N,n'-substituted 3,7-diazabicyclo[3,3,1]nonanes with pharmacological effect, pharmacological compositions on their base, and application method

FIELD: chemistry.

SUBSTANCE: invention concerns new N,N'-substituted 3,7-diazabicyclo[3.3.1]nonanes of the general formula 1: (HY), where HY is hereinafter a pharmacologically acceptable acid; E is , R1 is H, low-grade alkyl, C1-C10alkoxy; R2 is generally represented by the general formulae (1.1a) , (1.2a) , (1.3a) , (1.4a) , where L is CHR11, ; R11 is H, NH2; R15 is H, low-grade alkyl, C1-C10alkoxy; R19, R19', R20 and R20' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R24 and R25 can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R3 and R3' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R4 and R4' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; X is a group of the general formula: (CH2)m-Z, where m=0, while Z is acetyl, or X is a valence link. Compounds I are capable of AMPA receptor activity modulation and hence can be applied in pharmaceutical compositions.

EFFECT: obtaining compound capable of AMPA receptor activity modulation.

12 cl, 2 dgw, 2 tbl, 11 ex

 

This invention relates in General to new derivatives of N,N′-substituted diazabicyclononanes capable of allosteric modulation of AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid)receptors. More specifically, the present invention relates to new derivatives of N,N′-substituted 3,7-diazabicyclo[3.3.1]nonanes with pharmacological activity, and can be used for the treatment of AD (Alzheimer's disease), BP (Parkinson's disease) and other neurodegenerative pathologies. The present invention also relates to pharmaceutical compositions containing these compounds. Also the present invention relates to a method of treatment of the above diseases.

Glutamatergic system, which includes and AMPA receptors, is a major excitatory neurotransmitter system in the brain of mammals, including humans, and participates in the implementation of a series of physiological and pathological processes. It is known that a wide range of neuropsychiatric disorders, such as BP, BA and similar neurodegenerative disorders associated with dysregulation of these processes (Doble A. Pharmacology and Therapeutics. 1999, V.81, N3, pp.163-221).

AMPA receptors are unevenly distributed in the brain. High concentration of these receptors was detected in poverkhnostnykh new cortex (neocortex and in the hippocampus [Monaghan, Brain Res., 1984, V.324, pp.160-164]. Studies in humans and animals have shown that these structures are mainly responsible for sensorimotor processes and represent the matrix for vysokobaricheskikh reactions. Thus, due to AMPA receptor signals are transmitted in the neural networks of the brain responsible for a set of cognitive processes.

For the reasons stated above, drugs that enhance the functioning of AMPA-receptors involved in the regulation of processes that form the memory, and the processes responsible for the restoration of nerve cells. In experiments it has been shown [Arai, Brain Res., 1992, V.598, pp.173-184]that the enhancement of AMPA-mediated synaptic response increases the induction of long-term potentiation (LTP). LTP is an increase in the strength of synaptic contacts, which is accompanied by a constant physiological activity in the brain, which is typical during the learning processes. Substances that enhance the functioning of AMPA receptors contribute to the induction of LTP [Granger, Synapse, 1993, V.15, pp.326-329; Arai, Brain Res., V.638, pp.343-346].

There is much evidence that LTP is the physiological basis of memory. For example, substances that block LTP, inhibit the mechanisms of memory in animals and humans [Cerro, Neuroscience, 1992, V.46, pp.1-6].

At the moment there are many compounds that activate AMPA receptors. In the example, aniracetam [Ito, J. Physiol, 1990, V.424, R-543]. These authors have shown that aniracetam enhances synaptic signal at multiple sites in the hippocampus, not acting on NMDA-mediated signals [Staubli, 1990, Psychobiology, V.18 RR-381; Xiao, Hippocampus, 1991, V.1, pp.373-380]. Aniracetam has properties "quick attack", but it is unsuitable for long-term use because of the lack of lasting effect, which is characteristic for "behavioral-significant (relevant)" drugs. This medication works only at high concentrations (0.1 mm) and, as has been shown [Guenzi, J.Chromatogr., 1990, V.530, RR-406]when the peripheral application it turns into anisoyl-GABA (about 80% of drugs), which has no aniracetam-like effects. Unfortunately, in most cases, compounds with neuroprotective activity, or act in large doses, or have a high toxicity.

Recently discovered a fairly wide class of substances, which in its physiological action are allosteric modulators of AMPA receptors. These compounds are more stable and more efficient than previously known, as was shown in experiments [Staubli, PNAS, 1994, V.91: pp.11158-11162].

Due to the rapid development of research related to the study of pharmacological activity of these compounds was recently lips is oflen experimental fact, that intense ion current, which is caused by the action of such allosteric modulators of AMPA receptors with subsequent depolarization of postsynaptic membrane, triggers the expression of genes responsible for the synthesis of neurotrophins NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor), growth factors, nerve tissue [Legutko Century, Neuropharmacology, 2001, V.40, pp.1019-1027; Ebadi, Neurochemistry International, 2000, V.30, pp.347-374]. The process of expression of genes responsible for the synthesis of neurotrophins, is of great importance in the treatment of neurodegenerative disorders and other neuropsychiatric diseases. Thus, it was shown [Siuciak, Brain Research, 1994, V.633, pp.326-330]that BDNF has antidepressant effects in behavioral models of despair and reduces the concentration of blood glucose in mice with diabetes mellitus [Ono, J. Biochem. and Bioph. Res. Commun., 1997, Vol.238, pp.633-637].

The task to be solved by the invention, is expanding Arsenal of tools that can be used as a new efficient allosteric modulators of AMPA receptors.

As a result of research aimed at the search for such compounds, including trigger the expression of genes responsible for the synthesis of neurotrophins - growth factors, nerve tissue, in particular, among the compounds with similar activity, the inventors have found wide g is the UPP new derivatives of N,N′ -substituted 3,7-diazabicyclo[3.3.1]nonanes in the form of free bases and salts with pharmacologically acceptable acids, collectively described in detail below and is one aspect of the present invention.

Another aspect of the invention is the physiological activity of these compounds, which is manifested in the ability at various concentrations to cause positive allosteric modulation of AMPA receptors or antagonistic action. This gives grounds to consider these connections, on the one hand, as positive allosteric modulators, which have cognitive-enhancing properties, on the other - as potential blockers of AMPA receptors at higher concentrations.

An additional aspect of the invention is to provide pharmaceutical compositions comprising an effective amount of the derivative N,N′-substituted 3,7-diazabicyclo[3.3.1]nonanes in the form of free bases and salts with pharmacologically acceptable acids of General formula 1 and a therapeutically acceptable inert auxiliary agents, such as carriers, fillers, etc. and how they can be applied.

The technical result of the present invention is to provide new derivatives of N,N′-substituted 3,7-diazabicyclo[3.3.1]nonanes, including grounds and the x salts with pharmacologically acceptable acids, which in the aggregate represented by the General formula (1):

in which HY hereinafter, is pharmacologically acceptable acid;

E represents a carbonyl group;

R1represents H, lower alkyl, C1-C10alkoxy;

R2in the aggregate represented by the General formula (1.1A), (1.2A), (1.3a), (1.4):

In which L represents CHR11, carbonyl group;

R11represents H, amino;

R15represents H, lower alkyl, C1-C10alkoxy;

R19R′19, R20and R′20may be the same or different and each independently represents H, lower alkyl, C1-C10alkoxy;

R24and R25may be the same or different and each independently represents H, lower alkyl, C1-C10alkoxy;

R3and R′3may be the same or different and each independently represents H, lower alkyl, C1-C10alkoxy;

R4and R′4may be the same or different and each independently represents H, lower alkyl, C1-C10alkoxy;

X represents a group of General formula: (C 2)m-Z, where m=0, a Z means acetyl, or X represents a valence bond.

Used in the above definitions and the subsequent description, the term "lower alkyl" means alkyl group with straight or branched chain, containing from 1 to 10 carbon atoms, examples of which are methyl, ethyl, isopropyl, tert-butyl, isopentyl and similar.

The term "alkoxy" means the group AlkO-in which the alkyl part is as defined above alkyl group. Examples of alkoxy groups include methoxy, butoxy, isopropoxy and similar groups.

The term "pharmacologically acceptable acid" encompasses all pharmaceutically acceptable acids, both inorganic (e.g., hydrochloric, sulfuric, phosphoric, etc.); and organic (e.g., formic, acetic, oxalic, citric, tartaric, maleic, succinic, n-toluene-acid, metallinou etc).

Preferred variants of the embodiment of the invention.

Among the compounds of formula (1)constituting one of the objects of the present invention, preferred are the following four groups of compounds which can be represented by the formulas (1.1), (1.2), (1.3) and (1.4)below. In particular, preferred compounds are:

1.1. N,N′-substituted 3,7-diazabicyclo[3.3.1]nonanes General formula (1.1):

1.2. N,N′-substituted 3,7-diazabicyclo[3.3.1]nonanes General formula (1.2):

1.3. N,N′-substituted 3,7-diazabicyclo[3.3.1]nonanes General formula (1.3):

1.4. N,N′-substituted 3,7-diazabicyclo[3.3.1]nonanes General formula (1.4):

in which HY hereinafter, is pharmacologically acceptable acid;

E, R1, R3R′3, R4R′4, X, L, R15, R19R′19, R20R′20, R24and R25have the meanings given above for formula 1.

The most preferred compound of formula 1.1 (in the form of pharmacologically acceptable salts and/or free basis) is:

3,7-bis(2,3-dihydro-1,4-benzodioxin-6-ylcarbonyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-he.

The most preferred compound of formula 1.2 (in the form of pharmacologically acceptable salts and/or free basis) is:

3,7-bis(1,3-benzodioxol-5-ylcarbonyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-he.

The most preferred compounds of formula 1.3 (in the form of pharmacologically acceptable salts and/or free bases) are:

1,5-dimethyl-3,7-bis(cinoxacin-6-ylcarbonyl)was 3.7-diazabicyclo[3.3.1]nonan-9-he;

3,7-bis[(2,3-dimethylquinoxaline-6-yl)carbonyl]-1,5-dimethyl-3,7-disabi is yclo[3.3.1]nonan-9-he.

The most preferred compound of formula 1.4 (in the form of pharmacologically acceptable salts and/or free basis) is:

N,N′bis[4-methoxy-3-(1H-pyrazole-1-ylmethyl)benzyl]-1,5-dimethyl-9-oxo-3,7-diazabicyclo[3.3.1]nonan-3,7-dicarboxamide.

Below the invention is described in more detail by using examples of the preparation of specific compounds.

The initial reactants and final products obtained are known in the literature methods or are industrially available.

Scheme of synthesis of the final compounds are presented below:

Scheme 1:

Scheme 2:

Where in the case of scheme 1 R′′ represents halogen or hydroxy group, and in the case of scheme 2 R′′ represents an amino group.

The structure of the obtained compounds was confirmed by chemical data, spectral analysis and other physico-chemical characteristics.

The following examples illustrate but do not limit the invention.

Example 1. 3,7-bis(2,3-dihydro-1,4-benzodioxin-6-ylcarbonyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-he (connection 1, corresponding to the General formula 1.1).

To a solution of 39.8 g (0.2 mol) of acid chloride of benzodioxane acid in absolute benzene is added with stirring to 55.2 g (0.4 mol) of finely ground, dry is carbonate potassium and 24.1 g (0.1 mol) of the hydrochloride of 1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-it. Boil for six hours. After that, the precipitate is filtered off. The filtrate is evaporated to dryness. The remainder is applied to the chromatographic column with silica gel. As additionally separated by using chloroform. Selected fraction with Rf=0.43 on Silufol in the system CHCl3-EtOH (50:1). The solvent is distilled off and get a clear oil, which is about 30 min boiled in ethyl ether. Whereupon it crystallizes.

Yield: 72%.

PMR-spectrum (CDCl3δ, ppm): 1.00 C. (6N); 3.00 D. (2H, J 12 Hz); 3.34 D.(2H, J 12 Hz); 4.22 D. (2H, J 12 Hz), 4.84 D. (2H, J 12 Hz); 4.3 C. (8H); aromatic protons [7.06 Shostakovich (2H, J2,18.4 Hz, J2,32.4 Hz); 7.09 D. (2H, J3,22.4 Hz)].

Example 2. 3,7-bis(1,3-benzodioxol-5-ylcarbonyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-he (compound 2, corresponding to the General formula 1.2).

To a solution of 37 g (0.2 mol) of acid chloride of piperonylic acid in absolute benzene is added with stirring to 55.2 g (0.4 mol) of finely powdered potassium carbonate and 24.1 g (0.4 mol) of the hydrochloride of 1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-it. Boil for seven hours. After that, the precipitate is filtered off. The filtrate is evaporated to dryness. The remainder is applied to the chromatographic column with silica gel. As additionally separated by using chloroform. Selected fraction with Rf=0.4 on Silufol in the system CHCl3-EtOH (50:1). The solvent is distilled off and get a clear oil, to the / establishment, which is about 30 min boiled in ethyl ether. Whereupon it crystallizes.

Yield: 69%.

PMR-spectrum (CDCl3δ, ppm): 1.00 C. (6N); 3.00 D. (2H, J 12 Hz); 3.34 D. (2H, J 12 Hz); 4.22 D.(2H, J 12 Hz), 4.84 D. (2H, J 12 Hz); 4.3 C. (8H); aromatic protons [7.06 Shostakovich (2H, J2,18.4 Hz, J2,32.4 Hz); 7.09 D. (2H, J3,22.4 Hz)].

Example 3. 3,7-bis[(2,3-dimethylquinoxaline-6-yl)carbonyl]-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-he (compound 3, corresponding to the General formula 1.3). To a solution of 40.4 g (0.2 mol) of 2,3-dimethylquinoxaline-6-carboxylic acid in absolute dimethylformamide is added under stirring and cooling in an ice bath values 35,64 g (0.22 mol) CDI (N,N′-carbonyldiimidazole). Stirring is carried out for eight hours. Then to the reaction mixture add a solution to 24.1 g (0.1 mol) of the hydrochloride of 1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-she DBU (1,8-diazabicyclo[5.4.0]under-7). Heated to 50°and warm for nine hours. After that, the precipitate is filtered off. The filtrate is evaporated to dryness. The remainder is applied to the chromatographic column with silica gel. As additionally separated by using chloroform. Selected fraction with Rf=0.57 on Silufol in the system CHCl3-EtOH (20:1). The solvent is distilled off and get a clear oil which crystallizes.

Yield: 58%.

PMR-spectrum (CDCl3δ, ppm): 0.97 C. (6N); 3.00 D. (2H, J 12 Hz); 3.34 D. (2H, J 12 Hz); 4.22 D. (2H, J 12 Hz), 4.84 D. (2H, J 12 Hz); aromatic protons [7.80 D. (1H, J=Hz), 8.18 S. (1H), 8.20 D. (1H, J=5.8 Hz), 8.94 S. (2N)].

Example 4. N,N′bis[4-methoxy-3-(1H-pyrazole-1-ylmethyl)benzyl]-1,5-dimethyl-9-oxo-3,7-diazabicyclo[3.3.1]nonan-3,7-dicarboxamide (compound 4, corresponding to the General formula 1.4).

To a solution of 52 g (0.2 mol) of 4-methoxy-3-(1H-pyrazole-1-ylmethyl)benzoic acid in absolute dimethylformamide is added under stirring and cooling in an ice bath values 35,64 g (0.22 mol) of CDI. Stirring is carried out for six hours. Then to the reaction mixture add a solution to 24.1 g (0.1 mol) of the hydrochloride of 1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-it is in DBU. Heated to 50°and warm for seven hours. After that, the precipitate is filtered off. The filtrate is evaporated to dryness. The remainder is applied to the chromatographic column with silica gel. As additionally separated by using chloroform. Selected fraction with Rf=0.68 on Silufol in the system CHCl3-EtOH (50:1). The solvent is distilled off and get needle-like white crystals.

Yield: 79%.

PMR-spectrum (CDCl3δ, ppm): 0.97 C. (6N); 2.93 D. (2H, J 12 Hz); 3.22 D. (2H, J 12 Hz), 3.9 C. (6N), 4.05 D. (2H, J 12 Hz), 4.82 D. (2H, J 12 Hz), 5.36 square (4H); aromatic protons [6.23 S. (2H), 6.97 D. (2H, J 5.7 Hz), 7.05 S. (2H), 7.5 C. (4H), 7.62 D. (2H, J 5.9 Hz)].

Example 5. 3,7-bis[(cinoxacin-6-yl)carbonyl]-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-he(compound 5, the corresponding General formula 1.3). To a solution of 34.8 g (0.2 mol) cinoxacin-6-carboxylic acid in absolutehomemortgage added under stirring and cooling in an ice bath values 35,64 g (0.22 mol) of CDI. Stirring is carried out for five hours. Then to the reaction mixture add a solution to 24.1 g (0.1 mol) of the hydrochloride of 1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-it is in DBU. Heated to 50°and warm for eight hours. After that, the precipitate is filtered off. The filtrate is evaporated to dryness. The remainder is applied to the chromatographic column with silica gel. As additionally separated by using chloroform. Selected fraction with Rf=0.52 on Silufol in the system CHCl3-EtOH (20:1). The solvent is distilled off and get a clear oil which crystallizes.

Yield: 64%.

PMR-spectrum (CDCl3): 0.97 C. (6N); 3.00 D. (2H, J 12 Hz); 3.34 D. (2H, J 12 Hz); 4.22 D. (2H, J 12 Hz), 4.84 D. (2H, J 12 Hz); aromatic protons [7.80 D. (1H, J=5.8 Hz), 8.18 S. (1H), 8.20 D. (1H, J=5.8 Hz)].

Example 6. The basis of 3,7-bis{N-[4-methoxy-3-(1H-pyrazole-1-ylmethyl)benzyl]glycyl}-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-he.

To a solution of 48 g (0.15 mol) of 3,7-bis(chloroacetyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-it is in absolute dimethylformamide is added with stirring a solution of 64 g (0.3 mol) of [4-methoxy-3-(1H-pyrazole-1-ylmethyl)benzyl]amine in DBU. Stirring is carried out for 30 minutes Then evaporated the solvent to approximately 2/3 of the total volume. The residue is diluted five-fold excess of water relative to the solvent and extracted 4 times with methylene chloride. Extracts combine, evaporated to dryness and the nanos is t to the chromatographic column with silica gel. As additionally separated by using chloroform. Selected fraction with Rf=0.73 on Silufol in the system CHCl3-EtOH (50:1). The solvent is distilled off and get a clear oil, which was recrystallized from diethyl ether.

Yield: 85%.

PMR-spectrum (CDCl3δ, ppm): 0.97 C. (6N); 2.93 D. (2H, J 12 Hz); 3.22 D. (2H, J 12 Hz), C. 3,5 (4H), 3.9 C. (6N), 4.05 D. (2H, J 12 Hz), 4.5 OSS (2H), 4.82 D. (2H, J 12 Hz), 4.9 C. (4H), 5.3 D. (4H); aromatic protons [6.23 S. (2H), 6.97 D. (2H, J 5.7 Hz), 7.05 S. (2H), 7.3 days (4H, J 5.8 Hz), 7.62 D. (2H, J 5.9 Hz)].

Another aspect of the invention are compounds of General formula I, having the property of modulating the activity of AMPA receptors.

The authors used the definition of a potentiating effect of new compounds on Kainat-induced transmembrane currents in Purkinje neurons of the cerebellum of rats to focused search of compounds that can potentiate the response of AMPA receptors (and thereby cause the improvement of memory and cognitive functions).

Method of assessment potentiating AMPA receptor properties of the compounds, allowing them to influence glutamatergic neurotransmitter system in the Central nervous system.

Experiments evaluating the effects of substances on AMPA receptors were performed using the method of patch-clamp on svezhesorvannyh Purkinje neurons isolated from the cerebellum of rats (12-15 days). To highlight used the modified method. Slices of cerebellum thickness of 400-600 µm p who were located in a thermostatted chamber volume of 10 ml. The solution for isolation had the following composition (in mm): NaCl 150.0, KCl 5.0, CaCl22.0, MgSO4×7H2O 2.0, HEPES 10.0, glucose 15.0, pH 7.42. Slices were incubated in this solution for 60 minutes, after which the solution was replaced with the same solution containing pronase (2 mg/ml) and collagenase (1 mg/ml), and incubated for 70 minutes. After washing the initial solution for 20 minutes, the sections were placed in a Petri dish and pulled by mechanical means using a Pasteur pipette. The solution was continuously flushed with 100% O2at t 34°C. Purkinje Neurons were placed in the working chamber with a volume of 0.6 ml of the working solution had the composition (in mm): NaCl 150.0, KCl 5.0, CaCl22.6, MgSO4×7H2O 2.0, HEPES 10.0, glucose 15.0, pH 7.36.

Transmembrane currents were caused by the activation of AMPA receptors applique solutions agonist of these receptors - kainic acid (QC) method quick superfusion. Kainic acid is an agonist of AMPA receptors and is used to study the properties of AMPA receptors, since the very AMPA causes too strong desensitization of receptors and in such experiments is not used. Registration currents was performed using borosilicate microelectrodes (resistance 1.5-2.5 mω)filled with the following composition (in mm): KCl 100.0, EGTA 11.0, CaCl21.0, MgCl21.0, HEPES 10.0, 5.0 ATP, pH 7.2.

For Regis is the radio used the device EPC-9 (NEKA, Germany). Write currents was carried out on the PC hard disk, Pentium-4 with program Pulse, also purchased in the company of NEKA. Processing of the results was carried out using Pulsefit (NEKA).

Applique QC calls in Purkinje neurons transmembrane incoming currents. Add in perfusely solution of compounds of the formula I induces an increase in the amplitude of the currents. This increase depends on the connection, his concentration, the time that has passed after the start of application of the substance.

Example 1. Compound 1 at a dose of 0.001 μm causes an increase in Kainat-induced currents by 40-50%at a dose of 0.01 μm to 80%at a dose of 0.1 μm is at 0%and at a dose of 1 μm - block-20-40%. Washing within 3-5 minutes returns the response amplitude to the control value.

Example 2. Compound 2 at a dose of 0.00001 μm causes an increase in Kainat-induced currents by 10%at a dose of 0.0001 μm - 50%to 90%, in a dose of 0.001 μm - 60-140%, in a dose of 0.01 μm - 0-20%, and at a dose of 0.1 μm - block-20-40%). The hillshade for 4-6 minutes returns the response amplitude to the control value.

The results obtained are presented in table 1.

Table 1.
Activity of compounds in the potentiation of AMPA/Kainat-induced currents in Purkinje neurons of the cerebellum of rats.
No. of connectionsPotentiation to the inat-induced currents (%)
0.0001 μm - no potentiation,
10.001 μm - potentiation by 40-50%
0.01 μm - potentiation by 80%
0.1 μm is 0%
1 μm - blockade on-20-40%
20.00001 μm - potentiation by 20-40%
0.0001 μm - potentiation by 50-90%,
0.001 μm - potentiation at 60-140%,
0.01 μm - potentiation at 0-20%,
0.1 μm - blockade on-20-40%.
30.0001 μm - no potentiation
0.001 μm - potentiation by 10-15%
0.01 μm - potentiation 20-30%
0.1 μm - potentiation 20-50%
1 μm - no potentiation,
10 μm - blockade by 20-50%
40.001 μm - no potentiation
0.001 μm - potentiation by 10-15%
0.01 μm - potentiation 20-30%
0.1 μm - potentiation 20-50%
1 μm - no potentiation,
10 μm - blockade by 20-50%.
Memantine0-15% potentiation at 30 µm

As can be seen from the table, the compounds of General formula I possess properties to potentiate currents caused by activation of AMPA receptors. Connect is superior to standard activity substance Memantine in 30000-3000000 time on the test potentiation of AMPA responses. However, they do not have a significant neurotoxic effects (LD50ranges from 90 to 900 mg/kg in the active interval of the investigated doses), which makes them valuable for use in medicine, particularly in the treatment of neurodegenerative diseases such as Alzheimer's disease.

The experiment for the determination of acute toxicity.

Acute toxicity of the substances was determined on outbred mice-males weighing 22-26 g of the Substance was administered intraperitoneally in the form of a solution or suspension in a 1% solution of starch. The observation period was 14 days. Toxicity in the form LD50was calculated by the method of Litchfield and Wilcoxon [Litchfild J.T., Wilcoxon F.J., J. Pharmacol. Exp. Ther, 1949, v.96, pp.99-114].

Examples of toxicity of the inventive compounds are shown in table 2.

Table 2.
Acute toxicity of some compounds of formula 1.
Non connect the deposits LD50mg/kg
1350
2140
390
4900
Memantine1000

As a result of tests it is established that LD50the investigated compounds is from 90 to 900 mg/kg In accordance with the classification of the toxicity of chemical substances, these compounds are moderately and low-toxic substances. Although the acute toxicity of these compounds slightly exceeds the value of acute toxicity of Memantine, a comparison of the parameters of therapeutic index, defined as the ratio LD50/ED50(Dneprovskiy etc. - Chem. Pharm. J., 1986, N 10, 1209-1231), shows that most of the investigated compounds has a significant advantage over Memantine.

As is commonly the case in medicine, the compounds of formula I according to the present invention is recommended to be applied in the form of compositions comprising respectively the next aspect of the invention.

The pharmaceutical composition according to the invention is prepared using generally accepted engineering techniques and includes a pharmacologically effective amount of the active agent compound of the formula I or its pharmaceutically acceptable salt (called the e next "active connection"), typically constitutes from 5 to 30 wt.%, in combination with one or more pharmaceutically acceptable auxiliary additives, such as diluents, binders, loosening agents, absorbents, fragrances, flavoring agents. In accordance with known methods of the pharmaceutical compositions can be presented in various solid or liquid forms.

Examples of solid dosage forms include, for example, tablets, pills, gelatin capsules, etc.

Examples of liquid dosage forms for injection and parenteral administration include solutions, emulsions, suspensions, etc.

Composition, as a rule, obtained using standard procedures involving mixing the active compound with a liquid or powdered solid carrier.

Compositions according to the invention in the form of tablets containing from 5 to 30% of the active compound and the filler(s) or carrier(s). As such for tablets are used: a) diluents: beet sugar, lactose, glucose, sodium chloride, sorbitol, mannitol, ethylene glycol, calcium phosphate disubstituted; b) binders: magnesium aluminum silicate, starch paste, gelatin, tragakant, methylcellulose, carboxymethylcellulose and polyvinylpyrrolidone; disintegrating agents: dextrose, agar, alginic acid or its salts, starch, twin.

EXAMPLE 1.

100 mg tablets, containing 0.1 mg of compound 2

Connection 20.1 mg
Lactose54.9.0 mg
Alginic acid20.0 mg
Citric acid5.0 mg
Tragakant20.0 mg

The tablet may be formed by pressing or moulding of the active ingredient with one or more additional ingredients.

Obtaining a CT is performed on a special installation. The active ingredient in free form, such as powder or granules, in the amount of 10 grams (the amount of matter required to obtain 10,000 tablets) is mixed with the binder - tragakant (200 g), mixed with the diluent is lactose (590 g), the mixture is added loosening the substance - alginic acid (200 g) and odorant - citric acid (50 g).

For gelatin capsules are used optionally colorants and stabilizers. As the dyes used: tetrazine, Indigo; as stabilizers can be represented as: sodium metabisulfite, sodium benzoate. The proposed gelatin capsules contain from 1 to 20% of the active ingredient.

EXAMPLE 2.

500 mg capsules containing 0.5 mg of compound 2

Connection 20.5 mg
Glycerin100.0 mg
Sugar syrup339.5 mg
Mint oil40.0 mg
Sodium benzoate10.0 mg
Ascorbic acid5.0 mg
The tetrazine5.0 mg

5 g of the active substance (compound 2) (the amount needed for the preparation of 10,000 capsules) finely pulverized and mixed in a mixer with glycerol (1000 g) and sugar syrup (3490 mg). After stirring the mixture was added peppermint oil (400 g), sodium benzoate (100 g), ascorbic acid (50 g) and tetrazine (50 g). Gelatin capsules are prepared drip method. This method allows the simultaneous drip dosing of a solution of a medicinal substance and heated gelatinous mass (900 g of gelatin) in a chilled liquid paraffin. The result is the formation of seamless spherical gelatin capsules filled with a medicinal mixture, ready for use, containing 50 mg of active substance.

Injectable forms of the compositions preferably are isotonic solutions or suspensions. The above forms can be sterilized and may contain additives such as preservatives: sodium metabisulfite, benzoic acid, sodium benzoate, a mixture of methyl paraben and propyl paraben; stabilizers: apricot and Arabian gum, dextrin, starch paste, methyl cellulose, twin; salt, regulating the osmotic pressure (sodium chloride), or buffers. In addition, they can contain other therapeutically useful substances.

EXAMPLE 3.

2 ml ampoules containing 1 mg of compound 1

Connection 11.0 mg
Sodium chloride 0.9% solution1.6 ml
Benzoic acid10.0 mg
The methylcellulose10.0 mg
Mint oil0.4 ml

For the preparation of injectable active compound 1 (1 g; number needed to produce 1000 capsules) finely pulverized and mixed in a mixer with peppermint oil (400 ml), then add methyl cellulose (10 g)is mixed with 0.9% sodium chloride solution (1600 ml) and added benzoic acid (10 g). The resulting solution was Packed in ampoules of 2 ml and sterilized by steam for 30 minutes

Another aspect of the invention is the method of action on AMPA receptors by introducing an effective amount of compounds of General formula I.

Assigned to receive a dose of the active ingredient (compound of formula I or its pharmaceutically acceptable salts) var which varies depending on many factors, such as age, sex, weight of the patient, the symptoms and severity of the disease, specifically assigned to the connection, the route of administration, the form of the drug that is assigned to an active connection.

Usually the total prescribed dose is from 0.1 to 20 mg per day. The total dose can be divided into several doses, for example, to receive from 1 to 4 times a day. During oral assignment interval total dose of the active substance is from 0.1 to 20 mg / day, preferably from 0.1 to 10 mg of parenteral reception interval of doses range from 0.5 to 20 mg per day, preferably from 0.5 to 10 mg, and for intravenous injection is from 0.05 to 5.0 mg per day, preferably from 0.05 to 2.5 mg Accurately dose can be selected by the treating physician.

1. N,N′-substituted 3,7-diazabicyclo[3.3.1]nonanes General formula 1:

in which HY hereinafter, is pharmacologically acceptable acid;

E represents a carbonyl group;

R1represents H, lower alkyl, C1-C10alkoxy;

R2in the aggregate represented by the General formula (1.1A), (1.2A), (1.3a), (1.4):

in which L represents CR 11, carbonyl group;

R11represents H, amino;

R15represents H, lower alkyl, C1-C10alkoxy;

R19R′19, R20and R′20may be the same or different and each independently represents H, lower alkyl, C1-C10alkoxy;

R24and R25may be the same or different and each independently represents H, lower alkyl, C1-C10alkoxy;

R3and R′3may be the same or different, and each independently represents H, lower alkyl, C1-C10alkoxy;

R4and R′4may be the same or different, and each independently represents H, lower alkyl, C1-C10alkoxy;

X represents a group of General formula: (CH2)m-Z, where m=0, a Z means acetyl, or X represents a valence bond;

2. Compounds according to claim 1, represents the derivative N,N′-substituted 3,7-diazabicyclo[3.3.1]nonanes General formula (1.1):

in which HY hereinafter, is pharmacologically acceptable acid;

E, R1, R3R′3, R4R′4, X, L, R15, R19R′19, R20and R′20have the meanings defined above is La formula 1.

3. Compounds according to claim 1, represents the derivative N,N′-substituted 3,7-diazabicyclo[3.3.1]nonanes General formula (1.2):

in which HY hereinafter, is pharmacologically acceptable acid;

E, R1, R3R′3, R4R′4, X, L, R15, R19R′19, R20and R′20have the meanings given above for formula 1.

4. Compounds according to claim 1, represents the derivative of N,N-substituted 3,7-diazabicyclo[3.3.1]nonanes General formula (1.3):

in which HY hereinafter represents a pharmacologically acceptable

E, R1, R3R′3, R4R′4, X, L, R15, R19R′19, R20and R′20; R24and R25have the meanings defined above for formula 1.

5. Compounds according to claim 1, represents the derivative N,N′-substituted 3,7-diazabicyclo[3.3.1]nonanes General formula (1.4):

in which HY hereinafter, is pharmacologically acceptable acid;

E, R1, R3R′3, R4R′4, X, L, R15, R19, R'19, R20; R24and R25have the meanings given above for formula 1.

6. The compound according to claim 2, represents the future

3,7-bis(2,3-dihydro-1,4-benzodioxin-6-ylcarbonyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-he.

7. The compound according to claim 3, representing 3,7-bis(1,3-benzodioxol-5-ylcarbonyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-he.

8. Compounds according to claim 4, representing

1,5-dimethyl-3,7-bis(cinoxacin-6-ylcarbonyl)was 3.7-diazabicyclo[3.3.1]nonan-9-he;

3,7-bis[(2,3-dimethylquinoxaline-6-yl)carbonyl]-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-he.

9. The compound according to claim 5, representing N,N′bis[4-methoxy-3-(1H-pyrazole-1-ylmethyl)benzyl]-1,5-dimethyl-9-oxo-3,7-diazabicyclo[3.3.1]nonan-3,7-dicarboxamide.

10. Compounds of General formula 1 according to any one of claims 1 to 9 having the property of modulating the activity of AMPA receptors.

11. Pharmaceutical composition having the ability to modulate the activity of AMPA receptors containing the compound of General formula I according to any one of claims 1 to 9 in an effective amount and a pharmaceutically acceptable carrier.

12. Effect on AMPA receptors by introducing an effective amount of compounds of General formula 1 according to claim 1 at a dose of from 0.1 to 20 mg per day.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns malonamide derivatives of the formulae (IA) or (IB) , and pharmaceutically acceptable acid additive salts of them, where R1, R1',(R2)1,2,3, R3, R4, R14, L, and are such as described in this invention. Also the invention concerns a medicine with inhibition effect on γ-secretase, which can be applied in treatment of Alzheimer's disease.

EFFECT: obtaining new malonamide derivatives with beneficial biological properties.

17 cl, 188 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 1,4-diazabicycloalkane of the formula (IV): or its pharmaceutically acceptable addition salt wherein Ar represents carbocyclic aromatic (aryl) group or heterocyclic aromatic (heteroaryl) group that represents 5-6-membered ring comprising one nitrogen, sulfur or oxygen atom as a heteroatom and wherein aromatic group can be substituted with one substitute chosen from group consisting of (C1-C6)-alkoxy, halogen atom, -CF3, phenyl and benzyl. Also, invention relates to a pharmaceutical composition possessing inhibitory effect on nicotine acetylcholine receptors and containing the effective amount of compound of the formula (IV) or its pharmaceutically acceptable addition salt in combination with at least one pharmaceutically acceptable carrier or diluting agent. Invention provides derivatives of 1,4-diazabicycloalkane possessing inhibitory activity with respect to nicotine acetylcholine receptors.

EFFECT: valuable medicinal and pharmacological properties of compounds.

10 cl, 3 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel 3-phenyl-3,7-diazabicyclo[3,3,1]nonane compounds of the formula (I): wherein R1 means (C1-C6)-alkyl, (C4-C7)-cycloalkyl; R2 means (lower)-alkyl; R3 means (lower)-alkyl, or R2 and R3 form in common (C3-C6)-alkylene chain; R4 means phenyl monosubstituted at ortho- or para-position with nitro-, cyano-group or (lower)-alkanoyl, or disubstituted at ortho- and para-position with nitro-group, and their physiologically acceptable acid-additive salts. Compounds of the formula (I) possess anti-arrhythmic activity and therefore they can be used in pharmaceutical composition used in treatment and/or prophylaxis of cardiac rhythm disorders. Also, invention describes a method for synthesis of these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

8 cl, 6 tbl, 2 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to condensed heterocyclic succinamide compounds of the formula (I): , their pharmaceutically acceptable salts, solvates or isomers wherein G represents mono- or polycyclic aryl or heterocyclic group substituted possibly at one or more positions; L represents a bond, -(CR7R7')n (wherein n = 1; R7 and R7' represents independently hydrogen atom (H), alkyl or substituted alkyl) or -CH2-NH-; Z1 represents oxygen atom (O); Z2 represents O; A1 and A2 represent -CR7 or in common with R7 from group W is a heterocyclic ring wherein oxygen represents a heteroatom; Y represents -O-, -SO-, -N(V2)-, -CH2-N(V2)-, -CO-N-(alkyl)-, -CH2-S-, -CH2-SO2-; V2 represents hydrogen atom, alkyl, arylalkyl, -CO-alkyl, -CO-O-aryl, -CO-O-arylalkyl; W represents -CR7R7'-CR7R7'-, -CR7R7'-C=O, -NR9-, -CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'-, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo- or substituted heterocyclo-group, aryl or substituted aryl wherein if W doesn't mean -NR9-CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'- or heterocyclo- or substituted heterocyclo-group then Y must mean -O-, -CH2-S-, -SO-, -CH2-SO2-, -N-(V2)- or -CH2-N-(V2)-; Q1 and Q2 represent hydrogen atom (H). Also, invention describes a method for synthesis of intermediate compounds in synthesis of compounds of the formula (I), using the latter for preparing agents modeling function of the nuclear hormone receptors. Compounds of the formula (I) can be used in treatment of prostate cancer.

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

8 cl, 11 tbl, 463 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a novel chemical compound, namely, to biologically active compound of the formula (I): possessing anti-arrhythmic activity and representing 5'-bromolappaconitine hydrobromide. Toxicity of this compound is by 4.8-fold less toxic as compared with analog used in medicinal practice and representing lappaconitine hydrobromide. Proposed compound possesses the expressed anti-arrhythmic activity in models with calcium chloride and adrenaline arrhythmia and provides the complete blocking both types of arrhythmia after administration of the dose that is 10-fold less of the therapeutic dose of lappaconitine hydrobromide.

EFFECT: improved and valuable medicinal properties of compound.

2 cl, 2 tbl, 4 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a whitening composition comprising: (a) monomeric ligand or catalyst with transient metal of ligand of the formula (I): wherein R represents hydrogen atom; R1 and R2 are chosen independently from (C1-C4)-alkyl, pyridine-2-yl-methyl and (C2-C4)-alkylmethyl; X represents -C=O; R3 and R4 are similar and represent -(CH2)nC(O)O-(C1-C4)-alkyl; n = 0-4, and (b) equilibrating carriers and additional components. This composition is useful for catalytic whitening substrates with atmosphere oxygen. Also, invention describes a method for whitening the substrate involving applying step of the whitening composition on substrate in aqueous medium.

EFFECT: valuable properties of substances, improved whitening method.

11 cl, 2 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: compounds of formula I are disclosed, wherein R1, R2, R3, R4, R5, R6, R7, R41, R42, R43, R44, R45, R46, A, and B are as described in description.

EFFECT: new compounds with increased electrophysiological activity useful in treatment of cardiac arrhythmias.

132 cl, 1 tbl, 37 ex

The invention relates to metallogenica derivative containing four nitrogen atom of the macrocycle, fused with the pyridine cycle, methods for their preparation and their use in medicine to obtain an image

The invention relates to chemical-pharmacological industry and relates to new biologically active chemical compounds of the hydrochloride of 3-(2-hydroxyethyl)-1,5-dinitro-3-azabicyclo[3.3.1]non-6-ene of formula (1) with high antiarrhythmic activity and low toxicity

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns applications of an agent of the general formula 1a as an active component of a composition for treatment of people and the animals suffering from neurodegeneration unrelated to informative function, nervously-muscular degeneration unrelated to informative function, notor-sensoric neurodegeneration or disfunction, or losses of receptors.

EFFECT: invention allows for improving treatment of the said diseases.

3 cl, 11 tbl, 3 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyrazole derivatives of formula (IIa) or their pharmaceutically acceptable salts, where: Rx and Ry banded with intervening atoms while deriving benzol or cyclohexylene rings, optionally substituted by R3; R1 represents T-(ring D); ring D represents phenyl, optionally substituted by 1-2 groups R5, or naphtyl or imidazolyl or benzymidazolyl, optionally substituted by C1-C6alkyl group; T represents the linking; R2 represents hydrogen, C1-C6alkyl or C3-C6cycloalkyl; R2' represents hydrogen, or R2 and R2' is banded with their intervening atoms while deriving phenyl ring; R3 is selected from C1-C6alkyl, hydrogen, halogen, -OH, -NH2, -NHOH, -NO2, C1-C6alkoxy, optionally substituted -N(R4)2; each R4 independently selected from C1-C6alkyl, -CO2C1-C6alkyl or two R4 at the same nitrogen atom joined with nitrogen atom while deriving morpholine ring; each R5 represents one or two substitutes, independently selected from C1-C6alkyl, halogen, OH, -NH2, -CF3, C1-C6alkoxy, -COOH, -CO2C1-C6alkyl, -NHCO-C1-C6aliphatic group, NHCO(C1-C6alkyl)N(R4)2, -CONHC1-C6alkyl, -CONH(C1-C6alkyl)N(R4)2, and -NHSO2C1-C6alkyl. The compounds are useful as inhibitors of protein kinase, in particular as inhibitors Aurora-2 and GSK-3 for the treatment of cancer, diabetes and Alzheimer's disease. The subjects matter is also pharmaceutical composition on basis of their compounds and methods of the treatment of diseases mediated by the protein kinase.

EFFECT: production of new pyrazole derivatives - inhibitors of protein kinase.

25 cl, 12 tbl, 292 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds presented by the following formula (I), or to the pharmaceutically acceptable salts: , where R1 and R2 represent substitutes, adjoining with each other and with two carbonic atoms, to each of which they are adjoined forming the group presented by the following formula: 1) , or

2) , , , , , , , , or

3) or

4) , , or

where hydrogen atom in each cyclic group can be substituted bi 1-4 substitutes selected fro the following group of substitutes B1, R3 represents hydrogen atom or methyl group; and R6 represents substitute selected from the following group of A1 substitutes, the group of A1 substitutes: (1) hydrogen atom, (2) C1-C6 alkoxy group; substitute B1 group: (1) hydrogen atom, (2) hydroxyl group, (3) oxo group, (4) C1-C6 alkanoyl group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where C1-C6 alkyl group can be substituted by C1-C6 alkoxy group), (7) C1-C6 alkoxy group, (8) C1-C6 alkoxyimino group, (9) C5-C6 cycloalkyl group, derived by two C1-C3 alkyl groups joined to the same carbonic atom with hydrogen atom and the carbons. The invention is also relates to the pharmaceutical composition.

EFFECT: production of the new biologically active compounds and pharmaceutical compositions on their basis having inhibitor potency towards to serotonine1A receptor.

34 cl, 73 ex, 12 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: claim describes benzoxazepinone derivatives of formula : wherein R1 represents hydrogen, C1-C6 alkoxy, halogen or NR'R", n is 1 or 2, R', R" independently from each other represents hydrogen or C1-C6 alkyl; R2 represents hydrogen, C1-C6 alkyl -(CH2)m-C3-C7-cycloalkyl, -(CH2)m-phenyl or -(CH2)m-O-C1-C6 alkyl; m is 0.1 or 2; R3 represents C1-C6 alkyl,-(CH2)m-C(O)O-C1-C6 alkyl, C3-C7 cycloalkyl or -(CH2)m-phenyl which is unsubstituted or substituted by one or two substituents, selected from the group consisting of halogen, trifluoromethyl, -NR'R", nitro and -SO2NH2, or represents -C3-C7 -cycloalkyl, unsubstituted or substituted by phenyl, or is -(CR′R″)o-heterocyclyl, selected from the group consisting of tetrahydropyran-4-yl, pyridin-3-yl, indol-3-yl optionally substituted by halogen or C1-C6 alkoxy group, or thiophen-2-yl, furan-2-yl, NH-pyridin-2-yl optionally substituted by nitro group or benzoimidazol-2-yl, 2-oxo-tetrahydrofuran, and benzo[1,3]dioxol-5-yl and represents -tetrahydro-naphthalen-1-yl, -CHR′-naphthalen-2-yl, -fluoren-9-yl, -(CH2)o-S-lower alkyl, -(CH2)o-S-benzyl, -(CH2)o-C(O)NH2, -(CH2)oNR′R″, -CH[C(O)NH2]-(CH2)o-phenyl, -(CH2)o-CF3, or -(CH2)o-CR′R″-CH2-NR′R″; and o is 1 or 2; or their pharmaceutically suitable acid addition salts, excluding: phenetylamide 4-benzyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid, butylamide 4-benzyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid, phenetylamide 4-cyclohexyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid, butylamide 4-cyclohexyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid. The pharmaceutical on basis of the compounds of formula I aimed at the treatment of Alzheimer's disease is described.

EFFECT: production of the new compounds, benzoxazepinone derivatives having useful biological properties.

26 cl, 196 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compound with formula (I) or to its tartrate salt. The invention also relates to application of the composition as well as the method of inhibiting of monoamine receptor activation to inverse agonist and anti-dyskinesia agent in the combination with inverse agonist.

EFFECT: production of the new biologically active compound having inverse agonist activity of serotonin receptor.

54 cl, 7 ex, 3 tbl

FIELD: medicine; neurology.

SUBSTANCE: invention concerns treatment methods for neurodegenerative brain condition, such as Parkinson' and Alzheimer's disease, and methods of nerve cells death and degeneration. A therapeutically effective quantity of the composition containing brimonidin or its pharmaceutically acceptable salt is administered to a mammal.

EFFECT: treatment or prevention of nerve cells degeneration due to neuroprotective effect of brimonidin in respect of brain neurons.

6 cl, 1 ex, 1 dwg, 2 tbl

FIELD: medicine; neurology.

SUBSTANCE: individuals susceptible to eicosapentaenoic acid (EPA) treatment are identified by defining of CAG repetition number in Huntingtin gene within 36-45. To prevent and heal Huntington's disease (HD) symptom development, the persons with CAG repetition number within 36 to 45 are administered with EPA in any biologically viable form.

EFFECT: reduced brain tissue loss for patients and prevention of symptom development for persons prone to that; improved treatment results for patients with this genetic disease form.

16 cl, 20 ex

FIELD: medicine, pharmacology.

SUBSTANCE: medicine composition, possessing nootropic activity, represents 40% ethanolic extract of herb material, comprising grass of cottonweed, roots of Baikal scutellaria, sprouts of Pentaphylloides fruticosa, rhizome of officinal burnet, roots of deviating peony, fruits of rose, and grass of knotweed, cut to 1-3 mm pieces. The extraction is carried out at raw material to extragent proportion 1:10 and temperature 18-20°C.

EFFECT: medicine develops antiamnesic effect.

6 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, particularly to drug preparation of deanol aceglumate. An injection drug formulation is proposed, containing ingredients as follows: deanol aceglumate, sugars (sorbitol, xylitol, and others), aminoacetic versene, optionally succinic acid, malic acid, and N-dimethylaminoethanol. It was demonstrated, that the injection drug formulation of deanol aceglumate shows neuroprotective action and can be applied to acute cerebral circulation injury, preventing from cerebral ischemia damage.

EFFECT: generation of stable and sterile injection drug formulation of deanol aceglumate, suitable for applying in diabetes cases.

3 cl, 4 ex, 2 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns new enantiomers of (+)-and(-)-trans-2,3,4,4a,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indol and method of its obtaining. Being optical antipodes for each other, enantiomers exhibit different biological activity and can be applied as an active component in pharmaceutical compositions of nootropic and sedative action for treatment of different individual status of patients.

EFFECT: obtaining of the claimed compound.

1 ex, 5 tbl, 5 cl

FIELD: chemistry.

SUBSTANCE: invention concerns new nitrogen-containing heterocyclic derivatives represented by the formula (I): where symbols have the following meaning: R1 and R2 can be equal or different and denote H-, C1-C6-alkyl, C3-C14-cycloalkyl, C1-C6-alkyl-CO-, HO-CO-, C1-C6-alkyl-O-CO-, H2N-CO-, C1-C6-alkyl-HN-CO-, (C1-C6-alkyl)2N-CO-, C1-C6-alkyl-O-, C1-C6-alkyl-CO-O-, H2N-, C1-C6-alkyl-HN-, (C1-C6-alkyl)2N-, C1-C6-alkyl-CO-NH-, halogen, nitro, morpholine, pyrrolidin, imidazol or cyano; R3 and R4 can be equal or different and denote C1-C6-alkyl, C1-C6-alkyl-O-, (C1-C6-alkyl)2N- or halogen; R5 and R6 can be equal or different and denote H-, C1-C6-alkyl or halogen; R7 and R8 can be equal or different and denote H-, C1-C6-alkyl, HO-, C1-C6-alkyl-O- or halogen; R7 and R8 together can form oxo (O=); R9 denotes heterocyclic group -C1-C6-alkyl-CO-, which can be optionally substituted for at least one substitute selected out of a group b described further, where heterocyclic group is selected out of morpholine, piperazine, pyrrolidin, piperidine, thiomorpholine, azepine, diazepine, oxyazepine, decahydroquinoline, decahydroisoquinoline, hexahydroazepine or 2,5-diazabicyclo[2.2.1]heptane; R10, R11, R12 and R13 can be equal or different and denote H- or C1-C6-alkyl; group b: (1) HO, (2) C1-C6-alkyl-O-, (3) R101 R102N (where R101 and R102 can be equal or different and denote (i) H, (ii) C1-C6-alkyl), (4) halogen, (5) oxo (O=), (6) C3-C14-cycloalkyl, (7) phenyl, (8) pyrrolidine, (9) C1-C6-alkyl, which can be optionally substituted for HO, C1-C6-alkyl-O-, phenyl, C1-C6-alkyl-CO- or morpholine, (10) acyl, which can be optionally substituted for oxo (O=), where acyl is C1-C6-alkyl-CO- or heterocyclic -CO group, where heterocyclic group is imidazol, pyridine or pyrazine, (11) H2N-CO- and (12) C1-C6-alkyl-SO2; A denotes heterocycloalkyl group selected out of piperidine, pyrrolidine or hexahydroazepine; n is 0, or its pharmaceutically acceptable salts. The invention also concerns pharmaceutical composition and application of nitrogen-containing heterocyclic derivatives from each of pp. 1-11.

EFFECT: obtaining new biologically active compounds and pharmaceutical composition based on there, with inhibition effect on sodium channel activity.

16 cl, 226 ex, 32 tbl

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