Tosylate salt of trans-n-isobutyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutane carboxamide

FIELD: chemistry.

SUBSTANCE: invention relates to a tosylate salt of trans-N-isobutyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutane carboxamide of formula (1):

, which exhibits histamine-3 (H3) receptor antagonist activity.

EFFECT: possibility of use in a method of treating several diseases.

12 cl, 1 tbl, 6 dwg, 1 ex

 

The invention relates to tosylate salts of the compounds of formula 1, which is described in the context of this document, to pharmaceutical compositions containing this preferred salt, and to methods for treating disorders and pathological conditions that can be treated by antagonization receptor histamine-3 (H3) with the help of such preferred pharmaceutical compositions.

Histamine is a well-known mediator in allergic reactions (e.g., allergies, hay fever and asthma), which are usually treated with antagonists of histamine or "antihistamines". It was also found that there are histamine receptors, at least two different types, called H1and H2the receptors.

It is believed that the third histamine receptor (H3receptor) plays a role in neuropterida in the Central nervous system, where H3the receptor is thought to be located on presynaptic histaminergic nerve endings (Nature, 302, S32-S37 (1983)). The existence of H3the receptor was confirmed by the development of selective agonists and antagonists of H3receptor (Nature, 327, 117-123 (1987)) and was subsequently shown that it regulates the release of neurotransmitters in the Central nervous system and in peripheral organs, especially the lungs, serdechno-vascular system and the gastrointestinal tract.

A number of diseases or pathological conditions can be treated with ligands of the histamine receptor-3, while the ligand H3may be an antagonist, agonist or partial agonist (see

Such diseases and pathological conditions include cardiovascular disease, such as acute myocardial infarction; memory disorders, dementia and cognitive disorders such as Alzheimer's disease and attention deficit disorder and hyperactivity disorder; neurological disorders such as Parkinson's disease, schizophrenia, depression, epilepsy, and seizures or convulsions; cancer, such as carcinoma of the skin, medullary thyroid cancer and melanoma; respiratory diseases such as asthma; sleep disorders such as narcolepsy; vestibular dysfunction, such as Meniere's disease; gastrointestinal disorders, inflammation, migraine, motion sickness, obesity, pain and septic shock.

Antagonists of H3receptor have also been previously described, for example, in WO 03050099, WO 020769252, WO 0212224 and in patent publication U.S. No. 2005/0171181 A1. Histamine H3receptor (H3R) regulates the release of histamine and other neurotransmitters, including serotonin and acetylcholine. H3R is relatively neuron-specific and will ingibiruet the release of some of monoamines, such as histamine. Selective antagonism of receptors H3R increases the levels of histamine in the brain and inhibits such activity, as food consumption, while minimizing non-specific remote consequences. Antagonists of this receptor increases the synthesis and release of brain histamine and other monoamines. By this mechanism they cause prolonged wakefulness, improved cognitive function, reduced food consumption and normalization of vestibular reflexes. Respectively (although the application described in the context of this document, is not limited to data specified mechanisms) receptor is an important target for new therapies in Alzheimer's disease, the regulation of mood and attention, including attention deficit disorder/hyperactivity disorder (ADHD), cognitive failure, obesity, dizziness, schizophrenia, epilepsy, sleep disorders, narcolepsy and motion sickness, as well as various forms of anxiety.

To date, most of the antagonists histamine receptor H3,as histamine, contain imidazole ring which may be substituted, as described, for example, in WO 9638142. Nakedsoldier neuroactive compounds, such as beta histamines (Arrang, Eur. J. Pharm. 1985, 111:72-84), showed some activity against histamine cocktail recipes. is the H 3but with low efficiency. EP 978512 and EP 0982300A2 reveal nakedsoldier the bonds alkylamines as antagonists of the histamine H3 receptor. WO 0212224 (Ortho McNeil Pharmaceuticals) describes nakedsoldier bicyclic derivatives as ligands of the histamine receptor H3. Other antagonists of the receptor have been described in WO 0232893 and WO 0206233.

Compounds that are antagonists of the histamine receptor-3, including TRANS-N-isobutyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxylic and cleaners containing hydrochloride salt, and other related active compounds mentioned in the application U.S. ser. No. 11549175, filed October 13, 2006. The above-mentioned application, is fully included in the context of this document by reference, in General, describes pharmaceutically acceptable acid additive salts of the compounds that are mentioned.

The INVENTION

The present invention relates to tosylate salts of the compounds of formula 1:

to their solvate (e.g. hydrate), their polymorphs and their pharmaceutical compositions. The compound of formula 1 in the context of this document may be referred to asTRANS-N-isobutyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxylic, which may also be called isobutyramide (TRANS)3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanol is about acid.

The compound of formula 1 is a receptor antagonist of the histamine-3 (H3) and used to treat a number of disorders, diseases and pathological conditions of the Central nervous system. This connection, in particular, used in the treatment of disorders or pathological condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, cognitive disorders, Alzheimer's disease, attention deficit disorder (ADD), attention deficit disorder and hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergies, reactions of the respiratory tract caused by Allergy, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, cardiovascular disease, diseases of the LCD tract, Hyper - and hypokinesia and excretion of acid in the gastrointestinal tract.

In one embodiment, toiletry salt of the present invention is anhydrous or virtually anhydrous polymorphs.

Toiletry salt of the present invention exhibits properties, including properties and stability of solid state and compatibility with certain excipients of the composition of a medicinal product, which makes it better than previously and is known salt of TRANS-N-isobutyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxylic.

The compound of formula 1 (TRANS-N-isobutyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxylic) can exist in a wide variety of solid States ranging from fully amorphous to fully crystalline. The term "amorphous" refers to a condition in which a substance has no long-range order structure on the molecular level and, depending on the temperature can be physical properties of solids and liquids. Usually, such substances do not give the characteristic x-rays and, showing both the properties of solids, more formally described as fluid. When heated is changed from the properties of solids to liquid properties, which is characterized by change of state, usually the second order (the"glass transition temperature"). The term "crystalline" refers to a solid state in which the substance has a regular orderly internal structure at the molecular level and gives a characteristic x-ray with definable peaks. Such substances at sufficient heat will also show the properties of the fluid, and the change from solid to liquid is characterized by a phase transition, usually the first order ("melting point").

The compound of formula 1 may exist in desolvation is Oh and solvated forms. The concept of "MES" is used in the context of this document to describe a molecular complex containing the compound of this invention and one or more molecules pharmaceutically acceptable solvent, for example ethanol. The term "hydrate" is used when the above-mentioned solvent is water.

Generally accepted in the present classification system for organic hydrates is a system that defines unrelated hydrates, hydrates of channel type or hydrates, the coordinated metal ion (see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995)). Unbound hydrates represent hydrates, in which water molecules are separated intermediate organic molecules and have no direct contact with each other. In the hydrates channel-type water molecules lie in the structural channels, where they are adjacent to other water molecules. In the hydrates, the coordinated metal ions, water molecules are bound with a metal ion.

If the solvent or water is strongly connected, then the complex will have a well-defined stoichiometry, regardless of moisture content. However, if the solvent or water are weakly coupled, as in the case of the solvate channel type and hygroscopic compounds, the content of water/solvent will depend on the moisture content and services is by drying. In such cases, the lack of stoichiometry is the norm.

In the scope of the present invention also includes multi-component complexes (in addition to salts and solvate), which contain the drug and at least one component in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (inclusion complexes medicine-owner and co-crystals. The latter is usually defined as crystalline complexes of neutral molecular components that are linked together by non-covalent interactions, but could also be a complex of a neutral molecule with salt. Co-crystals can be obtained by crystallization from the melt, by recrystallization from solvents, or by physically grinding the components together (see Chem. Commun., 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004)). Intended as a General overview of multicomponent complexes, see J Pharm. Sci, 64 (8), 1269-1288, Haleblian (August 1975).

The compound of formula 1 may exist in a mesomorphic state (mesophase or liquid crystal) when the relevant exposure conditions. Mesomorphic state is an intermediate state between the true crystalline state and the real liquid (or melt or solution). Mesomorphism, arose the store as a result of changes in temperature, classified as "thermotropic"and mesomorphism, resulting from the addition of the second component, such as water or another solvent, is classified as "lyotropic". Compounds that can form lyotropic mesophases, are classified as "amphiphilic" and consist of molecules that contain ion (such as-COO-Na+, -COO-K+or-SO3-Na+) or non-ionic (such as-N-N+(CH3)3) polar end group. To get more information, see the Crystals and the Polarizing Microscope authors N.H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970).

In addition, toiletry salt of the present invention is characterized by the specific peaks of x-rays, expressed through 2Θ, which are measured using copper radiation (within a certain relative magnitude of error), as shown in the Table and figures 1 and 2A/2B, and as discussed in the context of this document.

The absorption was estimated using the technique of dynamic sorption in the vapor phase, in which a precisely weighed sample was subjected to a gradual change in the pressure of the water vapor, simultaneously recording the weight change. This experiment was performed isothermal at 25°C.

Another variant implementation of the present invention relates to farmaceuticas the second composition, containing tosylate salt of the compounds of formula 1 and pharmaceutically acceptable carrier or excipient, particularly to compositions for use in the treatment of depression, mood disorders, schizophrenia, anxiety disorders, cognitive disorders, Alzheimer's disease, attention deficit disorder (ADD), attention deficit disorder and hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergies, reactions of the respiratory tract caused by Allergy, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, cardiovascular disease, diseases of the LCD tract, Hyper - and hypokinesia and excretion of acid in the gastrointestinal tract.

In addition, the present invention relates to a method of treating depression, mood disorders, schizophrenia, anxiety disorders, cognitive disorders, Alzheimer's disease, syndrome disorders (ADD), attention deficit disorder and hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergies, reactions of the respiratory tract caused by Allergy, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, heart is a rule-vascular diseases, diseases of the gastrointestinal tract, Hyper and hypokinesia and excretion of acid in the gastrointestinal tract, including the introduction of salts of the compounds of formula 1 to a mammal in need of such treatment.

This invention also relates to a method for tosylate salts of the compounds of formula 1, which includes stages:

(i) the interaction of the compounds of formula 1 dissolved in an appropriate solvent, withpair-toluensulfonate acid (commonly called tasilova acid); and

(ii) collecting the formed crystals.

The present invention also relates to tosylate saltTRANS-N-isobutyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxylic (1)obtained in accordance with the method of this invention.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 represents a complete mapping in the data table of the relative intensities of the experimental peaks in the obtained powder x-ray tosylate salt of TRANS-N-isobutyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxylic.

Figa is an experimental powder x-ray (the y-axis represents the number of linear counts per second; X in degrees 2-theta) tosylate salt of TRANS-N-isobutyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxylic, when the servant of the other conditions 2Th/Th locked, the beginning of 3,000 degrees, ending 40,000 degrees, with a step 0,040 degrees. Step 1 at room temperature (25°C).

Figv identifies all measured peaks (for example, d=14,04179, d=10,58016), shown in figure 1, again with the working conditions 2Th/Th locked, the beginning of 3,000 degrees, ending 40,000 degrees, with a step 0,040 degrees. Step 1 at room temperature (25°C).

Figure 3 represents a curve of differential scanning calorimetry sample 4,1230 mg tosylate salt of TRANS-N-isobutyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxylic, ranging from 30 to 300°C at a speed of 5.00°C/min, with two dominant process is described as, (A) integral - 330,12 MJ, normalized - 80,07 j/g, the beginning 169,42°C, the peak 170,24°C; and (B) integral 487,67 MJ, normalized 118,28 j/g, the beginning 176,17°C, the peak 189,93°C.

Figure 4 represents the isotherm sorption moisture tosylate salt of TRANS-N-isobutyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxylic, where adsorption is lower curve and desorption upper curve is constructed as the percentage change in mass as a function of relative humidity, using kinetic flow-through method (17,17 mg, 25°C).

Figure 5 represents measured using VTI data moisture sorption isotherms for step, using water as absorbate, for tosylate salt of TRANS-N-isobutyl-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxylic.

DETAILED description of the INVENTION

The compound of formula 1 is a receptor antagonist of the histamine-3 (H3) and is used in the treatment of diseases, disorders and pathological conditions of the CNS. The free base of this compound and its hydrochloric salt can be obtained in accordance with the methods described in the application U.S. ser. No. 11549175, filed October 13, 2006 (see also "Histamine-3 Receptor Antagonists", WO 2007/049123). Tosylate salt can be obtained in a variety of different conditions. In one embodiment of this method the free base of the compounds of formula 1 are preferably dissolved in a suitable solvent to dissolve, and then to the solution was added para-toluensulfonate acid, thereby preparing for education tosylate salt accession of the present invention. Suitable solvents include ethyl acetate, methyl acetate, isopropylacetate, methanol, ethanol,n-propanol, isopropanol,tert-butanol, diethyl ether, diisopropyl ether and methyl-tert-butyl ether; preferably ethyl acetate or methanol. In another embodiment of this method the interaction of the compounds of formula 1 in the liquid phase occurs either with a solution ofpair-toluensulfonate acid, or solid formpair-toluensulfonate acid.

Preference is sustained fashion stage interaction is carried out in the period of time between 1 and 24 hours, more preferably between 10 and 20 hours, and it includes stirring or mixing the resulting mixture. The preferred embodiment of this method is that in which stage (i) of this process is in the range from ambient temperature to the boiling temperature of the solvent; more preferably in the range from ambient temperature to about 80°C; most preferably the method is carried out in the interval from 25 to 60°C. Preferred suitable solvent is ethyl acetate or methanol. Preferably the reaction mixture is cooled to ambient temperature immediately after completing the addition of thepair-toluensulfonate acid, and mix in the remaining period of interaction. In the preferred embodiment, see the description of Example 1.

Physical characteristics

1(a). The crystallinity

The sample prepared in silicone oil and examined under the action of cross-polarized light. This sample is crystalline and contains particles in the form of needles, which have a high affinity to double refraction. Amorphous particles in this sample was not observed.

1(b). Powder x-ray

Using powder x-ray diffraction determined that toileta with the ü of the present invention is crystalline. Powder x-ray tosylate salts of this invention were obtained using a diffractometer Bruker D5000 (Madison, Wisconsin)equipped with a copper source radiation, fixed slits (divergence 1.0 mm, antiRussian 1.0 mm and a reception signal of 0.6 mm) and a semiconductor detector Solex. Data received in theta-two (2Θ) configuration theta goniometer of the sample holder in the form of a flat plate at a wavelength copper Kα radiation1=1,54056 and Kα2=1,54439 (relative intensity 0.5) is in the range from 3.0 to 40.0 degrees two-theta with a step size 0,040 degrees and a time step of one second. The voltage and current of the x-ray tube were set at 40 kV and 30 mA, respectively.

Data were acquired and analyzed using software Bruker DIFFRAC Plus. Samples were prepared by placing them in a quartz cuvette. (It should be noted that diffractometer Bruker D5000 similar in operation since diffractometer Siemans model D5000.) The results obtained are summarized in the Table that represents the values of two-theta, and relative intensity for all signals reflection (lines)that have a relative intensity greater than or equal to 7% when the width of the signal reflection of 0.30 and a maximum value of 4.0.

Signals of powder x-ray diffraction of tosylation
*The relative intensity can vary depending on the size and shape of the particles.

The present invention includes tosylate salt of the compounds of formula 1, the major peaks of x-rays which, in terms of 2Θ, measured by using cu (Kα1=1,54056, Kα2=1,54439) radiation include any combination of peaks in the Table and is fully represented in figure 1. Figa shows a quantitative assessment of the heights of the major peaks identified. For example, the present invention includes tosylate salt of the compounds of formula 1, the major peaks of x-rays which, in terms of 2Θ (±0,2)represent 100, 10,6, 7,2, 9,2, 9,2, 17,7, 57,6, 11,1, 11,4 etc. or any combination or individual peak, for example, 100, 10,6, 7.2 and all of them together or separately. Figv shows quantification of certain heights of all the peaks.

2. Thermal analysis

Differential scanning calorimetry was performed in an aluminum vessel with a small hole in the lid in the temperature range from 30 to 300°C at heating rate 5°C/min. the Only endothermic process is documented at Ton the Alo approximately 169°C. an Exothermic process occurs immediately after melting. The profile is shown in figure 3. Schedule isotherms of adsorption/desorption (obtained using kinetic flow-through method) is shown in figure 4.

High temperature microscopy confirmed that the endothermic transition observed in the DSC corresponds to the melting process. The sample was prepared in silicone oil and examined under the action of cross-polarized light, as it was heated from room temperature to 160°C at a rate of 10°C/min, then from 160 to 200°C at 5°C/min, the Particles begin to melt at T (approximate) 164°C, the melting was completed by T 167°C. Browning occur melt was not observed, and there is no crystallization of the cooled melt.

3. Hygroscopicity

During the initial drying cycle (25°C, 1-3% RH) was observed mass loss of about 0.8%, which corresponds to the anhydrous form. This sample was acquired 0,5% of its original weight when exposed to a relative humidity from 0 to 90% at 25°C (CQG<2% weight gain at 90% RH). Data on the hygroscopicity obtained in this kinetic experiment (VTI), suggest that the product is slightly hygroscopic. Figure 5 (VTI data sorption moisture) represents the results obtained for the stepwise isotherms of prioroty warming of 1°C/min

4. Solubility

In water solubility was obtained the following information. Toiletry salt of this invention has a solubility of 5.0 mga/ml in 0.1 M phosphate buffer saline solution (final pH 6.3); solubility 7.0 mga/ml in 0.1 M phosphate buffer saline with 0.5 percent by weight of salts taurocholate sodium/phosphatidylcholine at the final pH of 7.4; and 8.4 mga/ml in nezabvennoi water (final pH of 4.7). These values represent the solubility of crystalline compounds identified through analysis of VASHS reversed phase after exposure to a mixture of medicines program cyclic temperature (40°C for 8 hours, 15°C for 5 hours and 25°C for 12 hours). Conditional solubility tosylate salt of this invention in a reproducible gastric juice without enzymes ranged from 7.1 to 14.2 mga/ml

Tosylate salt of the present invention can provide, for example, in the form of solid candles, powders or films through means such as precipitation, crystallization, freeze drying, spray drying or drying by evaporation. For this purpose you can also use the microwave and radio frequency drying.

Tosylate salt can be entered separately or in combination with one or more other drugs. Usually these songs are introduced in VI is e composition together with one or more pharmaceutically acceptable excipients. The concept of "excipient" applies in the context of this document to describe any ingredient in addition to the compound(s) of the present invention. The choice of excipient will largely depend on such factors as the specific route of administration, the effect of excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for delivery of the compounds of the present invention, and methods for their preparation are obvious to a person skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington''s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

Tosylate salt of this invention can be administered orally. Oral administration may include swallowing so that the connection enters the gastrointestinal tract, and/or buccal, lingual or sublingual introduction, through which the connection enters the bloodstream directly from the mouth.

Preparations suitable for oral administration include solid, semi-solid and liquid systems, such as tablets, soft or hard capsules containing multi - or nano-particles, liquids or powders; lozenges (including fluid filled); lollipops; gels; quickly dispergirujutsja dosage forms; film; suppositories; the buccal sprays and/mucoadhesive p is Asteri.

Liquid preparations include suspensions, solutions, syrups and elixirs. Such drugs can be used as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), and they usually include media such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspendida agents. Liquid preparations can also be obtained by dissolving solid substances, for example, from a bag.

Tosylate salt of this invention can also be applied in the instant, bystrousvaivaemyh dosage forms, such as dosage forms described in the expert evaluation in Therapeutic Patents, 11 (6), 981-986, authors Liang and Chen (2001).

As for the dosage forms of tablets, depending on the dose of the drug can be from 1 to 80 mass % of the dosage form, more usually from 5 to 60 mass % of the dosage form. In addition to metered funds pills usually contain disintegrant. Examples of disintegrants include sodium salt starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crosspovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, hydroxypropylcellulose, semese the ing the lowest alkilani, starch, pregelatinized starch, and sodium alginate. Usually disintegrant is from 1 to 25 mass %, preferably from 5 to 20 mass % dosage forms.

Binders are typically used to make the binding properties of the drug tablet. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hypromellose. Tablets may also contain diluents, such as lactose (monohydrate, spray dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic dihydrate calcium phosphate.

The pill can also optionally contain surface active agents such as sodium lauryl sulfate and Polysorbate 80, and glidant, such as silicon dioxide and talc. Surface-active agents, if present, can be from 0.2 to 5 mass % of the tablet and glidant can be from 0.2 to 1 mass % of the tablets.

Tablets also usually contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium fumarate and mixtures of magnesium stearate with sodium lauryl. Lubricants are usually accounted for the amount of 0.25 to 10 mass %, preferably from 0.5 to 3 mass % of the tablets.

Other possible ingredients include antioxidants, colorants, fragrances, preservatives and substances that corrective taste of the medicine. Usually the pills contain up to about 80% of the medicinal product, from about 10 to about 90 mass % binder, from about 0 to about 85 mass % diluent, from about 2 to about 10 mass % of disintegrant and from about 0.25 to about 10 mass % of the lubricant.

Mixture to obtain the tablets can be crushed directly or through a roller press to form tablets. Mixture to obtain tablets or part of the mixtures can alternatively be subjected to wet and dry granulation or pelletization of the melt, solidification of the melt or extrusion prior to pelletizing. The final product may contain one or more layers and may be coated or not coated; it can even be encapsulated.

Preparation of tablets described in Pharmaceutical Dosage Forms: Tablets. Vol. 1, authors H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Oral film, suitable for human consumption or for veterinary use, are usually well water-soluble or Nauheim in water dosage forms in the form of a thin film that can quickly dissolve the Li are mucoadhesive and usually contain a compound of formula 1, forming a film of a polymer binder, a solvent, a wetting agent, a softener, a stabilizer or emulsifier agent, viscosity modifier, and a solvent. Some components of this drug can perform more than one function.

Forming a film of the polymer may be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is usually present in amounts ranging from 0.01 to 99 mass %, more usually in the range from 30 to 80 mass %.

Other possible ingredients include antioxidants, dyes, flavor enhancers and smell, preservatives, substances that stimulate salivation, cooling agents, auxiliary solvents (including oil), emollients, fillers, antispyware, surface-active substances and substances corrective taste of the medicine. Films in accordance with this invention are usually obtained by drying by evaporation of thin water films deposited on the easily peelable substrate-based or paper. This can be done in a drying oven or tunnel dryer, generally, in the apparatus for thin film deposition, combined with a drying chamber, or by freeze drying or vacuum.

Solid preparations for oral administration can be prepared is so order was carried out immediately and/or a modified release of the active substance. Preparations of modified release include deferred, delayed, intermittent, controlled, targeted and programmed release.

Suitable for the purposes of this invention the compositions with delayed release described in U.S. Patent No. 6106864. Details of other appropriate technologies release, such as high energy dispersions and osmotic particles with a coating, should be sought in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al. (2001). The use of chewing gum to achieve a controlled release described in WO 0035298.

Tosylate salt of this invention can also be entered directly into the bloodstream, muscles or internal organs. Suitable methods of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, be, intrasternal, intracranial, intramuscular, intra-articular and subcutaneous administration. A suitable device for parenteral administration include needle (including microhylinae) syringes without needle syringes and equipment for infusion.

Parenteral drugs are typically aqueous solutions which may contain excipients such the AK salt, carbohydrates and bothersome agents (preferably pH 3 to 9), but for some applications a more appropriate may be that they were compiled in the form of a sterile non-aqueous solution or as a dried form, which must be dissolved together with a suitable vehicle such as sterile pyrogen-free water.

Receiving parenteral drugs in sterile conditions, for example, by lyophilization, can be readily implemented using standard pharmaceutical techniques well known to specialists in this field of technology.

Solubility tosylate salt of the present invention, which is necessary for receiving parenteral solutions can be improved by the use of appropriate formulation techniques, such as the inclusion of agents that increase the solubility.

Preparations for parenteral administration can be designed to make an immediate or modified release. Preparations of modified release include deferred, delayed, intermittent, controlled, targeted and programmed release. Thus, the compounds of this invention can be prepared in the form of a suspension or in the form of solid, semi-solid substances, or thixotropic liquid for administration in the form of implanter the bath depot, providing modified release of the active compounds. Examples of such drugs include drug-eluting stents and semi-solid substances and suspensions containing full of drug microspheres of a copolymer of lactic and glycolic acid (PGLA).

Tosylate salt of this invention can also be applied topically, intradermally or transdermal skin or mucosa. Typical drugs for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, capsules, implants, sponges, fibers, bandages and microemulsions. You can also apply liposomes. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. You can include substances that promote penetration (see, for example, J. Pharm. Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999)).

Other methods of local administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and mikrovalnova or without needle (for example, Powderject™, Bioject™, etc.) parenteral administration.

Preparations for local application can be designed to make an immediate or modified release of the active substance. Drugs modified visw is bogdania include deferred, slow, intermittent, controlled, targeted and programmed release.

Tosylate salt of this invention can also be entered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or in the form of a mixed composite particles, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised container, pump, spray, atomizer (preferably atomizer in which to obtain a fine mist is applied electrohydrodynamics) or a nebulizer, with the use of a suitable propellant, such as 1,1,1,2-Tetrafluoroethane or 1,1,1,2,3,3,3-Heptafluoropropane, or without him, or in the form of nasal drops. Powder for intranasal use may contain bioadhesive agent such as chitosan or a cyclodextrin.

Pressurised container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the present invention, including, for example, ethanol, aqueous ethanol or alternative agent, suitable for dispersion, improve the solubility or increase release of the active substance, the propellant(s) as solvent and optional surface is surface-active substance, such as triolein sorbitan, oleic acid or oligobrachia acid.

Before application of the drug in the form of a dry powder or suspension of a pharmaceutical product is finely pulverized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be accomplished by any suitable grinding method, such as grinding in a spiral jet mill, grinding in a jet mill, fluidized bed, the supercritical processing environment for nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator can be designed to contain a powder mix of the compound of the present invention, a suitable powder base such as lactose or starch and power efficiency, such asL-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Suitable drug in solution for use in the atomizer, in which to obtain a fine mist is applied electrohydrodynamics, may, with the keep from 1 to 20 mg of the compounds of this invention in one application, volume for one application may vary from 1 μl to 100 μl. A typical preparation may contain the compound of formula 1, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerin and polyethylene glycol.

Similar drugs of the present invention, intended for inhaled/intranasal, you can add the appropriate flavor additives, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.

Preparations for inhalation/intranasal route can be designed to make an immediate or modified release of the active substance, using, for example, PGLA. Preparations of modified release include deferred, delayed, intermittent, controlled, targeted and programmed release.

In the case of powder inhalers and aerosols dose is determined by a valve that delivers a metered quantity. Dose in accordance with this invention is usually set to enter specific metered quantity or "injection", containing from 1 μg to 20 mg of the compounds of formula 1. The total daily dose usually falls within the range from 1 to 200 m is, and can be entered at one time or usually, as divided doses throughout the day.

Tosylate salt of this invention can be entered rectally or vaginally, for example in the form of a suppository, pessary, or enema. Cocoa butter is a classic base for suppository, but if necessary you can apply various alternative substances.

Compositions for rectal/vaginal injection can be formulated in such a way to make a fast or slow release of the active substance. Compositions with delayed release include deferred, delayed, intermittent, controlled, targeted and programmed release.

Tosylate salt of this invention can also be entered directly in the eye or ear, typically in the form of droplets finely ground suspension or solution in isotonic sterile saline solution with a defined pH. Other formulations suitable for eye and ear introduction, include ointments, gels, biodegradable (for example, absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, gaskets, lenses and dispersed or vesicular systems, such as Nozomi or liposomes. Polymer, such as cross crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, CE is lulzy polymer, for example, hypromellose, hydroxyethylcellulose or methylcellulose, or heteropolysaccharide polymer, for example Galanova gum, may be included together with a preservative, such as benzalconi chloride. Such drugs may also be delivered via iontophoresis.

Drugs for eye/ear reference can be made in such a way to make an immediate or modified release of the active substance. Preparations of modified release include deferred, delayed, intermittent, controlled, targeted and programmed release.

Tosylate salt of this invention can be combined with soluble macromolecular forms, such as cyclodextrin and suitable derivatives or polietilenglikolsuktsinata polymers in order to improve their solubility, dissolution rate, taste masking and smell, bioavailability and/or stability for use in any of the above techniques.

For example, it turns out that for most dosage forms and routes of administration are usually complexes of drug-cyclodextrin. You can apply as inclusion complexes, and complexes without inclusions. As an alternative to direct complexation with l the drug by means of cyclodextrin can be used as an auxiliary additive, i.e. as a carrier, diluent or a solubilizer. The most widely used for these purposes, alpha-, beta - and gamma-cyclodextrins, examples of which can be found in international patent applications WO 9111172, WO 9402518 and WO 9855148.

Because it may be necessary to introduce combinations of active compounds, for example, to treat a specific disease or pathological condition, that the scope of the present invention turns on the fact that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with this invention, can be combined appropriately in the form of a kit suitable for co-administration of compositions.

Thus, the kit of the present invention contains two or more separate pharmaceutical compositions, at least one of which contains tosylate salt of the compounds of formula 1 in accordance with this invention, and devices for separate storage of the above-mentioned compositions, such as a container, divided vessel, or divided foil pack. An example of such a set is a well-known blister pack, used for packing tablets, capsules and the like.

The kit of the present invention, particularly suitable for the introduction of different dosage forms, for example orally and is parenteralnogo, for the introduction of separate compositions at different intervals between doses or for titration separate compositions each other. To ensure adherence in this set typically includes instructions for use and can be equipped with so-called memo.

Tosylate salt of this invention can be introduced through either oral, transdermal (e.g., using the patch), intranasal, sublingual, rectal, parenteral or local techniques. Preferred are transdermal or oral routes of administration. Active salt is most appropriate to enter in the dose range from about 0.001 mg/kg up to about 50 mg/kg / day, preferably from about 0.01 mg/kg to about 50 mg/kg / day once or divided doses, although it will inevitably be other options depending on the mass and pathological conditions of the patient to be treated and the particular route of administration. However, most desirable to apply the level of doses, which lies in the range from about 0.01 mg/kg to about 10 mg/kg of body weight per day. However, you may have other options depending on the mass and pathological conditions of patients that should be treated, and their individual reactions to the aforementioned pharmaceutical medium is in, and on the selected type of pharmaceutical preparation and the time period and interval at which such introduction is carried out. In some examples, the dosage levels below the lower limit of the above range can be more than satisfactory, while in other cases it is possible to use much higher doses without causing harmful side effects, provided that such higher dose pre-divided into several small doses for administration throughout the day. Sizes, dosages set forth in this description and in the accompanying claims, it is possible to apply, for example, in relation to the average human subject having a weight from about 60 kg to about 70 kg Skilled practitioner will readily be able to determine any change in dosage, which may be required for patients whose weight falls outside the range from about 60 kg to about 70 kg, such as children and the elderly, based on the medical history of the patient. Pharmaceutical combination can be entered mode up to 6 times per day, preferably from 1 to 3 times a day, 2 times a day or once a day.

In order to avoid misinterpretation of the meaning of "treatment" in the context of this document includes healing, temporarily debilitating manifestation of the disease and profile the political treatment.

The following example illustrates the method and the compound of the present invention. It should be understood, however, that the invention is not limited to this particular example.

Example

Toiletry salt of TRANS-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxylic (1)

Isobutyramide 3-fluoro-3-(3-fluoro-4-pyrrolidin-1-ylmethylene)-cyclobutanecarbonyl acid (13.8 g, 79,0 mmol) was dissolved in EtOAc (250 ml) and addedp-toluensulfonate acid (15.2 g, 79,9 mmol) in EtOAc (150 ml). The resulting solution was stirred over night, the white precipitate was collected and dried in a stream of nitrogen to obtain 16.5 g monotonicity salt. Received pre-salt was dissolved under heating in a mixture of 20 ml of MeOH and 40 ml of EtOAc. After filtration through a nylon filter for ~40 min was added EtOAc (250 ml). After stirring for a further 1 hour, the obtained white solid was collected and dried in a stream of nitrogen. The recrystallization procedure was repeated two more times with getting 12,19 g of the substance, which had a purity 99,44%, as determined by HPLC-analysis: LRMS m/z calculated for C20H28F2N2O, 350,2 found 351,2 (M+H) APCI;1H-NMR (CDCl3) δ 7,79-7,24 (m, 3H), 7,32-7,28 (m, 2H), 7,19 (d, J=7.9 Hz, 2H), 5,78 (user. s, 1H), 4,32 (d, J=5.4 Hz, 2H), 3,79-to 3.73 (m, 2H), 3,29 (p, J=8,4 Hz, 1H), 3,10-of 3.07 (m, 2H), 2,93-of 2.66 (m, 6H), a 2.36 (s, 3H), 2,24-to 2.18 (m, 2H), 2,08-2,02 (m, 2H), 1,76 (hept., of 6.7 Hz, 1H), 0,89 (d, J=,6 Hz, 6H);13C-NMR (CDCl3) δ 174,0, 161,3 (l, JC-F= 248,7 Hz), USD 147.4 (DD, JC-F=24,0, 7.5 Hz), 142,5, 140,3, 133,6 (l, JC-F=2.3 Hz), 129,1, 126,1, the level of 121.8 (DD, JC-F=to 8.7, 3.3 Hz), 116,4 (l, JC-F=14,3 Hz), 112,6 (DD, JC-F=23,7, and 9.4 Hz), 96,7 (l, JC-F=196,9 Hz), 53,4, 50,3, 47,2, 38,9 (d, JC-F=24,8 Hz), 32,8, 28,7, 23,0, 21,5, 20,3; elemental analysis calculated for C20H28F2N2O-C7H8O3S, C 62,05; H 6,94; N Are 5.36; F 7,27; S 6,14; found C 61,85; H 7,03; N 5,32; F 7,21; S 6,34, with a molecular mass of 522,66.

1. Toiletry salt of TRANS-N-isobutyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxylic.

2. Toiletry salt of the compounds of formula 1

3. The compound according to claim 1 or 2, having an x-ray, which is essentially characterized by the peak of the x-rays, measured under the action of copper radiation (Kα1=1,54056, Kα2=1,54439) at 100 2Θ±0,2.

4. The compound according to claim 1 or 2, having an x-ray, which is essentially characterized by the peak of the x-rays measured with copper radiation (Kα1=1,54056, Kα2=1,54439) at 2Θ of 10.6±0,2.

5. The compound according to claim 1 or 2, having an x-ray diffraction pattern, which is essentially characterized by the peak of the x-ray diffraction pattern measured under the action of copper radiation (Kα1=1,54056, Kα2=1,54439) at 2Θ 7,2±0,2.

6. The compound according to any one of claims 1 and 2, have roentgenol is the Amma, which, essentially, is characterized by the peak of the x-rays measured with copper radiation (Kα1=1,54056, Kα2=1,54439) at 2Θ of 9.2±0,2.

7. The compound according to any one of claims 1 and 2, having an x-ray, which is essentially characterized by the peak of the x-rays measured with copper radiation (Kα1=1,54056, Kα2=1,54439) at 2Θ of 17.7±0,2.

8. The compound according to claim 1 or 2, having an x-ray, which is essentially characterized by the peaks of the x-rays measured with copper radiation (Kα1=1,54056, Kα2=1,54439) at 2Θ(±0,2) 100, 10,6, 7,2, 9,2, 9,2, 17,7, 67,6, 11,1, 11,4, 36,8, 12,9, 18,9, 32,9, 39,2, 13,9, 7,6, 13,1 and 7.8.

9. The connection of claim 8, having an x-ray, which is essentially characterized by the peaks of the x-rays measured with copper radiation (Kα1=1,54056, Kα2=1,54439) at 2Θ(±0,2) 100, 17,7, 57,6, 36,8, 12,9, 18,9, 32,9 and 39.2.

10. The compound according to claim 1, where the connection represented in anhydrous or nearly anhydrous form.

11. The pharmaceutical composition exhibiting antagonistic activity against histamine receptor-3 (H3)containing the compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

12. A method of treating depression, mood disorders, schizophrenia, anxiety disorders, cognitive disorders, Alzheimer's disease, attention deficit disorder (ADD), attention deficit disorder, and GI is reactively (ADHD), psychotic disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergies, reactions of the respiratory tract caused by Allergy, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, cardiovascular disease, diseases of the LCD tract, Hyper and hypokinesia and excretion of acid in the gastrointestinal tract in a mammal, comprising the administration to a patient in need of treatment, a therapeutically effective amount of a compound according to claim 2.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to an agent, which is in form of fluorinated 1,4-naphthoquinone derivatives of general formula (I) which have cytotoxic effect on human cancer cells in a culture. In general formula (I) 1) R1=NHC(CH3)3, R2, R3=F; 2) R1=NHCH2CH2SCH3, R2, R3=F; 3) R1=N(CH2CH2)2, R2, R3=F; 4) R1=N(CH2CH2)2, R2, R3=F; 5) R1=NHCH2CH2CH2CH3, R2, R3=F; 6) R1=NHC6H5R2, R3=F; 7) R1=H(CH3)CH2CH2OH, R2, R3=F; 8) R1, R3=NHCH2CH2CH2CH3, R2=F; 9) R1=N(CH2CH2OH)2, R2, R3=F; 10) R1=NHC6H5, R2=CH3, R3=F; 11) R1=OCH3, R2, R3=F; 12) R1=NH(CH2)2SS(CH2)2NH(2-pentafluoro-1,4-naphthoqunonyl), R2, R3=F; 13) R1=NHC2H5, R2, R3=F; 14) R1=N+C5H5, R2=O; R3=F; 15) R1=NHCH2CH2OH, R2,R3=F; 16)R1, R2=OCH3, R3=F.

EFFECT: proposed compounds can be used in medicine as a base for designing drug formulations of preparations used in malignant growth therapy.

2 dwg, 4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: compound refers to new biologically active N-2-(2'-methylphenoxy)-ethylmorpholine hydrochloride (I) of formula . The compound is produced from reacted 1-bromine-2-(2'-methylphenoxy)ethane and morpholine. The produced compound represents a white crystalline matter, soluble in hot water, ethanol, chloroform, dimethyl sulphoxide, dimethyl formamide.

EFFECT: there is produced a new long-lasting hypotensive compound.

1 tbl

The invention relates to the field of synthesis of medicinal substances, specifically, to obtain the dihydrochloride of 1-(2,3,4-trimethoxybenzyl)piperazine (I), which is the substance of a drug Trimetazidine

FIELD: chemistry.

SUBSTANCE: invention relates to use of 1,2,4-triazole derivatives of formula I:

, where R1, R2 and R3 independently denote hydrogen or halogen; R4 denotes C1-C6 alkyl; R5 and R6 independently denote C1-C6 alkyl or, together with a nitrogen atom to which they are bonded, form a 5-7-member heterocyclyl group, in which the 6-member heterocyclyl can further contain one oxygen or nitrogen atom and can be substituted with acetyl, C1-C6 alkyl or phyenyl; X-S-, -SO-, -SO2- or O; and n is a whole number selected from 1-8; or pharmaceutically acceptable salts, stereoisomers or solvates thereof, when producing a drug for treating or preventing sigma-1 receptor-mediated diseases or conditions, methods of producing said compounds, intermediate compounds and pharmaceutical compositions which contain compounds of formula 1.

EFFECT: improved compounds.

19 cl, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to molecular biology, virology, immunology and medicine. The invention presents a composition which contains a sequenced and repetitive antigen or antigen determinant array, and particularly a composition which contains an Aβ1-6-peptide-HPV conjugate. More specifically, the invention provides the composition which contains a virus-like particle and at least one coupled Aβ1-6-peptide. Also, the invention describes a method for preparing the conjugates and the sequenced and repetitive arrays respectively.

EFFECT: compositions presented in the invention may be applicable for producing vaccines intended for treating Alzheimer's disease, and as pharmaceutical agents intended for preventing or treating Alzheimer's disease and for effective immune response induction, particularly antibody responses; besides, the compositions presented in the invention are established to be applicable first of all for effective induction of autoantigenic responses.

45 cl, 35 dwg, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and pharmacology. An agent for treating and preventing diseases associated with stress-related conditions in diseases and disorders in human and animals represents nonapeptide KND by formula as follows: Trp-Lys-Gly-Gly-Asn-Ala-Ser-Gly-Glu, or nonapeptide Trp-Lys-Gly-Gly-Asp-Ala-Ser-Gly-Glu or hexapeptide Trp-Lys-Gly-Gly-Asn-Ala or their pharmaceutically acceptable salts. A pharmaceutical composition for treating and preventing the diseases associated with stress-related conditions in diseases and disorders in human and animals contains nonapeptide KND or nonapeptide Trp-Lys-Gly-Gly-Asp-Ala-Ser-Gly-Glu or hexapeptide Trp-Lys-Gly-Gly-Asn-Ala and glycin and/or a natural antioxidant, particularly, carnosine or homocarnosine. The ingredients of the pharmaceutical composition are related as follows: nonapeptide or hexapeptide: glycin:natural antioxidant makes 1:(10-125):(10-125) by weight. The pharmaceutical composition is used in the form of nasal drops, in the form of spray, powder spray, aerosol, sublingually in the form of lozenge, capsules and powders, in the form of various injections, in the form of suppositories, ointments, creams, lotions. A method of treating and preventing the diseases associated with stress-related conditions in diseases and disorders in human and animals consists in introducing in an organism said pharmaceutical composition 10 mcg/kg to 10 mg/kg at nonapeptide KND or nonapeptide Trp-Lys-Gly-Gly-Asp-Ala-Ser-Gly-Glu or hexapeptide Trp-Lys-Gly-Gly-Asn-Ala.

EFFECT: invention provides higher clinical and preventive effectiveness in the diseases associated with stress-related conditions in diseases and disorders in human and animals.

6 cl, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and medicine, and concerns using heptapeptide Thr-Lys-Pro-Arg-Pro-Gly-Pro (Selinc).

EFFECT: intranasal application of the preparation in the concentration of 0,15 % in dose four to six drops in each nostril every 4-5 hours for 2-3 weeks allows higher clinical effectiveness in Parkinson's disease ensured by correction of neuropsycological disorders.

3 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered agent and method of treating essential tremor (ET). The drug preparation Selanc on the basis of heptapeptide of general formula Thr-Lys-Pro-Arg-Pro-Gly-Pro is offered as the agent for treating it. Using the preparation enables higher clinical effectiveness in ET ensured by correction of neuropsycological disorders and less manifested kinetic tremor.

EFFECT: improvement of dynamic praxis (patients could repeat 2-3 series of movements independently), direct and complicated choice behaviour is shown; in two weeks after the termination of treatment a long-term positive effect has been noted.

3 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely neurooncology and may be used for treating benign cerebral tumours. That is ensured by using 4-methyl-3-[[4 (3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide and its N-oxide or pharmaceutically acceptable salt for preparing a pharmaceutical composition.

EFFECT: group of inventions allows treating benign cerebral tumours, particularly neurofibromatoses by means of inhibiting both signal pathways involving PDGFR and Kit receptors.

7 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: there are described substituted imidazo[2,1-b]thiazoles of general formula the R1, R1, R3 R4, M1, M2 radical values are presented in the patent claim cl. 1, as well as methods for making them, drug preparations containing these compounds and application of these compounds for making the drug preparations.

EFFECT: higher efficacy.

23 cl, 3 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: claim describes novel vinylogous acid derivatives of formula , in which ring A is as defined in claim 1, R1 denotes hydrogen, C1-C6-alkyl or -NR'R", -( C0-C6-alkylene)-NR'R'', where R' and R" are independently selected from a group comprising hydrogen, C1-C6-alkyl, formyl, C1-C6-alkylcarbonyl; R2, R2' and R2" independently denote hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy group; R3 denotes phenyl; R4 denotes hydrogen, C1-C6-alkyl, optionally substituted phenyl or phenyl- C1-C6-alkyl, R5 denotes hydrogen or C1-C6-alkyl; as well as physiologically acceptable salts thereof.

EFFECT: compounds inhibit chymase and can be used as medicinal agents.

15 cl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: drug for respiratory diseasescontains a basidiomycetes extract, herbal proteolytic enzyme Bromeline, succinic acid, rutin and calcium stearate in the following ratio (wt %): proteolytic enzyme Bromeline - 3-10; edible basidiomycetes extract - 20-25; rutin (vitamin) - 20-25; succinic acid - 40-50; calcium stearate - the rest. As the basidiomycetes extract, it contains hiratake extract, shiitake mushroom extract or reishi extract. The drug Glucaferon® has an integrated effect on a body, allows essentially increasing anti-infective properties. It can be used both independently, and with underlying conventional therapy with using antiviral preparations or antibiotics.

EFFECT: invention refers to medicine, namely to pathogenetic preparations for infectious respiratory diseases produced of natural herbal raw material.

4 cl, 5 tbl, 5 ex, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound - 6-(4-benzylpiperazino)-1,3-dimethyluracyl dihydrochloride of formula I showing antispasmodic and bronchial spasmolytic activity.

EFFECT: invention extends the range of antispasmodic and bronchial spasmolytic low-toxic agents.

3 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound - 6-(4-benzylpiperazino)-1,3-dimethyluracyl dihydrochloride of formula I showing antispasmodic and bronchial spasmolytic activity.

EFFECT: invention extends the range of antispasmodic and bronchial spasmolytic low-toxic agents.

3 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula l

in the form of a salt wherein W means a group of formula and A means acetate or xinafoate, as well as to based pharmaceutical compositions which may be used for treating the diseases accompanied by bronchospasms.

EFFECT: what is offered is a new effective bronchial spasmolytic.

7 cl, 23 ex, 4 tbl, 8 dwg

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to therapy, and may be used for treating the disorders related to CXCL13 activity in an animal's cell, tissue, organ or body wherein the disorders represent chronic obstructive pulmonary disease (COPD) or systemic lupus erythematosus. That is ensured by introducing a CXCL13 antagonist into the animal's cell, tissue, organ or body in an amount effective for CXCL13 activity inhibition together with a TNFα antagonist in an amount effective for TNFα activity inhibition in said animal's cell, tissue, organ or body.

EFFECT: group of inventions provides treating chronic obstructive pulmonary disease and systemic lupus erythematosus due to the combined use of the CXCL13 and TNFα specific monoclonal antibodies that leads to decreased CD4 expressing B-cell infiltration, and also reduced glomerulonephritis related urinary protein in an animal with symptoms of systemic lupus erythematosus.

19 cl, 8 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) which is selected from gentisate, maleate, citrate, fumarate and semitartrate salts, which possess improved properties in their application, in particular higher stability.

EFFECT: invention also relates to method of obtaining acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) and to pharmaceutical composition, containing them, for treatment and prevention of erectile dysfunction, pulmonary arterial hypertension, chronic obstructive lung disease, benign prostate gland hypertrophy and diseases of lower urinary tract.

11 cl, 30 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

Up!