Pharmaceutical formulation for treating diseases associated with endothelial dysfunction

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine. A pharmaceutical formulation for the treating diseases associated with endothelial dysfunction contains an active ingredient presented by a methyl pyridine derivative - 1.0-6.0 wt %; purine - 10.0-80.0 wt % and additive agents - the rest. The active substance is presented by compounds of a group: 3 -(N,N-dimethyl carbamoyloxy)-2-ethyl-6-methylpyridinium succinate, 3-methylpyridinium succinate, 2-ethyl-6-methyl-3-hydroxypyridinium hydrochloride, 6-trichloromethyl-2-chloropyridine (nitrapyrin), 2-ethyl-6-methyl-3-hydroxypyridine succinate. Purine is presented by inosine, adenosine, hypoxanthine. The pharmaceutical formulation may be presented in the form of injections, lyophilisate, solid capsules, tablets and suppositories.

EFFECT: formulation according to the invention provides creating the stable drug dosage form which considerably exceeds the existing analogues in pharmacodynamics activity on the endothelial dysfunction and toxicological properties.

4 cl, 4 tbl, 9 ex

 

The technical field to which the invention relates.

The present invention relates to medicine, specifically to create new generation equipment based on open or synthetic chemical molecules with biological and pharmacological activity, used as causal, pathogenetic and symptomatic therapy.

Cardiovascular and cerebrovascular diseases are often based on numerous "vicious circles"are autocatalytically and contributes to the development of clinical manifestations of the development of systemic inflammation and endotoxemia in patients. Although the exact mechanism and the sequence of events in the formation of dysfunction of the organs is still not defined, the development of hypoxic/ischemic processes, increased inflammatory activity and secondary inflammation plays an important role in the development of a universal mechanism of pathogenesis of atherosclerosis, arterial hypertension, diabetes mellitus and other endothelial dysfunction. The barrier role of the vascular endothelium as an active body defines its main role in the human body: maintaining homeostasis by regulating the equilibrium state the opposite of processes and vascular tone (vasodilation/vasoconstriction); b) anatomy of blood vessels (synthesis/inhibition of factor the proliferation); b) hemostasis (synthesis and inhibition factors, fibrinolysis and platelet aggregation); d) local inflammation (generation of Pro - and anti-inflammatory factors).

It should be noted that each of the four functions of the endothelium, which determines thrombogenicity vascular wall, inflammatory changes, vasoreactivity and stability of atherosclerotic plaques, directly or indirectly connected with the development, progression of atherosclerosis, arterial hypertension and its complications [8-10]. Thus, dermatillomania endothelium, which includes vosstanovleniya its structural and functional changes and homeostasis synthesized in its biologically active substances, under the influence of drugs plays an important role in targeted (targeted) therapy of cardiovascular diseases, cerebrovascular and many other diseases, hypoxia/ischemia and reperfusion Genesis. Develops the concept of the endothelium as a target for prevention and treatment of pathological processes leading or implementing cardiovascular and cerebrovascular diseases.. moreover the understanding of atherosclerosis as a macrophage-dependent granulomatous inflammation with impaired lipid metabolism and increased in far-advanced stages, thrombosis allow you to plug the em select "atherogenic" targets/effects of endotoxin, include damage to the endothelium, the induction of the formation of foam and froth-like cells from macrophages, thrombogenic effects and other Tissue dysoxia serves as the basis for the formation of anomalous mechanism of extraction of oxygen to peripheral tissues. This happens due to the lack of desaturation entering the capillary hemoglobin. This systemic release of cytokines, catecholamines, angiotensin II, prostaglandins promote the formation of a tissue graft with a decrease in perfusion. Adaptive release of endothelin-1 by endothelial at the initial stage of development of endothelial dysfunction is a trigger release of purine nucleotides, which through interaction with purine A1, A2 and A3 receptors exert a protective effect of exogenous. However, the increase in the duration of ischemia leads to depletion of the pool of purine nucleotides and the predominance of the vasoconstrictor effect of endothelin-1. special importance is given to inosine (ligand adenosine receptor A3 and A2A), are able to exert inotropic, vasodilating and anti-inflammatory effect [Hasko G, Kuhel DG, Nemeth ZH, et al. Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induved shock. J Immunol 2000, 164:1013-1019.]. It turned out that the purines, in particular, inosine, but not adenosine, inhibit hyperactively poly-ADP-ribose polymerase in the nucleus, and therefore the way, regulate the processes of cell death, the severity of processes ischemia-reperfusion lesions, lesions of the endothelium [G. Veres, T. Radovits, SeresL. Effects of inosine on reperfusion injury after cardiopulmonary bypass. J. Cardiothoracic Surgery. 2010, 5:106-112.]. Another regulator of metabolic processes is the system associated with G-protein associated receptor, in particular subtype of GPR91, which is a structural homologue of the P2Y1 purinergic receptors modulated by succinate [W, Miao FJ, Lin DC, Schwandner RT, Wang Z, Gao J, Chen JL, Tian H, Ling L. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature. 2004;429:188-93]. This suggested possible synergism in the action of succinate-containing drugs and inosine in dermatillomania endothelium in various lesions of blood vessels. In addition, based on data about the active immunomodulating action of inosine (stimulates activity immunokompetentnykh cells (monocytes, macrophages and NK-cells) appeared, the possibility of increased anti-inflammatory effect succinatecontaining derived methylpyridine.

The analysis of the above information materials naturally formulated the purpose of the present invention, namely the creation of safe (increasing the breadth of therapeutic action), medicines on the basis of succinate containing derivatives of methylpyridines, including pharmaceutically acceptable salts, the La treatment of diseases associated with endothelial dysfunction, the strength of the immune system and a reduction in their detoxifying properties.

According to the invention proposes a method of exposure to infectious agents (including intracellular localized) and/or stimulation of T-cell and humoral anti-infective immunity along with providing cytoprotective and antihypoxic effects, which consists in the introduction to the mammals of an effective amount of a succinate-containing derivatives of methylpyridine with purine nucleotides nature.

In medicine known substance having antihypoxic activity using a 3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridine succinate (RF patent 2995350 - prototype). Experimental data show that under conditions of acute hypobaric hypoxia (AGBG) the claimed compound exhibiting the properties of strong antihypoxic drug increases the life expectancy of animals at a height of 11000 m 2-rata for discostick (WELL) animals and 2-4 times for highly stable (WU) rats. Maximum antihypoxic action of the claimed compound has a dose of 40 mg/kg, with an increase in dose efficiency antihypoxic action is reduced. The claimed connection 2-4 times higher than in antihypoxic activity of the drug gamma hydroxybutyric acid (GHB), used at a dose of 7 R is h higher than the effective dose to the claimed compounds. In addition, antihypoxic action of the claimed compounds is evident as WELL, and WU animals in contrast to the reference antihypoxic drug GHB, which in terms AGBG increases the life expectancy of only WELL krisscouture the analogue of the claimed compounds Mexidol in similar experimental conditions does not show antihypoxic properties as WELL, and WU animals.

However, 3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridin succinate more toxic than Mexidol and GHB. When intravenous administration to mice of his LD50is 97,94 (91,13-to 105.3) mg/kg for females and 109,0 (97,0-to 121.0) for males. Intraperitoneal injection LD50is 146,4 (135,0-157,0) mg/kg for females and 159,7 (149,2-169, 5mm) mg/kg for males. When perilium introduction for females LD50is 189,7 (161,0-224,0) mg/kg and for males 197,7 (190,2-204,5) mg/kg and in rats: intraperitoneally - LD50is 146,8 (124,2-173.5 metric) mg/kg, oral for females LDO is 181,7 (154, 6mm-213,5) mg/kg and for males 189,5 (168,1-213,7) mg/kg

The level of technology.

Described isoxazol derivative of the following General formula I, where R1represents a hydrogen atom; a halogen atom; alkyl group; alkoxygroup; a hydroxyl group; alkylthiols; the amino group; alkylamino; alkanoyloxy; aldoxycarb the ilen group; carboxypropyl; karbamoilnuyu group; a nitro-group; or a cyano, as compounds with inhibiting the monoamine oxidase activity and anti-inflammatory activity (patent of the Russian Federation 2140414).

Known invention, which represents a salt of 1,3-dialkyl-4,5-bis(optionally N-substituted carbarnoyl)imidazole, which is used to stimulate the healing process and attenuation of inflammation (RF patent No. EAPO / Eurasian server publications / Patent No. 008173).

On models cyclophosphamide immunosuppression and lipopolysaccharide immune stress were studied psychoimmunological the properties of the new derived fenotropil - succinate of Phenotropil - intraperitoneal injection of different rate (from single to 7-day) in different doses (25 mg/kg 50 mg/kg and 100 mg/kg). It is established that the target substance exhibits the ability to resolve violations of the various components of the immune system [Tyurenkov I.N., Magomedov M.M., Warm DL, et al. Medical immunology, 2011. - N 1. - C.55-60].

According to the invention proposes a method of exposure to infectious agents (including intracellular localized) and/or stimulation of T-cell and humoral anti-infective immunity along with providing cytoprotective and antihypoxic effects, which consists in the introduction into the body m is capitalship effective amount of a succinate containing derivatives of 6-methylpyridine with purine nucleotides nature.

In medicine known substance having antihypoxic activity using a 3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridine succinate (RF patent 2995350 - prototype). Experimental data show that under conditions of acute hypobaric hypoxia (AGBG) the claimed compound exhibiting the properties of strong antihypoxic drug increases the life expectancy of animals at a height of 11000 m 2-rata for discostick (WELL) animals and 2-4 times for highly stable (WU) crysalline antihypoxic action of the claimed compound has a dose of 40 mg/kg, with an increase in dose efficiency antihypoxic action is reduced. The claimed connection 2-4 times higher than in antihypoxic activity of the drug gamma hydroxybutyric acid (GHB), used at a dose of 7 times higher than the effective dose to the claimed compounds. In addition, antihypoxic action of the claimed compounds is evident as WELL, and WU animals in contrast to the reference antihypoxic drug GHB, which in terms AGBG increases the life expectancy of only WELL rats. A structural analogue of the claimed compounds Mexidol in similar experimental conditions does not show antihypoxic properties as WELL, and WU animals.

However, 3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridin succinat more toxic than Mexidol and GHB. When intravenous administration to mice of his LD50is 97,94 (91,13-to 105.3) mg/kg for females and 109,0 (97,0-to 121.0) for males. Intraperitoneal injection LD50is 146,4 (135,0-157,0) mg/kg for females and 159,7 (149,2-169, 5mm) mg/kg for males. When administered orally to female LD50is 189,7 (161,0-224,0) mg/kg and for males 197,7 (190,2-204,5) mg/kg and in rats: intraperitoneally - LD50is 146,8 (124,2-173.5 metric) mg/kg, oral for females LD50is 181,7 (154, 6mm-213,5) mg/kg and for males 189,5 (168,1-213,7) mg/kg

The mechanism of the immunomodulating effect of inosine not fully understood, but based on recent literature data, it can be assumed that this drug is specifically active immunomodulator, stimulate the activity of immunokompetentnykh cells (monocytes, macrophages and NK-cells) by enhancing their chemotaxis and phagocytosis, processing and antigen presentation, production of interferons and interleukins. Inosine refers to non-toxic and safe products of purine series. Inosine is a metabolic activator that supports the ability of muscle cells to contract and erythrocyte - binding with oxygen and the activity of blood flow in coronary vessels. The known properties of inosine to stimulate the synthesis of nucleotides, to enhance the activity of some enzymes of the cycle To which EBSA and reduce the aggregation capacity of platelets. Inosine inhibits the production of superoxide radicals stimulated neutrophils. Unlike adenosine inosine chemically more resistant, so is widely used in cardiology practice in the form of drugs Riboxin and inosine-F. Thanks to the above characteristics, inosine can be used for the treatment and prevention of acute and chronic viral infections, to reduce the damaging effects of radio and chemotherapy. According to the invention proposes a method of exposure to infectious agents (including intracellular localized) and/or stimulation of T-cell and humoral anti-infective immunity along with providing cytoprotective and antihypoxic effects, which consists in the introduction to the mammals of an effective amount of a succinate derivatives containing methylpyridine with purine nucleotides nature.

Disclosure of the invention.

The use of the invention for the first time will receive the following technical result: to create a safe, stable dosage form succinate-containing derivative methylpyridine, which pharmacodynamic activity on endothelial dysfunction and Toxicological properties greatly superior to existing analogues (compared to the prototype 3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridazine). For the first time are encouraged to use the inosine as pharmacological modulator activity of biologically active compounds, in particular derivatives of methylpyridines and their pharmaceutically acceptable salts, to improve therapeutic efficacy and stabilization of the structure of chemical molecules with known biological activity and pharmacological activity. Currently, the creation of new highly effective and safe medicines antihypoxic and cytoprotective actions that can be applied in the treatment of various diseases in the acute and subacute periods for the treatment of endothelial dysfunction is of great importance.

The claimed pharmaceutical composition has a toxicity lower than those derived methylpyridine separately. At the same time declared the pharmaceutical composition can achieve fast positive changes and reverse the development of endothelial dysfunction and thereby significantly reduce the risk of complications in acute ischemic lesions of the brain, myocardium, after surgery, and cerebrovascular insufficiency in various diseases, reduce the dose and increase the effectiveness of succinate-containing derivatives of methylpyridines and their pharmaceutically acceptable salts, to enhance the protective system of the organization is mA to remove or facilitate removal from the body of mediators that cause complications or even lead to the development of multiple organ failure.

Received therapeutic effect is persistent, as is achieved by the simultaneous and balanced impact on the various links and protective forces and detoxifying systems of the body. therapeutic effect of the developed tools is achieved by cupping complex cascade Ableton molecular changes, restore the balance between the intimate mechanisms of regulation of homeostasis of the organism in various diseases.

The implementation of the invention

The invention consists in the creation of a pharmaceutical composition containing methylpyridine derivative or its pharmaceutically acceptable salt - 1,0-6,0; purine - 10,0-80,0 and excipients to obtain a stable form-the rest. As auxiliary substances, depending on the dosage form used compounds that are recommended for use as auxiliaries of the State Pharmacopoeia of the XI edition of the Russian Federation, European and British Pharmacopoeias, content, and method of administration in the dosage form is described in the manuals "excipients in pharmaceutical forms. Bolshakov V.N. 1991; Tohono the A.I. "Technology of drugs". 2002.

A pharmaceutical composition characterized by the fact that it additionally contains a pharmaceutically acceptable carrier.

A pharmaceutical composition characterized by the fact that it is made in the form of injectable dosage forms.

A pharmaceutical composition characterized by the fact that it is in the form of a lyophilisate.

A pharmaceutical composition characterized by the fact that it is made in the form of solid dosage forms.

A pharmaceutical composition characterized by the fact that it is made in the form of hard capsules.

A pharmaceutical composition characterized by the fact that it is made in the form of a suppository.

Used in the formula to the quantitative proportions of the components included in the pharmaceutical composition, reflect the result of experimental observations, which showed that beyond presents concentrations reduce the synergistic effect of the ingredients and, as a consequence, therapeutic efficacy of the drug.

A new structure is proposed for release in glass or plastic vials or ampoules containing a clear liquid or lyophilized white powder (in the latter case, it is possible to complete the solvent), or in the form of enteric and sublingual tablets of white color, as well as suppositories, the next time accounted for the e component 1 vial-ampoule or tablet or suppository.

Example 1. In accordance with the process mixer poured the ingredients of the composition in the following proportions based on 100 mg, mg:

Succinate containing derived methylpyridine - 5 mg,

inosine - 60 mg,

auxiliary substances permitted for use in the pharmaceutical industry link - 35 mg

then mix thoroughly.

Example 2. In the mixer poured the ingredients of a medicinal product in the following ratios, mg:

3-hydroxy-6-methyl-2-ethylpyridine succinate 5 mg,

inosine - 80 mg,

excipients - 15 mg

then mix thoroughly.

Example 3. In the mixer poured the ingredients in accordance with the technological procedure of composition in the following proportions, mg:

3-hydroxy-6-methyl-hydroxypyridine hydrochloride 2 mg,

inosine - 80,

excipients - the rest,

then mix thoroughly.

Example 4. In the mixer poured the ingredients of a medicinal product in the following ratios, mg:

3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridine succinate - 4 mg,

inosine - 80 mg,

excipients 16 mg

For the preparation of injectable form of the ingredients are mixed in the required proportions of the ingredients, the mixture was diluted in pre-purified water used in the pharmaceutical industry, add accessories, vases the VA, passed through Millipore filters with a diameter of 22 μm and then poured into ampoules or vials and check for tightness and sterility. Option lyophilized injectable form (more stable), in this case, the drug is filled into ampoules or vials, dried in a special freeze-drying at low temperatures [Azarenka YU. Liquid dosage forms". 2000; Milovanova LN. and other "production Technology of medicinal forms". 2002].

For the preparation of a medicinal product in the form of solid dosage forms, in particular enteric tablets, the mixture is pressed into tablets and cover gastro-resistant shell (enteric tablets), or by pressing granules and particles pre-coated gastro-resistant shell or compaction of pharmaceutical substances in a mixture with a gastro-resistant filler (Guruli). In the manufacture of tablets for use in the oral cavity make uncoated tablets obtained according to a special technology in order to release the medicinal substance or substances in the oral cavity and provide local or obscherezorbtivnymi actions (pill cheek, sublingual and other). It is possible to manufacture tablets forms with modified release coated or uncoated table the weave contain special excipients or received by a special technology that allows you to program the speed or place of release of the medicinal substance.

In technology use auxiliary substances permitted by the Pharmacopoeia of the USSR XI edition, it is preferable to use technology pre-granulation of the ingredients (wet granulation) in the manufacture of dosage forms. In the preparation of a medicinal product in the form of suppositories (solid dosage form consisting of a base and medicinal substances, rasplavljajushchajasja (dissolving, disintegrating) at body temperature) used the framework provided by the Pharmacopoeia of the USSR XI edition. The technological process is carried out in aseptic conditions with oversight of research the quality of the finished dosage form. The proposed tool regardless of the method of production has a high stability [Tikhonov A.I. "Technology of drugs". 2002].

Example 5. The defeat of the endothelium was investigated with hypertension in normotensive rats. Arterial hypertension was reproduced by an operation under General anesthesia. Opened the abdominal cavity was exposed area of the aorta and the radiating arteries of the kidneys and put titanium spiral ring, reduce the surrounding lumen of the aorta to 2/3 of its diameter. Blood pressure was measured by using a sensor with a rubber cuff on the tail of the animal. The signal from the sensor was registered on mingograph EMT-118. animals were subjected to euthanasia at 15, 20 and 35 days after surgery.

Table 1
Dynamics of changes in the content of endothelin-1 and vascular endothelial growth factor in arterial hypertension under the influence of various tools
ConnectionThe control (intact animal)Arterial hypertension
control+ Inosine+ 3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridine succinate, 6 mgThe pharmaceutical composition of (3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridine succinate 6 mg, inosine - 80 mg)
Endothelium-1, pkg/mg0,4±0,13,9±0,1*2,8±0,1*3,0±0,2*1,7±0,1#
Safr, PCG/ml54±430 is 5* 50±4#45±4#68±4#
The tumor necrosis factor - α (TNF-α), PCG/ml6,1±0,212,1±0,2*9,2±0,3*#10,4±0,5*#6,5±0,2*#
Note: compared with the control (intact animals) - *with monitoring (arterial hypertension) -#, - reliability of differences average, P<0,01

Table 1A
Dynamics of changes in the content of endothelin-1 and vascular endothelial growth factor in arterial hypertension under the influence of different tools in different doses (continued).
ConnectionThe control (intact animal)Arterial hypertension
+ 2-methyl-6-ethylpyridine, 1.0 mg+2-methyl-6-ethylpyridine, 1.0 mg + inosine 40 mg+3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridine succinate, 2.0 mgThe pharmaceutical composition of (3-(N,N-dime is ylcarbamate)-2-ethyl-6-methylpyridine succinate - 2 mg inosine - 40 mg)
Endothelin-1, pkg/mg0,4±0,12,9±0,2*1,3±0,2*2,0±0,3*1,5±0,1#
Safr, PCG/ml54±433±3*44±3#49±4#66±2#
The tumor necrosis factor - α (TNF-α), PCG/ml6,1±0,28,9±0,1*6,9±0,3*#7,1±0,4*#5,8±0,3#

Studies have shown the pharmaceutical composition of 3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridine succinate and purine - inosine, allows to achieve a stable reduction of endothelin-1 in the blood and to increase the activity of endothelial growth factor. The positive factors changes the state of the endothelium is closely associated with reduced marker of the inflammatory response, proinflammatory cytokines - tumor necrosis factor - α (TNF-α). The positive therapeutic effect of the combination significantly superior effect as the optimal dose of inosine (purine)and 3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridine succina the and. The obtained data confirm the direct effect of the developed tools on the functional activity of the endothelium.

Example 6. The defeat of the endothelium was investigated in an experimental model of diabetes mellitus type II in rats-males (weight 200-250 g)reproduced by the introduction of streptozotocin (50 mg/kg intraperitoneally once in 1 ml of 0.9% NaCl solution). After the introduction of streptozotocin 10 days the animals of the 1st experimental group was administered a composition prepared in accordance with example 2, the 2nd experimental group was administered a composition prepared in accordance with example 3, the 3rd experimental group was administered a composition prepared in accordance with example 4, intramuscularly (dissolved in 1 ml of 0.9% NaCl solution per 1 animal) daily for 10 days. Rats of the 1st control group after the introduction of streptozotocin on a similar scheme was received injections of 0.9% NaCl solution, 2nd control group was injected 3-hydroxy-6-methyl-2-ethylpyridine succinate 5 mg (dissolved in 1 ml of 0.9% NaCl solution per 1 animal), 3rd control group - 3-hydroxy-6-methyl-hydroxypyridine hydrochloride 2 mg (dissolved in 1 ml of 0.9% NaCl solution per 1 animal). The comparison group served prkticheski healthy intact animal. Each group consisted of 20 animals. Determination of blood glucose was performed on an empty stomach (food cleaned up after 14 hours on the 10th and 30th days after the introduction of streptozotocin. IP is the study of the influence of the pharmaceutical composition on fasting glucose, insulin content of endothelin-1 and SAR held on the 10th and 30th day after the introduction of streptozotocin.

Table 2
Dynamics of changes in the content of endothelin-1 and vascular endothelial growth factor when streptozotocin diabetes under the influence of various tools
ConnectionIndicators
Glucose, mol/lInsulin, mkme/mlThe endothelium-1, pkg/mgSafr, PCG/ml
The intact4,2±0,424,0±2,51,2±0,254±4
Control group 18,5±0,5*5,0±0,8*3,5±0,462±4
10,2±0,5*2,3±0,3*6,8±0,8*25±8*
Control group 28,9±0,4*5,3±0,5* 3,2±0,364±5
9,6±0,5*5,3±0,3*5,6±0,5*35±7*
Control group 38,6±0,4*5,0±0,3*3,4±0,469±3
9,1±0,2*6,2±0,3*#5,4±0,2*#39±2*#
Experimental group 19,1±0,4*4,2±0,3*#4,3±0,5*#65±4*#
7,1±0,4*#7,8±0,4*#3,3±0,3*#66±5*#
Experimental group 29,1±0,4*4,2±0,3*#4,3±0,5*#68±4*#
6,6±0,4*12,0±0,9*3,0±0,272±4*#
Experimental group 39,0±0,4*4,1±0,3*#3,9±0,5*#6±5*#
9,1±0,4*4,2±0,3*#2,3±0,5*#78±4*#
Note: the first line of each group are the indicators to 10 days after the introduction of streptozotocin (before treatment), the second on the 30th day after the introduction of streptozotocin and 20-day course of treatment. Compared with the control (intact animals) - *with monitoring (diabetes without treatment, control group 1) -#, - reliability of differences average, P<0,01

As shown by studies of pharmaceutical compositions based on derivatives methylpyridine or its pharmaceutically acceptable salts and purine, allows to achieve a stable reduction of endothelin-1 in the blood and to increase the activity of endothelial growth factor and in all respects superior to the action methylpyridine derivatives separately. The obtained data confirm the direct effect of developed drugs on the functional activity of the endothelium.

Example 7. The effect of the pharmaceutical composition was performed on a model of experimental atherosclerosis in rabbits in accordance with the requirements of the Pharmacological Committee of Ministry of health of Russia [Methodical recommendations on experimental preclinical studied the Yu of new pharmacological substances. M., 2000: 224-227]. Modeling alimentary atherosclerosis in rabbits was accompanied by the creation of a powerful dyslipidemia in the blood and a significant accumulation of lipids in organs: liver, adrenal gland and aorta. Thus, the level of total Palestrina (LDL) increased 40 times, triglyceride - 15 times, with 3.6 times decreased concentration XC antiatherogenic high-density lipoproteins (HDL) in serum as compared with intact animals. In aorto control rabbits occurred multiple increase cholesterol and the extent of involvement of the aorta, the visual assessment and analysis using morphometric studies were translated into a large number of atherosclerotic lesions as layered and diffuse character.

In the midst of dyslipidemia and atherosclero introduction pharmaceutical composition obtained in accordance with example 3 was improved lipid profile, blood (LDL serum decreased 1.5 times, and the indicator HDL cholesterol increased in 2 times). The content of endothelin-1 in aortic homogenates decreased from 7.8±1,1 PCG/ml to 3.1±0,5 (p<0,001) against 10-day intraperitoneal administration of the pharmaceutical composition. Whereas, under the influence of only 3-hydroxy-6-methyl-hydroxypyridine hydrochloride (2 mg, dissolved in 0.9% NaCl), also injected intraperitoneally for 10 days does not lead what about the significant decrease in the level of endothelin-1 in aortic homogenates (7,1±0,6 PCG/ml).

Example 8. Experimental investigations carried out on 60 white mongrel rats-females weighing 150-180 g Animals were kept in standard vivarium conditions of 10 animals in the cage. The diet of rats consisted of standard granulated feed, which they received 1 time per day. 24 hours before the experiment, the feeding of the animals that were on the open water mode, stopped. Calculation of LD50were made using the rapid method V.B. have been on the Prozorovsky [Prozorovsky V.B. have been, Prozorovsky BTW, Demchenko V.M. rapid method for determination of the average effective dose and its error // Pharmacology and toxicology, 1978, - s-502]. The objects of study were administered in a fixed time; days. In control;

experiments, animals were injected with saline, the amount, which was equivalent to the amount entered in the experimental groups. Research conducted by intraperitoneal injection of drugs, the control group was administered a placebo in the form of 0.9% NaCl solution.

Table 3
Comparative evaluation of sub-lethal doses (mg/kg) of aqueous solutions derived methylpyridine and their pharmaceutically acceptable salts for the various compounds and pharmaceutical composition defined in albino male rats the ri intraperitoneal administration
The compound or pharmaceutical compositionLD50mg
3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridin succinate109,5
2-ethyl-6-methyl-3-hydroxypyridinone808,7
2-methyl-6-ethylpyridine1296
3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridin succinate+inosine656,9
2-ethyl-6-methyl-3-hydroxypyridine succinate+inosine (6 mg+80 mg+auxiliary substances to 100 mg)1000,1
3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridin succinate+adenosine (6 mg+80 mg+auxiliary substances to 100 mg)433,4
3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridin succinate+gipoksantin (6 mg+80 mg+auxiliary substances to 100 mg)500,1
Note: the Toxicity and hazard class, respectively, the ability of the drug to cause poisoning and the level of this ability. The degree of toxicity of the substances are divided into 4 hazard class. First: highly toxic substances is TBA, LD50less than 1 mg of the drug per 1 kg of body weight. Second: highly toxic substances with LD50up to 200 mg/kg Three: srednetonnazhnye substances with LD50from 200 to 1000 mg/kg Four: toxic substances LD50more than 1000 mg/kg

Thus, as follows from the table, the present invention significantly reduces the toxicity of 3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridin succinate and thereby to expand the indications for its therapeutic application, there is a transition from the second risk class of the third class of danger of toxicity. This is important because, for example, antihypoxic effect 3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridin succinate significantly superior to 2-ethyl-6-methyl-3-hydroxypyridine succinate, however, conceded to him by therapeutic Diaconu safe use.

Example 9. A study of the stability of the preparations by the method of accelerated aging. The samples were put in storage at a temperature of 55°C.

Table 4
The results of the analysis of the aging of aqueous solutions of various derivative methylpyridine and their pharmaceutically acceptable salts for intravenous and intramuscular wvedeniami.detam accelerated aging at 55°C
No.Dosage formRetention at 55°CEquival. shelf life in usledDescriptionColorNote
13-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridin succinate 20 g + sodium chloride 5 g dissolved in 1 l of water for injection461 yearTransparentColorlessQuantity of the substance below the lower limit in the ampoule
days3 yearsColorless
138
2765 yearsTransparentColorless
Colorless
2If fileset 3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridin succinate + inosine + sodium chloride (in the ratio 2:80:18 wt.%) 46 days1 yearTransparent after dissolution in water for injection. ColorlessColorless ColorlessQty 3-(HN-dimetilan bamileke)-2-ethyl-6-metylene-DIN succinate on average limit of the norm, the number of inosine - average limit of normal during the whole period
1383 yearsTransparent after dissolution in water for injection. Colorless
2765 yearsTransparent after dissolution in water for injection. Colorless

3-hydroxy-6-methyl-2-ethylpyridine succinate - 60 mg 100 ml of water for injections46 days1 yearTransparent ColorlessColorless or stands comparison with the benchmark 6b
1383 years TransparentYellowish-green fluid exceeds the color pattern 6b and 6b
The lyophilisate 3-hydroxy-6-methyl-2-ethylpyridine succinate + inosine + excipients (in the ratio 5:80:15) wt.%)46 days1 yearTransparent after dissolution in water for injection Colorless
2765 yearsTransparent after dissolution in water for injection Colorless

The claimed invention allows to obtain a stable pharmaceutical composition for the treatment of diseases associated with endothelial dysfunction, characterized by the fact that as the active ingredient contains methylpyridine derivative or its pharmaceutically acceptable salt, purine and excipients, is in the form of a stable dosage forms and indicators of pharmacological efficacy, safety and stability during storage significantly exceeds existing drug among the STV.

1. Pharmaceutical composition for the treatment of diseases associated with endothelial dysfunction, characterized by the fact that as the active ingredient contains methylpyridine derivative or its pharmaceutically acceptable salt, purine and excipients, is in the form of a stable dosage forms in the following ratio, wt.%:

Derived methylpyridine1,0-6,0
or its pharmaceutically acceptable salt
purine10,0-80,0
ExcipientsRest

2. The pharmaceutical composition according to claim 1, characterized in that the active substance contains compounds from the group of: 3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridine succinate, 3-methylpyridin succinate, 2-ethyl-6-methyl-3-hydroxypyridine hydrochloride, 6-trichloromethyl-2-chloropyridin (nitrapyrin), 2-ethyl-6-methyl-3-hydroxypyridine succinate.

3. The pharmaceutical composition according to claim 1, characterized in that as purine contains inosine, adenosine, gipoksantin, mainly inosine.

4. The pharmaceutical composition according to claim 1, characterized by t the m that is by injection, freeze-dried, hard capsules, tablets, suppositories.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to diastereomers of isobornyl compounds of the structural formula (I), where R1=H and isobornyl fragments have the configuration (1S, 2R, 4R, 1'S, 2'R, 4'R) and (1R, 2S, 4S, 1'R, 2'S, 4'S), where R1=CH3 and isobornyl fragments have the configuration (1S, 2R, 4R, 1'R, 2'S, 4'S) or the isobornyl fragments have the configuration (1S, 2R, 4R, 1'S, 2'R, 4'R) and (1R, 2S, 4S, 1'R, 2'S, 4'S).

EFFECT: high antioxidant activity.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cosmetology. What is presented is using a cell culture prepared of one or more homogenous cell lines originated from cambium Panax ginseng, or extract thereof when preparing an anti-aging cosmetic composition.

EFFECT: invention provides the effective agent for preventing or suppressing the aging ensured by the antioxidant effect of the natural materials being the ingredients of the above composition.

7 cl, 7 dwg, 20 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a polyphenol derivative formulation and is used in cosmetics, nutrition science and therapy. The polyphenol derivative formulation possessing antioxidant and antiradical activity and having an effect on carbonyl stress. A method for preparing the formulation. The cosmetic formulation possessing antioxidant and antiradical activity and having an effect on carbonyl stress. Using the formulation in nutrition science. The formulation to be used as a therapeutic agent possessing antioxidant and antiradical activity and having an effect on carbonyl stress. The pharmaceutical formulation possessing antioxidant and antiradical activity and having an effect on carbonyl stress.

EFFECT: formulation has an effect on carbonyl stress.

23 cl, 11 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to an antioxidant preparation containing 5-aminosalicylic acid, quercetic and 5% alcoholic extract of propolis as an active agent, and Lutrol F127, Cremophore RH-40 and glycerol as a base in certain proportions.

EFFECT: preparation has the pronounced antioxidant action and is recommended for the correction of the free-radical oxidation processes.

1 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to pharmacology, neurology and cell engineering. What is described is using Napelline as a cerebroprotective agent. The mode of action of the agent is activation of cerebral neural stem cells.

EFFECT: invention achieves extending the range of high-effective cereroprotective agents.

3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely preparing an agent of hindu lotus seed extract (Nelumbo nucifera) possessing immunotropic and antioxidant activity. The agent possessing immunotropic and antioxidant activity prepared by extraction of hindu lotus seed extract (Nelumbo nucifera) in 50% ethanol in a Soxhlet extraction apparatus in the specific proportions.

EFFECT: agent possesses manifested immunotropic and antioxidant activity.

6 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery, and may be used for prevention of acute postoperative pancreatitis. For this purpose, the underlying background therapy is combined with intravenous bolus administration of dalargin 0.002 g and the antioxidant thioctic acid depending on a risk level of the complication measured in terms of the area of intervention in abdominal operations. A high risk level requires thioctic acid to be administered in a dose of 600 mg intravenously drop-by-drop 1 hour before the operation and on the following day, and thioctic acid in a dose of 300 mg on the third day intravenously drop-by-drop. In a moderate risk level thioctic acid is administered intravenously drop-by-drop in a dose of 600 mg 1 hour before the operation and in a dose of 300 mg on the following day. And in a low risk level, thioctic acid is administered intravenously drop-by-drop in a dose of 300 mg 1 hour before the operation.

EFFECT: method enables the more effective prevention of acute postoperative pancreatitis ensured by the combined use of drugs with antisecretory and antioxidant activity.

2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and represents application of calix[6]arene of formula (1A) or (1B) for treatment of skin contamination with uranium, plutonium or americium.

EFFECT: invention ensures stability of calix[6]arenes with actinides in static mode.

5 cl, 4 ex, 11 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to otolaryngology. Dissection of adhesion between lateral and medial wall of nasal cavity is performed by heated distal end of semiconductor laser lightguide in contact way in continuous mode. Power of laser radiation is 8.5 W. Time of exposure from 5 to 15 seconds. 1% solution of emoxipin is introduced into zone of coagulation necrosis in form of injection. Lighting of necrosis zones is carried out by means of laser physiotherapeutic apparatus "LA-2". Course of treatment constitutes 5-7 days.

EFFECT: method ensures recovery of nasal respiration, prevents possibility of recurrence development.

1 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to otorhinolaryngology. A heated distal flat end of a light guide of ATKUS-15 semi-conductor laser is used to excise a cicatrical diaphragm in a contact continuous mode. Laser radiating power is 8.5-9 Wt. An exposure length is 30 to 60 seconds. That is followed by introducing 1% emoxipin 1 ml into a formed coagulation necrosis. The necrotic areas are exposed to LA-2 physiotherapeutic laser apparatus. The therapeutic course makes 7 days.

EFFECT: method provides the nasal breathing recovery, prevents any possible recurrences.

1 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: present compounds can be used, for example, in treating diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system and the endocrine system.

EFFECT: described compounds are useful in treating a range of diseases or conditions in which interaction with the histamine H3 receptor is beneficial.

9 cl, 216 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel phenylaminopyrimidine compounds of formula I, which are JAK kinase inhibitors. In particular, these compounds selectively act on JAK2 kinase. The compounds can be used to treat diseases such as immunological and inflammatory diseases; hyperproliferative diseases, myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases. In the compound of formula I , Q and Z are independently selected from N and CR1; R1 is independently selected from hydrogen, halogen, R2, OR2, OH, R4, OR4, CN, CF3, (CH2)nN(R2)2, where n equals 1,2 or 3, NO2, R2R4, NR2SO2R3, COR4, NR2COR3, CO2H, CO2R2, NR2COR4, R2CN, R2OH, R2OR3 and OR5R4; or two substitutes R1 together with carbon atoms with which they are bonded form an unsaturated 5- or 6-member heterocyclic ring containing 1-4 N atoms; R2 is C1-4alkyl; R4 is R2, C2-4alkenyl or phenyl; R4 is NH2, NHR2, N(R1)2, substituted or unsubstituted morpholine, CH2morpholine, substituted or unsubstituted thiomorpholine, substituted or unsubstituted thiomorpholino-1-oxide, substituted or unsubstituted thiomorpholino-1,1-dioxide, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted imidazolyl, substituted or tetrahydrofuranyl unsubstituted and substituted or unsubstituted tetrahydropyranyl; R5 is C2-4alkylene; R6-R9 are independently selected from H, RXCN, halogen, substituted or unsubstituted C1-4alkyl, OR1, CO2R1, N(R1)2, NO2 and CON(R1)2, wherein at least one of R6-R9 is RXCN; the rest of the values of the radicals are given in the claim.

EFFECT: high efficiency of treatment.

29 cl, 7 dwg, 2 tbl, 93 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (1) or salts thereof, where in formula (1) R1 is a lower C1-C6alkyl group, a lower C3-C6cycloalkyl group, a phenyl group, a heterocyclic group, which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom and a sulphur atom, or a phenyl(C1-C6alkyl) group; in cases when R1 is a lower C1-C6alkyl group, that lower C1-C6alkyl group can have, as substitute(s), one, two or three groups selected from a halogen atom, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one or two heteroatoms in the ring, selected from a nitrogen atom and an oxygen atom, a carboxyl group, a lower C1-C6alkoxycarbonyl group, a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a phenyl group; in cases when R1 is a phenyl group, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom or a sulphur atom, or a phenyl(C1-C6alkyl) group, that phenyl, heterocyclic or phenyl(C1-C6alkyl) group can contain, as substitute(s), one, two or three groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group or a lower C1-C6alkoxy group; R2 is a hydrogen atom or a lower C1-C6alkyl group; R3 is a hydrogen atom or a lower C1-C6alkyl group; R4 and R5 can be identical or different and are a hydrogen atom or a lower C1-C6alkyl group; R6 is a hydrogen atom or a lower C1-C6alkyl group; R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom; in cases where R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom, that phenyl or heterocyclic group can contain, as substitute(s), one or two groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group, a lower C1-C6alkoxy group and a nitro group; W is an oxygen atom or NR8; R8 is a hydrogen atom or a lower C1-C6alkyl group; X is an oxygen atom or a sulphur atom; Y is a lower C1-C6alkylene group; Z is an oxygen atom, a sulphur atom, NR9 or OCO; R9 is a hydrogen atom or a lower C1-C6alkyl group. The invention also relates to a pharmaceutical composition based on said compounds, having GR binding activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine as glucocorticoid receptor modulators.

10 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to naphthalene carboxamide derivatives of general formula I which possess the properties of protein kinase or histone deacetylase inhibitors. The compounds can find application for preparing a drug for treating inflammatory diseases, autoimmune diseases, oncological disease, diseases of the nervous system and neurodegenerative diseases, allergies, asthma, cardiovascular diseases and metabolic diseases or disease related to hormonal diseases. In general formula I: , Z represents CH or N; each of the groups R1, R2 and R3 represents hydrogen, halogen, alkyl, alkoxy or trifluoromethyl; R4 represents or X represents a benzene ring or a pyridine ring; R5 represents one or more substitutes specified in a group consisting of hydrogen, halogen, alkyl, alkoxy or trifluoromethyl. The invention also refers to a method for preparing the above compounds, a pharmaceutical preparation and using them.

EFFECT: preparing the compounds which possess the properties of protein kinase or histone deacetylase inhibitors.

13 cl, 10 tbl, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention also relates to pharmaceutical compositions. Compounds of the formula given below are used for treatment of diabetes mellitus of type 1 or type 2, hyperglycemia, diabetic complications, insulin-resistance, metabolic syndrome, hyperinsulinemia, hypertension, obesity, edema, dislipidemia, chronic heart failure, atherosclerosis or related diseases, and can be introduced simultaneously or successively with at least one additional therapeutic agent, selected from group consisting of anti-diabetes agent, agent, which reduces content of lipids/modulates lipids, agent for treatment of diabetic complications, anti-obesity agent, hypotensive agent, anti-hyperuricemia agent and agent for treatment of chronic heart failure, atherosclerosis or related diseases.

EFFECT: claimed are compounds which possess inhibiting action on sodium-dependent co-carrier of glucose SGLT.

8 cl, 50 ex, 1 tbl, 15 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely paediatric resuscitation, and may be used for treating depressed cases in newborns with a surgical pathology. That is ensured by intravenous administration of 20% neat human serum albumin 3-5 ml/kg (no more than 1 g/kg) a day for 10 minutes. Observing persistent arterial hypertension requires an additional intravenous infusion of normal saline 3 ml/kg for 15 minutes, while in the presence of recurrent persistent arterial hypertension, 6% hydroxyethyl starch 3 ml/kg for 30 minutes is administered intravenously.

EFFECT: method enables a higher effect of the performed anti-shock therapy combined with reduced postoperative complications ensured by the prevented liquid outflow from the blood flow that might happen due to high oncotic and osmotic pressure of the concentrated solution of human albumin with contracting the infusion therapy extent.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of the following general formula [1a], wherein R1 represents (1) a hydrogen atom, (2) C1-C6alkyl group, (3) C2-C6alkenyl group, (4) C2-C6alkynyl group, (5) C1-C6alkoxygroup, (6) hydroxyC1-C6alkyl group, (7) C1-C6alkoxy(C1-C6)alkyl group, (8) -CONR11R12, wherein R11 and R12 are identical or different, and each represents a hydrogen atom or C1-C6alkyl group, (9) phenyl group or (10) a five-member heteroaryl group which contains at least one heteroatom specified in a group consisting of a nitrogen atom and oxygen atom, and which may be substituted by C1-C6alkyl group; R2 represents (1) a halogen atom, (2) C1-C6alkyl group, (3) hydroxy group or (4) C1-C6alkoxy group; p is equal to 0, 1, 2 or 3; X represents a carbon atom or nitrogen atom; m1 is equal to 0, 1 or 2; m2 is equal to 0 or 1; the spiro ring AB may be substituted by 1-5 identical or different, specified in a group consisting of (1) hydroxy group, (2) C1-C6alkyl group, (3) C1-C6alkoxygroup and (4) oxo group; n1 is equal to 0, 1, 2, 3 or 4; n2 is equal to 1, 2, 3 or 4; n3 is equal to 0, 1 or 2, provided n2+n3 is equal to 2, 3 or 4; and a bond presented by the symbol means a single bond or a double bond, provided the three adjoining carbon atoms forms no allene bond presented by formula: C=C=C, or a pharmaceutically acceptable salt thereof.

EFFECT: invention refers to a pharmaceutical composition possessing GPR40 agonist activity, to a GPR40 agonist drugs; to a hypoglycemic agent stimulating insulin secretion on the basis of the above compounds.

45 cl, 42 tbl, 120 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to using the preparation Infliximab as an agent regulating erythrocytes metabolism in the patients with inflammatory intestinal diseases.

EFFECT: invention provides normalising the cell metabolic processes.

1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 1,2-dihydroquinoline derivatives of general formula , or to a pharmaceutically acceptable salt thereof, wherein R1 represents a lower alkyl group; R2 represents a hydrogen atom; each of R3 and R4 represents a lower alkyl group; R5 represents a lower alkyl group; R6 represents a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group; X represents -CO-, -C(O)NR8 - or -S(O)2-; each of R7 and/or R8 may be identical or different, and represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, a phenyl or naphthyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a lower alkoxy group, a phenoxy group; provided R7 and/or R8 represent a lower alkyl group, a lower alkoxy group, the mentioned lower alkyl group and lower alkoxy group may contain one or three groups specified in a halogen atom, a phenyl group, an unsubstituted monocyclic 6-member heterocyclyl with one heteroatom specified in a nitrogen atom, and 5 carbon atoms in a cycle, a lower alkoxy group, and -NRaRb as a substitute (substitutes); provided R7 and/or R8 represent a phenyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a phenoxy group, the mentioned phenyl group, saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, phenoxy group may contain one or two groups specified in a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a phenyl group, a hydroxyl group, a lower alkoxy group, a halogen-substituted lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group, -NRaRb, a nitro group and a cyano group as a substitute (substitutes); Ra and Rb may be identical or different, and each of them represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group; Y represents a lower alkylene group; Z represents an oxygen atom; p is equal to 2, provided p is equal to 2, R6 may be identical or different. The invention also relates to a pharmaceutical composition and a glucocorticoid receptor modulator of the compound of formula (1).

EFFECT: there are produced new 1,2-dihydroquinoline derivatives possessing glucocorticoid receptor binding activity.

7 cl, 1 tbl, 4 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to new compounds represented with common formula (I) to its pharmaceutically acceptable salts that have inhibiting activity in relation to products of amyloid β-protein (Aβ42) or decomposition with ferment of beta-site of amyloid-β (BACE1) precursor. In general formula , circle A represents aryl chosen from phenyl, which can be replaced with substitutes with number of 1 to 3, which have been chosen from a group of substitutes α, 5-6-membered heteroalkyl with sulphur atom as heteroatom that can have 1 to 3 substitutes chosen from a group of substitutes α, or 9-10-membered benzo-condensed heterocyclic group having 2 atoms of oxygen in heterocyclic part of the above group, which can be replaced with substitutes with number of 1 to 3, which have been chosen from the group of substitutes α, L means ordinary bond, -NRLCO- (in which RL means hydrogen atom) or -NRLCO-C1-6alkyl (in which RL means hydrogen atom). Circle B represents 5-6-membered heteroaryl or saturated heterocyclic group with 1-3 heteroatoms in a cycle, which have been chosen from a group of hydrogen, oxygen or sulphur atoms, each of which can have 1 to 3 substitutes chosen from the group of substitutes α, or 9-10-membered benzo-condensed group having 2 oxygen atoms in heterocyclic part of the above group, X means methylene that can have 1 to 2 substitutes chosen from the group of substitutes α, Y means methylene that can have 1 to 2 substitutes chosen from the group of substitutes α, and Z means oxygen atom. The rest substitutes are specified in the claim.

EFFECT: compounds can be used for treatment of neurodegenerative diseases caused with Aβ presented with Alzheimer disease as a typical case.

9 cl, 13 dwg, 12 tbl, 88 ex

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