by mixing them). Used the base is, for example, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate or base obtained by mixing them. The number of used 4-hydroxybutyl(isopropyl)amine may be, as a rule, value in the range from 1.5 to 5.0 moles that are multiples relative to 6-iodo-2,3-diphenylpyrazine, preferably in the range from 2 to 3 fold molar ratio. Reaction temperature varies depending on the nature of the substances used and the type of Foundation, but as a rule, can be in the range from 170°C to 20°C. The reaction time varies depending on the nature of the substances used and used from the base, and reaction temperature, but generally may be in the range from 5 hours to 9 hours.

Stage 3:

Compound a can be obtained from 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine by means of its reaction with N-(2-chloroacetyl)methanesulfonamide. The reaction is conducted in the presence of base in solvent (N-methylpyrrolidone, 2-methyl-2-propanol or in a solvent obtained by mixing them). Used the base is, for example,tert-butoxide potassium,tert-butoxide, sodium or base obtained by mixing them. The number of used N-(2-chloroacetyl)methanesulfonamide may be, as a rule, value in the range from 2 to 4 moles of a that are multiples relative to 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine, preferably in the range from 2 to 3 fold molar ratio. Reaction temperature varies depending on the nature of the substances used and the type of Foundation, but as a rule, can be in the range from -20°C to 20°C. the reaction Time varies depending on the nature of the substances used and used from the base, and reaction temperature, but generally may be in the range of from 0.5 hours to 2 hours.

Compounds used in �the quality of the starting materials in the above method of obtaining the compounds A, are known compounds or can be prepared by known methods.

V. receipt of Form-I crystal of the invention, the Form-II crystal of the invention and the Form-III crystal of the invention (hereinafter in this document, all together referred to as "crystals of the invention")

(I) the acquisition of Form-I crystal of the invention

Form-I crystal of the invention may be obtained, for example, in accordance with the method described below.

(1) stage of dissolution

This stage represents the stage of dissolution of the compound in the solvent by heating. Suitable for use in the solvent at this stage is, for example, an alcohol solvent, a mixed solvent of alcohol solvent and ketone solvent. Suitable for use of an alcohol solvent at this stage is, for example, methanol, ethanol, 2-propanol, preferably ethanol. Suitable for use ketone solvent at this stage is, for example, methyl ethyl ketone.

Particularly preferred to use the solvent at this stage is an ethanol or a mixed solvent of ethanol and methyl ethyl ketone. In the case of a mixed solvent of ethanol and methyl ethyl ketone ethanol is a number in the range of 1.5-Crat�(about./about.) up to 100-fold (about./about.) in relation to the amount of methyl ethyl ketone, preferably in the range from 3-fold (about./about.) up to 50-fold (about./vol.), more preferably in the range of 6-fold (about./about.) to 20-fold (about./vol.).

The total volume of solvent used at the stage is preferably in the range from 2-fold (ml/g) to 30-fold (ml/g) relative to the number of connections And, more preferably in the range from 3-fold (ml/g) to 20-fold (ml/g), still more preferably in the range from 4-fold (ml/g) up to 15-fold (ml/g). The heating temperature varies depending on the nature of the solvent and the used amount of the solvent, but generally it is lower than the boiling point of the used solvent, and is preferably in the range from 60°C to 100°C, more preferably in the range from 70°C to 90°C.

At this stage the solution can be filtered to remove insoluble components, if necessary. To prevent the filtering process of precipitation of crystals preferably filtering under pressure, using a funnel, equipped with a heating device. In the case where the filtrate is observed the precipitation of crystals, preferably the precipitate is dissolved again by re-heating after filtering.

(2) the stage of cooling

This stage represents the stage of�of ardania Form-I crystal of the invention from the solution, obtained in the above stage (1), by means of cooling. Stage is preferably carried out using the mold, equipped with a heating function and a mixing function.

Cooling temperature (the temperature at which accumulated the precipitated crystals) has a suitable value in the range from -10°C to 50°C, preferably in the range from 0°C to 20°C and more preferably in the range from 0°C to 10°C. the Stage is preferably carried out with cooling over time in the range from 3 hours to 95 hours, slowly reaching temperatures of cooling.

In addition, at this stage you can add the crystal is a seed crystal of Form-I crystal of the invention. In this case, preferably, the crystal is a seed crystal of Form-I crystal of the invention was added when the solution has cooled down to a temperature in the range from 60°C to 90°C. the Amount of crystal seeds of Form-I crystal of the invention is preferably in the range from 1% to 10% of the mass. regarding the number of compound A.

(3) stage of the accumulation of the crystals and drying

This stage represents the stage of accumulation of the precipitated crystals in the above stage (2) using known methods such as filtration, centrifuging, and drying of accumulated crystals.

The drying stage can be done �a standard way such as drying under reduced pressure through a drying reagent. Preferably, the carrying out drying under reduced pressure (e.g., 10 mm Hg.PT. or less), at a temperature in the range from 20°C to 70°C for a time from one hour to 48 hours.

In addition, based on the above stage (1), after partial precipitation of crystals by removal of the solvent in the process of heating and mixing the solution obtained in the above stage (1), Form-I crystal of the invention may be obtained through the implementation of the above stages (2) and (3). At the stage of removal of the solvent, it is possible to add the crystal is a seed crystal of Form-I crystal of the invention. The number of crystal seeds of Form-I crystal of the invention is preferably a value in the range from 0.1% to 10 wt%. regarding the number of connections As used in the above stage (1).

(II) the acquisition of Form-II crystal of the invention

Form-II crystal of the invention may be obtained, for example, in accordance with the method described below.

(1) stage of dissolution

This stage represents the stage of dissolution of the compound in the solvent by heating. Suitable for use in the solvent at this stage is, for example, an alcohol solvent, ketone solvent, solution�tel in the form of saturated hydrocarbon, the solvent in the form of simple ether and water, or a solvent obtained by mixing them. Preferred mixed solvent is a mixture solvent in the form of simple ether and the solvent in the form of saturated hydrocarbon or water, or a mixture of an alcoholic solvent and ketone solvent or water.

Used at this stage, the alcoholic solvent is, for example, alcohol with a straight or branched chain, having from one to 8 carbon atoms. Namely, the alcohol solvent may include methanol, ethanol,npropanol, isopropanol, 1-butanol, 2-butanol,tert-butanol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol. Used at this stage, the solvent in the form of simple ether may include tetrahydrofuran, 1,4-dioxane. Used at this stage, the solvent in the form of saturated hydrocarbon is, for example, alkane with a straight or branched chain having 6 to 8 carbon atoms, or cycloalkyl having 6 to 8 carbon atoms. Namely, the solvent in the form of saturated hydrocarbon may include heptane, octane, cyclohexane, Cycloheptane, cyclooctane. Used at this stage of ketone solvent is, for example, Premiery or branched chain, having from 3 to 8 carbon atoms. Namely, ketone solvent mo�et include acetone, the methyl ethyl ketone.

Total used at this stage of the solvent is advisable, the amount in the range from 2-fold (ml/g) to 20-fold (ml/g) ratio relative to the amount of compound A, preferably in the range from 3-fold (ml/g) up to 15-fold (ml/g), more preferably in the range of 5-fold (ml/g) to 10-fold (ml/g). The heating temperature varies depending on the nature of solvent, volume of solvent, but generally it is below the boiling point of the used solvent and is a value preferably in the range from 60°C to 90°C, more preferably in the range from 70°C to 80°C.

At this stage the solution can be filtered to remove insoluble components, if necessary. To prevent the filtering process of precipitation of crystals preferably filtering under pressure, using a funnel, equipped with a heating device. In the case where the filtrate is observed the precipitation of crystals, preferably the precipitate is dissolved again by re-heating after filtering.

(2) the stage of cooling

This stage represents the stage of deposition of Form-II crystal of the invention from the solution obtained in the above stage (1), by means of cooling. One hundred�Oia should preferably be performed with the use of the mold, equipped with a heating function and a mixing function.

Cooling temperature (the temperature at which accumulated the precipitated crystals) has a suitable value in the range from -10°C to 50°C, preferably in the range from 0°C to 20°C and more preferably in the range from 0°C to 10°C.

In addition, at this stage you can add the crystal is a seed crystal of Form-II crystal of the invention. The number of crystal seeds of Form-II crystal of the invention is preferably in the range from 1% to 10% of the mass. regarding the number of compound A.

In the case where the Form-II crystal of the invention obtained by using alcoholic solvent or by using as the solvent a mixture of an alcoholic solvent and ketone solvent, then you need to add the crystal is a seed crystal of Form-II crystal of the invention in the solution obtained in the above stage (1), and the solution to cool or necessary solution obtained in the above stage (1), fast cooling. Suitable is the cooling rate in the range from 60°C/h to 600°C/hour.

(3) stage of the accumulation of the crystals and drying

This stage represents the same stage as the method described in "(3) stage of the accumulation of the crystals and drying" in the above "(I) the acquisition of Form-I crystal of the invention."

(III) Obtaining Formi crystal of the invention

Form-III crystal of the invention may be obtained, for example, in accordance with the method described below.

(1) stage of dissolution

This stage represents the stage of dissolution of the compound in the solvent by heating. Suitable for use in the solvent at this stage is, for example, the solvent in the form of an ester, an aromatic hydrocarbon solvent. Suitable for use a solvent in the form of an ester at this stage is, for example, diethylcarbamyl,nbutyl acetate, isoamyl acetate,n-amyl acetate, preferablynbutyl acetate. Suitable for use aromatic hydrocarbon solvent at this stage is, for example, ethylbenzene.

The total volume of solvent used at the stage is preferably in the range of 5-fold (ml/g) to 30-fold (ml/g) relative to the number of connections And, more preferably in the range of 7-fold (ml/g) to 20-fold (ml/g), still more preferably in the range of 10-fold (ml/g) up to 15-fold (ml/g). The heating temperature varies depending on the nature of the solvent and the used amount of the solvent, but generally it is lower than the boiling point of the used solvent, and is preferably in diapazonom 40°C to 90°C, more preferably in the range from 50°C to 80°C.

At this stage the solution can be filtered to remove insoluble components, if necessary. To prevent the filtering process of precipitation of crystals preferably filtering under pressure, using a funnel, equipped with a heating device. In the case where the filtrate is observed the precipitation of crystals, preferably the precipitate is dissolved again by re-heating after filtering.

(2) the stage of cooling

This stage represents the stage of deposition of the Form-III crystal of the invention from the solution obtained in the above stage (1), by means of cooling. Stage is preferably carried out using the mold, equipped with a heating function and a mixing function.

A suitable cooling rate is in the range from 0.5°C/hour up to 120°C/h. Cooling temperature (the temperature at which accumulated the precipitated crystals) has a suitable value in the range from -10°C to 30°C, preferably in the range from 0°C to 20°C and more preferably in the range from 0°C to 10°C.

(3) stage of the accumulation of the crystals and drying

This stage represents the same stage as the method described in "(3) stage of the accumulation of the crystals and drying" � above "(I) the acquisition of Form-I crystal of the invention."

S.Medical use and pharmaceutical composition of the invention

Compound a according to the present invention has a very strong agonistic effect on prostacyclin PGI2 and exhibits an inhibitory effect on platelet aggregation, vasodilating effect, bronchodilatory effect, the effect of inhibiting the deposition of lipids, the effect of inhibition of leucocyte activation, etc.

In view thereof, the crystals of the invention or pharmaceutical composition of the invention suitable for use as a preventive or therapeutic agents in the case of transient ischemic attack (TIA), diabetic neuropathy, diabetic gangrene, peripheral circulatory disorders (e.g., chronic obstruction of the arteries, intermittent claudication, obstruction of peripheral blood vessels, vibration syndrome, Raynaud's disease), connective tissue diseases (eg, systemic lupus erythematous, scleroderma, mixed connective tissue disease, the syndrome of inflammation of blood vessels), occlusion/restenosis after percutaneous transluminal coronary angioplasty (RTSA), arteriosclerosis, thrombosis (for example, the acute phase of thrombosis of cerebral vessels, pulmonary embolism), high blood Yes�tion, pulmonary hypertension, ischemic diseases (e.g., cerebral infarction, myocardial infarction), angina pectoris (e.g. stable angina, unstable angina), glomerulonephritis, diabetic nephropathy, chronic renal failure, allergic reactions, asthma, ulcers, pressure ulcers (bedsores), restenosis after coronary angioplasty, such as atherectomy and stent implantation, thrombocytopenia due to dialysis, in the case of diseases that cause fibrosis of organs or tissues [e.g., renal failure (e.g., tubulointerstitial nephritis), respiratory diseases (e.g., interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease), diseases of the digestive tract (e.g., liver cirrhosis, viral hepatitis, chronic pancreatitis, scirrhous malignant tumor of the stomach), diseases of the cardiovascular system (e.g. myocardial fibrosis), diseases of bones and joints (e.g., bone marrow fibrosis and rheumatoid arthritis), skin diseases (e.g., surgical scar, burn scar, keloid and hypertrophic scar), post-Natal illness (e.g. hysteromyoma), diseases of the urinary tract (e.g., prostatic hypertrophy), other diseases (such as illness And�of lzgamer, sclerodermia peritonitis, type I diabetes and postoperative spike bodies)], in the case of erectile dysfunction (for example, diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after intrapelvic surgery removal of prostate and vascular erectile dysfunction associated with aging and atherosclerosis), inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease, intestinal tuberculosis, ischemic colitis and intestinal ulcer associated with Behcet's disease), in the case of gastritis, gastric ulcer, ischemic ophthalmopathy (e.g., occlusion of retinal artery, occlusion of retinal vein, ischemic optic neuropathy) sudden hearing loss, avascular bone necrosis, gastrointestinal lesions induced by administration of nonsteroidal anti-inflammatory drugs (such as diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, Ketoprofen, naproxen, celecoxib) (there is no specific limitation gastrointestinal lesions, since this defeat, appearing in the duodenum, the small intestine and the large intestine, and examples of it in�exclude a lesion of the mucous membrane, such as erosion and ulcer arising in the duodenum, the small intestine and the large intestine), and in the case of symptoms associated with spinal stenosis of lumbar region (for example, paralysis, weak activity sensory perception, pain, numbness, reduced movement capability, etc., associated with stenosis cervical spinal stenosis thoracic spinal stenosis of the lumbar spinal canal, with undifferentiated spinal stenosis or sacral stenosis). in addition, the crystals of the invention or pharmaceutical composition of the invention are also suitable for use as an accelerating means in angiogenic therapy, in the case of gene therapy or autologous bone marrow transplantation, as a means for accelerating angiogenesis during recovery of peripheral artery or angiogenic therapy, etc. If the crystals of the invention are used as a medicament, pharmaceutical composition of the invention is a crystal of the invention by themselves or contains crystals of the invention in pharmaceutically acceptable, nontoxic and inert carrier in an amount in the range from 0.1% to 99.5%, preferably in the range from 0.5% to 90%.

Examples of the carrier include solid�, semi-solid or liquid diluent, filler and other auxiliary means of pharmaceutical drug. They can be used individually or as mixtures of two or more of their representatives.

Pharmaceutical composition of the invention may be in any form of finished dosage forms for oral administration such as powder, capsules, tablets, coated with sugar-coated tablets, granules, diluted powder, suspension, liquid, syrup, elixir or a lozenge, and in the form of a medicinal product for parenteral administration, such as injection or suppository in solid or liquid dosage form with a single dose. It can also be in the form of drugs with a slow release. Among them are oral drugs such as tablets, are particularly preferred.

The powder can be made by turning the crystals of the invention in a corresponding small size.

Dilute the powder can be manufactured by the same method of turning the crystals of the invention in a corresponding small size and with subsequent mixing with a pharmaceutical carrier, which is similarly converted into a small size, such as carbohydrate food (such as,starch and mannitol). Wgusercpatrol in�society, preservative, a dispersing agent, the colorant, fragrant substance, etc. can optionally be added there.

Capsules can be manufactured by such a method, when the powder or dilute the powder, thus obtaining a powder is carried out as indicated above, or pellets, as will be described in connection with pills, used for filling a capsule shell, such as in the case of gelatin capsules. Also it is possible to manufacture by this method, when the powder or dilute the powder in powder form are mixed with a sliding substance or thinning additive such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol, followed by the filling process. In that case, when you add a substance to improve tablet disintegration or solubilizers agent such as the calcium salt of carboxymethylcellulose, maltamedia hydroxypropyl cellulose, the sodium salt of croscarmellose, the sodium salt of carboxymethylcel, calcium carbonate or sodium carbonate, the efficiency of a drug with capsules inside can be improved. It is also possible to fine powder of crystals of the invention was suspended/dispersed in vegetable oil, polyethylene glycol, glycerin� or surface-active substance and enclosed in a gelatin coating with obtaining a medicinal product in the form of hard capsules.

Tablets can be obtained by this method in which a powder mixture is prepared by adding the filler to the crystals of the invention that have been turned into powder and formed into pellets or grains, and then the substance to improve tablet disintegration or moving substance is added to the same, and then form tablets.

The powdery mixture can be obtained by mixing, respectively, of powdered crystals of the invention with a diluent or base. If necessary there can be added a binder (such as sodium salt of carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, gelatin, polyvinylpyrrolidone or polyvinyl alcohol), a thinning Supplement to slow solidification (such as paraffin), reabsorbing additive (such as a Quaternary salt), absorbent (such as bentonite or kaolin), etc.

The powdery mixture can be formed into pellets by this method, first, moisturize by using a binder such as syrup, starch paste, gum, solution of cellulose or polymer solution, a mixture under stirring and dried then milled. Instead of turning powder into granules as such is also possible to use powder in teletrauma car, and �alwaysas result in grains of incomplete forms, constitute the basis for obtaining granules. If you add a moving substance, such as stearic acid, stearate, talc or mineral oil, thus obtained pellets it is possible to prevent adhesion of the granules to each other.

Tablets can also be obtained by this method in which the crystals of the invention are mixed with an inert carrier liquid and then immediately make them with pills, without the implementation of the above stages of obtaining from them pellets or grains.

Thus obtained tablets may be film-coated or sugar-coated. Also possible to use a transparent or translucent protective coating, made of shellac sealed film coating made of sugar or polymeric material, or smooth coating, made of wax.

In the case of other oral drugs such as a liquid solution, syrup, lozenge, or elixir, it is also possible their production in the form of finished dosage forms with one-time dose, in which a predetermined quantity contains a predetermined amount of the crystal of the present invention.

The syrup can be obtained by dissolving crystals of the invention in a suitable aqueous solution vkusoaromaticheskih substances. The elixir can be obtained by using non-toxic SP�stowage media.

The suspension can be obtained by dispersing crystals of the invention in a non-toxic carrier. If necessary you can also add solubilizers agent or emulsifier such as ethoxylated isostearoyl alcohol and the ester polyoxyethylenesorbitan), preservative or substance that provides flavor properties (such as peppermint oil or saccharin).

If necessary dosage form with a single dose for oral administration can be obtained in the form of microcapsules. Dosage form also can be coated or encapsulated in a polymer or wax to obtain a prolonged action or sustained release of the active ingredient.

Parenteral drug may be in the form of liquid formulations with a one-time dose for subcutaneous, intramuscular or intravenous injection as a solution or suspension. Parenteral drug can be obtained in this method where a predetermined amount of the crystals of the invention are suspended or dissolved in a non-toxic liquid media that is appropriate to the purpose of injectione, such as water or an oil medium, and then the suspension or solution is sterilized. There can be added non-toxic with�ü or her solution to give the injection solution isotonic properties. You can also add a stabilizer, preservative, emulsifier and similar products.

Suppositories can be obtained by dissolving or suspending crystals of the invention in low-melting and water-soluble or insoluble solid substance, such as polyethylene glycol, cacao butter, semisynthetic grease/oil (such as Witepsol (registered trademark)), high molecular weight ester such as an ester of ministervalletta) or a mixture thereof.

Although the dose may vary depending on characteristics of the patient's condition, such as body weight or age, the method of administration, or the severity of symptoms, the dose in the range of 0.001 mg to 100 mg per day in terms of the number of crystals of the invention generally is an acceptable dose for adults, and the dose range is from 0.01 mg to 10 mg is a more preferred dose. In some cases, a smaller dose than the above may be sufficient or, on the other hand, a larger dose than specified above may be necessary. Also may be inserted several times a day or you can enter it at intervals of from one to several days.

[Examples]

The present invention is described in more detail by reference to examples and test examples, refurbished new descriptio�e below; thus the present invention should not in any way be limited by these examples.

For powder x-ray diffractometry used the device Rigaku Corporation's RINT-Ultima III (the mirror of the x-ray tube anode: Cu, voltage: 40 kV, current: 40 mA, scanning speed: 4 ° /min).

Example 1:The acquisition of Form-I crystal of the invention

Ethanol (440 ml) was added to compound A (40 g) and the mixture was stirred and heated in an oil bath to a temperature of from 100°C to 110°C. After dissolving the compounds And ethanol (280 ml) was removed. The resulting concentrate was stirred and heated to boiling on a water bath with a temperature of 80°C for 1 hour. The solution was gradually cooled to 10°C for 20 hours with stirring and the precipitated crystalline substance was separated by filtration. The obtained crystalline substance was washed with a small amount of ethanol (48 ml) and dried under reduced pressure at 60°C, receiving the Form-I crystal of the invention (38,93 g, 97.3 per cent). Range of powder x-ray diffraction of Form-I crystal of the invention shown in Fig.1.

T. PL.: 140,4°C (Pharmacopoeia of Japan, method 1 of Determining the melting temperature)

Example 2:The acquisition of Form-I crystal of the invention

Ethanol (99 g) and methyl ethyl ketone (11 g) was added to compound A (20 g) and heated to 77°C for dissolution SOEDINENIYa and then the solution was gradually cooled to 10°C for 20 hours. During the cooling process, to the solution was added a small amount of Form-I crystal of the invention. After cooling, the precipitated crystalline substance was separated by filtration, washed with ethanol and dried under reduced pressure, obtaining the Form-I crystal of the invention (18,72 g, 93,6%).

Example 3:The acquisition of Form-II crystal of the invention

Ethanol (550 g) and methyl ethyl ketone (55 g) was added to compound A (100 g) was heated to 77°C and filtered under pressure, while maintaining the heat. While stirring the resulting filtrate was cooled from 70°C to 0°C, which lasted 30 minutes, and after reaching 0°C, it was stirred at 0°C for 2.5 hours. The precipitated crystalline substance was separated by filtration, washed with ethanol (200 ml) and dried under reduced pressure. Ethanol (99 g) and methyl ethyl ketone (11 g) was added to the obtained crystalline substance (20 g), was heated to 70°C and kept at 70°C for 1 hour, and gradually cooled to 10°C, which lasted 20 hours; and after reaching 10°C was stirred at 10°C for 1 hour. The precipitated crystalline substance was separated by filtration, washed with ethanol (40 ml) and dried under reduced pressure, obtaining the Form-II crystal of the invention (18,73 g, 93.7 per cent). Range of powder x-ray diffraction of Form-Cristalla of the invention shown in Fig.2.

T. PL: 135,2°C (Pharmacopoeia of Japan, method 1 of Determining the melting temperature)

Example 4:The acquisition of Form-II crystal of the invention

Ethanol (99 g) and methyl ethyl ketone (11 g) was added to compound A (20 g) and heated to 77°C to dissolve the compound, and then the solution was gradually cooled to 10°C for 20 hours. During the cooling process, to the solution was added a small amount of Form-II crystal of the invention. After cooling, the precipitated crystalline substance was separated by filtration, washed with ethanol and dried under reduced pressure, obtaining the Form-II crystal of the invention (19,70 g, 98.5 per cent).

Example 5:The acquisition of Form-III crystal of the invention

n-butyl acetate (500 ml) was added to compound A (36,7 g) and heated to 75°C to dissolve the compound, and then cooled to 5°C. Then the process was conducted by heating to 60°C and cooling to 5°C and the process repeated. The precipitated crystalline substance was separated by filtration, washed with a small amount of isopropylacetate (50 ml) and dried under reduced pressure, obtaining the Form-III crystal of the invention (29.0 g, 79.0 percent). Range of powder x-ray diffraction of Form-III crystal of the invention shown in Fig.3.

T. PL: 138,0°C (Pharmacopoeia of Japan, method 1 of Determining the melting temperature)

Crystalline substances from�retenu, used in the following test examples 1 to 3 were obtained as follows.

Form-I crystal of the invention, the Form-II crystal of the invention and the Form-III crystal of the invention obtained by the same methods as in example 2, example 4 and example 5, respectively.

Test example 1:Measurement of particle size

(1) measuring the distribution of particle size for crystalline substances of the invention

After dispersing the substance (10 ml) was added to the crystals of the invention (20 mg) and then shook the crystals of the invention have dispersively using ultrasonic waves. The distribution of particle sizes of the crystals of the invention was measured using a HORIBA LA-910. The result is presented in table 1.

Used dispersing the substance is a filtered saturated solution of the compound And about 0.1./vol.% an aqueous solution of Polysorbate 80.

[Table 1]
Crystalline formD10D50D90
1Form-I crystal of the invention5,612,825,8
2Form-II crystal of the invention5,211,322,0
3Form-III crystal of the invention4,38,014,4
D10: cumulative particle diameter defined by sieve analysis, with a 10% volume ratio [µm]
D50: cumulative particle diameter defined by sieve analysis, at 50% volume ratio [µm]
D90: cumulative particle diameter defined by sieve analysis at 90% volume ratio [µm]

(2) Observation of crystalline compounds of the invention using a scanning electron microscope

The crystals were observed under scanning electron microscope (HITACHI HIGH TECHNOLOGIES TM-1000 Miniscope).

Fig.4 shows a micro-image of a scanning electron microscope to Form-I crystal of the invention. Fig.5 shows the same micro-image for the Form-II crystal, and Fig.6 shows the same micro-image for the Form-III crystal.

Proceeding from the results of the above (1) and (2), it was concluded that the particle size of Form-I crystal of the invention is greater than in the case of Form-II and Form-III Krista�fishing.

Test example 2:Determination of the residual content of solvent in the crystals of the invention

The concentration of the residual solvent contained in the crystals of the invention was determined using the following measurement conditions. The result is presented in table 2.

(Measurement conditions)

Tools for gas chromatography

Detector: Flame ionization detector

Column: Capillary column

Column temperature: 150-230°C

Injector temperature: 200°C

Temperature detector: 300°C

The carrier gas:Helium

[Table 2]
Crystalline formSolventContent
(M. D.)
1Form-I crystal of the inventionEthanol
Methyl ethyl ketone
371
82
2Form-II crystal of the inventionEthanol
Methyl ethyl ketone
2169
246
3Form-III crystal of the invention93
2781

Although each crystal form and does not contain any significant amounts of residual solvents, the amount of residual solvent in the Form-I crystal of the invention was smaller than in the case of Form-II and Form-III.

Test example 3:The effect of the removal of impurities during recrystallization

The efficiency of removal of impurities in the process of recrystallization of each crystalline form was determined using the following measurement conditions (reversed-phase liquid chromatography)

(Measurement conditions)

Tools for HPLC

Detector: absorption spectrophotometric detector in the ultraviolet region

Column: octadecylsilyl (ODS) column

Column temperature: 40°C

Mobile phase: a Mixture of water, acetonitrile and methanesulfonic acid.

Purity (%) of each crystal of compound A was calculated by the following equation

Purity (%)=(peak Area of compound (A)/(Total area)×100.

The relative amount of impurities removed (%) for each crystal was calculated by the following equation

The relative amount of impurities removed (%)={[(Purity of each crystal compounds (A)-(Purity unpurified compound (A)]/[100-(Purity neochi�military compounds A)]}×100.

The result is presented in table 3.

[Table 3]
Crystalline formThe purity of compound A (%)The relative amount of impurities removed (%)
Untreated substanceTo 98.04
1Form-I crystal of the invention99,5175
2Form-II crystal of the invention99,3366
3Form-III crystal of the invention98,9747

From the results shown in table 3, it is seen that the removal efficiency of impurities in the case of Form-I crystal of the invention was higher than that of a Form-II and III crystals.

Test example 4:Study on the selection of the solvent for the crystallization of compounds And

Research crystallization of compounds And was performed in accordance with Pref�denna following methods (1) and (2).

(1) Solvent for crystallization (see tables 4 and 5) was added to the mix Andand the mixture was stirred at 50°C for 60 minutes. The resulting mixture was filtered. After filtration dedicated mother liquor was stirred at 60°C for 30 minutes and cooled to 5°C for 11 hours. After stirring at 5°C for 72 hours, the precipitated solid substance was separated by filtration. The solid is dried at 20°C under reduced pressure, resulting in the obtained solid substance.

Spectra were recorded powder x-ray diffraction of the obtained crystals and determined the shape of each crystal.

The results are presented in table 4 (study of individual solvents) and table 5 (study of mixed solvents).

In the study of the mixed solvents (table 5) each solvent were mixed and used in equal quantities.

[Table 4]
Solvent for crystallizationCrystalline form
1tert-butyl methyl etherThe solid is not vypadalo sediment
2AcetoneForm-II crystal of the invention+Form-III crystal of the invention
3ChloroformThe solid is not precipitated
4MethanolForm-II crystal of the invention+Form-III crystal of the invention
5TetrahydrofuranForm-II crystal of the invention+Form-III crystal of the invention
6Isopropyl etherThe solid is not precipitated
72-MethyltetrahydrofuranForm-II crystal of the invention+Form-III crystal of the invention
8EthanolThe solid is not precipitated
9CyclohexaneThe solid is not precipitated
10AcetonitrileForm-II crystal and�gaining+Form-III crystal of the invention
111,2-DichloroethaneThe solid is not precipitated
12TorbensonForm-II crystal of the invention+Form-III crystal of the invention
131,2-DimethoxyethanForm-II crystal of the invention+Form-III crystal of the invention
14MethylcyclohexaneThe solid is not precipitated
15NitromethaneForm-II crystal of the invention+Form-III crystal of the invention
161,4-DioxaneThe solid is not precipitated
173,3-Dimethyl-2-butanoneForm-II crystal of the invention+Form-III crystal of the invention
18IsobutanolThe solid is not precipitated
19TolueneForm-II crystal from�retenu+Form-III crystal of the invention
20DiethylcarbamylForm-III crystal of the invention
21nButyl acetateForm-III crystal of the invention
22ChlorobenzeneForm-II crystal of the invention+Form-III crystal of the invention
23EthylbenzeneThe solid is not precipitated
24p-xyleneThe solid is not precipitated
25Isoamyl acetateForm-III crystal of the invention
26n-amyl acetateForm-III crystal of the invention
27Methyl phenyl etherForm-II crystal of the invention+Form-III crystal of the invention
28CyclohexanoneThe solid is not precipitated
29bis(2-Methoxyethoxy) etherForm-III crystal of the invention
301,3,5-TrimethylbenzoylAmorphous substance
314-Hydroxy-4-methyl-2-pentanonForm-II crystal of the invention+Form-III crystal of the invention
322,6-Dimethyl-4-heptanonForm-III crystal of the invention

[Table 5]
Solvent for crystallizationCrystalline form
1ChloroformThe solid is not precipitated
Acetonitrile
2TetrahydrofuranForm-II crystal of the invention
Cyclohexane
3EthylformateFort�a-II crystal of the invention+Form-III crystal of the invention
Water
4MethanolThe solid is not precipitated
Water
5AcetonitrileForm-II crystal of the invention+Form-III crystal of the invention
Water
61,2-dimethoxyethanForm-II crystal of the invention+Form-III crystal of the invention
Water
7EthanolForm-II crystal of the invention
Water
8CyclohexaneForm-II crystal of the invention
1,4-dioxane
92-propanolForm-II crystal of the invention
Water
10CyclohexanoneSolid n� to precipitate
Tetrahydrofuran
111-propanolForm-II crystal of the invention
Water
121,4-dioxaneForm-II crystal of the invention
Water
132-butanolForm-II crystal of the invention
Water
14CyclohexanoneForm-II crystal of the invention+Form-III crystal of the invention
Cyclohexane
151-butanolForm-II crystal of the invention
Water
16CyclohexanoneForm-II crystal of the invention+Form-III crystal of the invention
1,4-dioxane

(2) Further research was performed using the following method with such conditions, �ri which crystalline substances not precipitated (see tables 4 and 5), and with conditions similar to them. The solvents used in further experiments was chosen taking into account the toxicity, solubility of compounds A and possibility of application in industry.

The amount of solvent that is smaller compared to the above test (1) was added to the compound A and the mixture was heated to 75°C with stirring. After dissolving the compounds And the mixture stirred at 65°C for a time from 5 to 8 hours. The mixture was cooled to 20°C for 9 hours. The precipitated crystalline substance was separated by filtration and dried at 70°With under reduced pressure, whereby was obtained a crystalline substance. The results are presented in table 6.

In the study of the mixed solvents, each solvent were mixed and used in equal quantities.

[Table 6]
Solvent for crystallizationCrystalline form
1tert-butyl methyl etherThe solid is not precipitated
2Isopropyl ether The solid is not precipitated
3CyclohexaneThe solid is not precipitated
4EthanolForm-I crystal of the invention
52-propanolForm-I crystal of the invention+Form-III crystal of the invention
6EthylbenzeneForm-III crystal of the invention
7MethanolForm-I crystal of the invention+Form-III crystal of the invention
Water
8CyclohexanoneThe solid is not precipitated
Tetrahydrofuran

According to the results of the above experiments (1) and (2) concluded that the Form-II crystal of the invention and the Form-III crystal of the invention can be obtained from various solvents.

On the other hand, crystalline materials that contain a Form-I crystal of the invention can be obtained tol�to from alcoholic solvents, and the Form-I crystal of the invention with high purity can be obtained from ethanol.

1. Form-I crystal of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]bucalossi}-N-(methyl-sulfonyl)acetamide, showing diffraction peaks in the spectrum of the powder x-ray diffraction, at least with the following diffraction angles 2θ: 9.4 degrees, 9.8 degrees, 17.2 degrees and 19.4 degrees, where the range of x-ray powder diffraction obtained using Cu α radiation.

2. Form-II crystal of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]bucalossi}-N-(methyl-sulfonyl)acetamide, showing diffraction peaks in the spectrum of the powder x-ray diffraction, at least with the following diffraction angles 2θ: 9.0 degrees, 12.9 degrees, 20.7 degrees and 22.6 degrees, where the range of x-ray powder diffraction obtained using Cu α radiation.

3. Form-III crystal of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]bucalossi}-N-(methyl-sulfonyl)acetamide, showing diffraction peaks in the spectrum of the powder x-ray diffraction, at least with the following diffraction angles 2θ: 9.3°, 9.7°, 16.8°, 20.6 degrees and 23.5 degrees, where the range of x-ray powder diffraction obtained using Cu α radiation.

4. Pharmaceutical composition containing crystalline prophetic�STV according to any one of claims.1-3 as an active ingredient.

5. Agonistic agent in respect of the PGI2 receptor containing the crystalline substance according to any one of claims.1-3 as an active ingredient.

6. Prophylactic or therapeutic agent against transient ischemic attack, diabetic neuropathy, diabetic gangrene, peripheral circulatory disorders, diseases of the connective tissues, occlusion/restenosis after percutaneous transluminal coronary angioplasty (RTSA), arteriosclerosis, thrombosis, high blood pressure, pulmonary hypertension, ischemic disease, stroke, glomerulonephritis, diabetic nephropathy, chronic renal failure, allergic reactions, asthma, ulcers, pressure ulcers (bedsores), restenosis after coronary angioplasty, such as atherectomy and stent implantation, thrombocytopenia due to dialysis, diseases that cause fibrosis of organs or tissues, erectile dysfunction, inflammatory bowel disease, gastritis, gastric ulcer, ischemic ophthalmopathy, sudden hearing loss, avascular bone necrosis, gastrointestinal lesions induced by administration of nonsteroidal anti-inflammatory drugs, and in the case of symptoms associated with spinal stenosis of the lumbar area, include�in her crystalline substance according to any one of claims.1-3 as an active ingredient.

7. Accelerating agent for angiogenic therapy, gene therapy or autologous bone marrow transplantation containing crystalline substance according to any one of claims.1-3 as an active ingredient.

8. Accelerating agent for angiogenesis during recovery of peripheral artery or angiogenic therapy containing crystalline substance according to any one of claims.1-3 as an active ingredient.

9. A method of producing Form-I crystal of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]bucalossi}-N-(methyl-sulfonyl)acetamide, characterized in that 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]bucalossi}-N-(methyl-sulfonyl)acetamide was dissolved in ethanol under heating, and then crystallized by gradual cooling of the solution from 80°C to 10°C for 20 hours.

10. A method of producing Form II crystal of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]bucalossi}-N-(methyl-sulfonyl)acetamide, characterized in that 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]bucalossi}-N-(methyl-sulfonyl)acetamide crystallized from an alcoholic solvent, ketone solvent, a solvent which is a saturated hydrocarbon solvent which is a simple ether, and water or a solvent obtained by mixing them.

11. A method of producing the Form-III crystal of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino�about]bucalossi}-N-(methyl-sulfonyl)acetamide characterized in that 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]bucalossi}-N-(methyl-sulfonyl)acetamide crystallized from the solvent, representing an ester, or a solvent, which represents an aromatic hydrocarbon.



 

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FIELD: medicine, pharmaceutics.

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wherein J means ethylene or lower alkynylene; L means a bond; M means a bond; X means -(CH2)m-, -(CH2)m-O- or -(CH2)m-NR2- (wherein m is an integer of 0 to 3, and R2 means hydrogen); D means -NR3-, wherein R3 means hydrogen; and E means amino, or its pharmaceutically acceptable salt. The compounds of formula (I) are used for preparing a pharmaceutical agent or a pharmaceutical composition for treating or preventing the VAP-1 related diseases.

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2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of synthetic biologically active heterocyclic substances as purinoreceptor antagonists, said substances having antagonist activity on purinoreceptors and being a product of modifying pyridoxin, particularly n-(1,5-dihydro-3-R1-3-R2-8-methyl-9-hydroxy-[1,3]dioxepino[5,6-c]pyridinyl-6-azo)phenyl sulphonic acid and salt forms thereof of general formula I , where R1 is a hydrogen atom or methyl, R2 is methyl, isopropyl.

EFFECT: compounds of the given formula have high antagonist activity on purinoreceptors and can be used in medicine and veterinary.

2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

possessing properties of binding with delta opioid receptors. In formula I R1 is selected from the group, consisting of phenyl, pyridinyl and thiazolyl, with R1 being optionally substituted with one or two substituents, independently selected from the group, consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanogroup; in addition, R1 is optionally substituted with di(C1-4alkyl)aminocarbonyl; Y represents O, S, H3, vinyl, ethinyl or S(O); R2 represents a substituent, selected from the group, consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy; Ra represents hydrogen or methyl; R3 is selected from the group, consisting of pyrrolidin-2-ylmethyl; pyrrolidin-3-ylmethyl; piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperidin-2-ylethyl, piperidin-3-ylethyl, piperidin-4-ylethyl, pyridine-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl; morpholin-2-ylmethyl, morpholin-3-ylmethyl, imidazolylmethyl, thiazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[2.2.2]octanyl, guanidinylethyl, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylaminobut-2-yl, piperidin-3-yl, piperidin-4-yl and pyrrolidin-3-yl; with piperidin-3-yl being optionally substituted on a carbon atom with phenyl; with pyrrolidin-2-yl in pyrrolidin-2-yl-methyl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted on a nitrogen atom with methyl, phenylmethyl, phenethyl or methylcarbonyl.

EFFECT: compounds can be used in the treatment of pain, induced by diseases or conditions, such as osteoarthritis, rheumatoid arthritis, migraine, burn, fibromyalgia, cystitis, rhinitis, neuropathic pain, idiopathic neuralgia, toothache, etc.

24 cl, 3 tbl, 19 ex

Hypotensive means // 2554815

FIELD: medicine.

SUBSTANCE: invention represents a hypotensive means, which contains felodipinum as an active component, as well as target additional components: mesoporous silicon dioxide, lactose, hypromeloza. Realisation of the invention ensures the high technological efficiency of the claimed medical means production with the provision of a prolonged release of an active substance with the application of available components. Felodipinum is included into spherical particles with a highly developed mesoporous structure of silicon oxide.

EFFECT: increase of stability in storage and protection from unfavorable environmental factors.

4 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of structural formula I

which can be used for protecting cardiomyocytes or for preventing or treating a disease or a disorder related to cardiomyocyte apoptosis. In formula I A represents =S, -SR4 or =O, X represents F, Cl, Br or I, R1 represents phenyl, R2 and R3 are connected to form morpholine, and R4 represents C1-C6-alkyl.

EFFECT: invention refers to using the compound for producing the therapeutic agent for protecting cardiomyocytes or for preventing or treating a disease or a disorder related to cardiomyocyte apoptosis, and to the method for producing the above compounds.

8 cl, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I, possessing ability of binding with delta-opioid receptors. In formula R1 is selected from the group, consisting of i) phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxyl, di(C1-4alkyl), aminocarbonyl, chlorine and fluorine, in such a way that only one di(C1-4alkyl)aminocarbonyl is present; ii) naphthyl; iii) pyridinyl, optionally substituted with one substituent, selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxy, fluorine, chlorine and cyano; iv) pyrimidin-5-yl; v) furanyl; vi) thienyl; vii) 5-oxo-4,5-dihydro-[1,2,4]oxodiazol-3-yl; and viii) di(C1-2alkyl)aminocarbonyl; Y represents ethyl, vinyl or bond; or Y represents O, when R1 represents optionally substituted phenyl, where substituent represents C1-4alcoxy; R2 represents phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, fluorine, chlorine and cyano, trifluoromethoxy and hydroxy; or R2 represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alcoxycarbonyl or carboxysubstituent; R3 is selected from the group, consisting of i) 3-aminocyclohexyl; ii) 4-aminocyclohexyl; iii) piperidin-3-yl; iv) piperidin-4-yl; v) pyrrolodin-2-yl-methyl, in which pyrrolodin-2-yl is optionally substituted by 3-rd or 4-th position with one or two fluorine-substituents; vi) azetidin-3-yl; vii) 2-(N-methylamino)ethyl; viii) 3-hydroxy-2-aminopropyl; ix) piperidin-3-yl-methyl; x) 1-azabicyclo[2.2.2]octan-3-yl; and xi) 8-azabicyclo[3.2.1]octan-3-yl; or R3 together with Ra and nitrogen atom, which they both are bound to, form piperazinyl, optionally substituted with 4-C1-4alkyl; Ra represents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted with azetidin-3-yl.

EFFECT: compounds can be used in treatment of pain in the range from medium to strong, caused by diseases or conditions, such as osteoarthritis, migraine, burn, fibromyalgia, cystitis, rhenite, neuropathic pain, idiopathic neuralgia, toothache, etc.

21 cl, 4 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 3-phenylpropionic acid derivatives of formula

wherein R1A represents hydrogen, methyl, ethyl, cyclopropyl or cyclobutyl, R1B is hydrogen or methyl, R2A represents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl, R2B is hydrogen or methyl or R1A and R2A are combined together, and in a combination to carbon atoms to which they are attached, form a cyclopropyl ring of formula

wherein R1B and R2B have the values as specified above, or R2A and R2B are combined together, and in a combination to a carbon atom, to which they are attached, form a cyclic group of formula or

wherein n means a number 1 or 2, R3 is hydrogen, fluorine or methyl, R4 represents hydrogen, fluorine, chlorine or a cyanogroup, R5A represents methyl, R5B is trifluoromethyl or R5A and R5B are combined together, and in a combination to a carbon atom, to which they are attached, form a difluorosubstituted cycloalkyl ring of formula or

R6 represents chlorine, alkyl with 1-4 carbon atoms, alkenyl with 2-4 carbon atoms, cyclopropyl or cyclobutyl; alkyl with 1-4 carbon atoms and alkenyl with 2-4 carbon atoms can contain up to three fluorine atoms, cyclopropyl and cyclobutyl up to three fluorine atoms as substitutes, and R7 represents hydrogen, fluorine, chlorine, methyl or a methoxy group. The invention also refers to a therapeutic agent containing the above compounds and to a method for producing the compounds of formula (I).

EFFECT: compounds of formula (I) activate the form of soluble haem-free guanylate cyclase and are applicable in the method of treating and/or preventing cardiac failure, angina, hypertension, pulmonary hypertension, ischemia, vascular diseases, disturbed microcirculation, thromboembolic diseases and arterial sclerosis.

6 cl, 4 tbl, 113 ex

FIELD: food industry.

SUBSTANCE: invention relates to a polyphenol grape extract, a compound for oral administration, a food product, beverage, a taste additive, a nutraceutical product, a revitalising composition and therapeutic remedy including the said grape extract. According to the invention, the grape extract contains nearly 5-15 wt % of monomers, nearly 5-20 wt % of dimers, nearly 3-10 wt % of trimers, nearly 2-10 wt % of tetramers and nearly 2-10 wt % of pentamers.

EFFECT: grape extract reduces blood pressure with patients suffering from prehypertonic condition or metabolic syndrome.

27 cl, 4 dwg, 8 tbl, 7 ex

Vasopressor agent // 2552529

FIELD: chemistry.

SUBSTANCE: invention refers to N, S-substituted isothiourea derivatives of the general formula (1) in the form of salts with pharmacologically acceptable acids as a NOS-inhibitory and vasopressor agent wherein: n=1, 3, i.e. an acyl substitute represents cyclobutanoyl or cyclohexanoyl; R represents an alkyl group: C2H5, i-C3H7; HX represents a pharmacologically acceptable inorganic or organic acid: HCl, HBr, HI, hydrogen methyl sulphate, oxalic, succinic acids, etc.

EFFECT: extending the range of products of the vasopressor action.

6 cl, 7 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: what is involved is an integrated pathogenetic therapy containing detralex 3 tablets two times a day (a daily dose of diosmin 2,700 mg, hesperidin 300 mg) for 4 days, then 2 tablets two times a day (a daily dose of diosmin 1,800 mg, hesperidin 200 mg) for 9 days, Trombovazim 1 tablet (800 units) 2 times a day for 15 days as a basic course, then 1 tablet (800 units) 1 time a day) 15 days as a supporting course, and a preparation of thioctic acid 600 mg intravenously in normal saline 200.0 drop-by-drop at max. 60 drops/min for 13 days, then 600 mg a day in the form of tablets for 17 days.

EFFECT: effective reduction of reperfusion syndrome in the given category of patients by increasing venous vascular tone, improving rheological blood properties and trophism of injured nerve terminals.

2 cl, 10 dwg, 9 tbl, 3 ex

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