5-[1'-(decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1h-cyclopropa[a]naphthalen-4-yl)-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzene dicarboxaldehyde as medicinal agents

FIELD: chemistry.

SUBSTANCE: invention relates to a pharmaceutical composition containing primary material in form of at least one compound selected from 5-[(1'R)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalen-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzene dicarboxaldehyde and 5-[(1'S)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalen-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzene dicarboxaldehyde, in a combination with an acceptable carrier, for treating and/or preventing disorders or pathologies which are a result of a disorder of reuptake of the following neuromediators: dopamine, serotonin and/or noradrenaline, as well as to use of at least one compound selected from 5-[(1'R)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalen-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzene dicarboxaldehyde and 5-[(1'S)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalen-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzene dicarboxaldehyde to obtain a medicinal agent.

EFFECT: improved method.

9 cl, 2 ex, 1 tbl

 

The present invention relates to new compounds of the formula (I)belonging to the family of macrocarpaea, and to their use as medicines. Preferably, these compounds are used to obtain drugs, or dietary supplements intended for treatment and/or prevention of disorders or pathologies resulting from disorders reuptake of the following neurotransmitters: dopamine, serotonin and/or norepinephrine.

He macrocephaly are compounds chemical family allforgirls. In the plant world, they are found mainly in various species of the genus Eucalyptus.

Cosmetic properties have been described for, among others, macrocarpaea L and M (JP 2001055325 and Y. SHIBUYA et al, 2001 - Isolation and structure determination of new Macrocarpals from a Herbal Medecine, Eucalyptus globulus Leaf - Natural Medecines 55 (1), 28-31).

Conducting active research on inhibitors of reuptake of neurotransmitters, the inventors have unexpectedly found that the new compounds of the family macrocarpaea, and in particular has macrocephaly L and M, exhibit pharmacological properties in this area.

One of the objects of the present invention is to obtain new chemical compounds of the formula (I)which may be considered therapeutic applications of the Oia.

The present invention relates thus also to those compounds of formula (I) as pharmaceuticals and to pharmaceutical compositions or food supplements, including as applicable the beginning of at least one compound of formula (I).

Finally, another object of the present invention relates to the application of the above compounds (I) for the treatment and/or prevention of neurological and psychiatric disorders or pathologies and related disorders, functional somatic disorders, obesity, excess body weight and dependency on addictive substances resulting from disorders reuptake of dopamine and/or serotonin and/or norepinephrine.

Compounds according to the present invention meet the following General formula (I)

Empirical formula: C28H40O6.

Molecular weight of 472 g/mol.

By "compounds of formula (I)in the framework of the present invention understand the totality of enantiomeric and diastereoisomeric forms of 5-[1'-(decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalene-4-yl)-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxolyl, and mixtures thereof.

Below, the applicant clarifies used numbering of carbons:

This is formula (I) includes 7 asymmetric carbon atoms, schematically shown in the following formula as "C*":

The present invention encompasses novel compounds corresponding to the formula (I), except for the two following forms:

• 5-[(1'R)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalene-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxole and

• 5-[(1'S)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalene-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxole.

Another object of the present invention relates to compounds of formula (I), as defined on the previous page, for which the first therapeutic application has just been installed by the applicant.

These compounds of formula (I), used individually or in mixtures, as medicines are also described thus in the present invention.

Preferably, the compound (I) as a drug according to the invention is selected from the group consisting of the following compounds:

• 5-[(1'R)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalene-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxole formula below:

(macrocarpon L)

• 5-[(1'S)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3,7-tetramethyl-1H-cyclopropa[A]naphthalene-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxole formula, the following:

(macrocarpon M)

• 5-[(1'R)-1'-[(1aR,3aS,4S,7R,7aR,7bR)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalene-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxole and

• 5-[(1'S)-1'-[(1aR,3aS,4S,7R,7aR,7bR)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalene-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxole

used individually or in a mixture.

In the private embodiment of the present invention the compounds of formula (I) are obtained on the basis of plant extract. Preferably plant extract is obtained from eucalyptus.

Under the "eucalyptus" in the framework of the present invention understand the species belonging mainly to the subgenus Eudesmia, Symphomyrtus and Corymbia and especially the following species: Eucalyptus globulus L., Eucalyptus pulverulenta Sims, Eucalyptus kartzoffiana L. A. S. Johnson 1 Blaxell, Eucalyptus macrocarpa Hook., Eucalyptus cinerea F. Muell.ex Benth., Eucalyptus dorrigoensis (Blakely) L.A.S. Johnson 1 K. D. Hill, Eucalyptus leptopoda Benth., Eucalyptus occidentalis Endl., Eucalyptus viridis R. T. Baker, Eucalyptus polybractea R.T. Baker et Eucalyptus smithii R.T. Baker.

These examples illustrate the present invention without limiting its scope.

Preferably the extract of eucalyptus receive from the leaves, flowers, fruits, seeds, shoots or stems of eucalyptus, preferably from the leaves of eucalyptus.

The present invention also relates to pharmaceutical compositions or food is obascam, including as applicable the beginning of at least one compound of formula (I). Preferably the compounds of formula (I) are included in the form containing plant extracts.

In the private embodiment of the present invention, the mass fraction of compound (I) according to the invention and preferably macrocarpas L or macrocarpas M in the extract of eucalyptus exceed 0.05% and strictly less than 90%.

Specified plant extracts, including extracts of eucalyptus, can be obtained by extraction, carried out by regular stages, known to the specialist.

Leaves, flowers, fruits, seeds, shoots or stems of eucalyptus (Eucalyptus sp.) or a mixture of these parts are crushed, then extracted with an organic solvent, which can be an alkane (pentane, hexane, heptane, octane, cyclohexane), a simple oxide ether (tetrahydrofuran, dioxane, simple diethyl ether), esters (ethyl acetate, isopropylacetate), alcohol (methanol, ethanol, propanol, isopropanol, butanol, octanol), ketone (methyl ethyl ketone, methyl isobutyl ketone), halogen-substituted hydrocarbon (chloroform, dichloromethane) or a mixture of water and one or more organic solvents miscible with water (such as water-alcohol mixture).

The extraction is carried out in respect of plant/solvent of PR is about 1/1 to about 1/20, and it can be repeated 2-3 times. The temperature of the solvent for extraction may be equal to the ambient temperature or higher, which can reach the boiling point of the used solvent. The time of contact of the plant with the solvent is from about 30 minutes to about 72 hours.

Then carry out the separation of solid/liquid phases, and the plant is separated from the solvent by filtration or centrifugation.

The resulting filtrate can be either

- dried directly shared by evaporating the solvent for extraction and to compile the final extract;

any more or less concentrated.

In the case of a mixed solvent for extraction (e.g., water-alcohol mixture), the concentration continues to evaporation presence of an organic solvent. In the case of an organic solvent in the obtained concentrate, add some water. Purification step liquid-liquid carried out by adding to the aqueous phase of the solvent is not miscible with it, which can be an alkane (e.g., hexane), the simple oxide ether (for example, a simple diethyl ether), esters (e.g. ethyl acetate), alcohols (e.g. butanol), a ketone (e.g. methyl) or halogen-substituted hydrocarbon (e.g. chloroform). Carry on the well, two or three extraction liquid-liquid. The combined organic phase can be dried over sodium sulfate prior to complete drying.

The resulting solution was concentrated in vacuo and at a temperature of from ambient temperature to the boiling point.

The final drying of the extract is carried out by lyophilization or more conventional drying means known to the expert (spraying, drying Cabinet, ...).

Preferably, the temperature of the drying does not exceed about 60°C.

The extract can be stabilized by the addition of an antioxidant, such as ascorbic acid, citric acid, in amounts comprising from about 0.05 to about 1 g per 100 g of dry extract.

Thus obtained extract includes a mass fraction of compounds of formula (I) more than 0.05% and strictly less than 5%, preferably specified mass fraction is approximately 0.8%.

The extract obtained above can be enriched compounds of formula (I) and especially macrocarpum L or macrocarpum M

Under "extract of eucalyptus enriched macrocarpum L or M" in the framework of the present invention realize the extract of eucalyptus, in which the mass fraction of macrocarpas L or M is greater than or equal to 5% and strictly less than 90%, preferably greater than or equal to 5% and n is 50%, more preferably greater than or equal to 5% and below 30% and even more preferably greater than or equal to 5% and below 15%.

The way to obtain this extract consists of the following stages:

- grinding the leaves and/or flowers and/or fruit and/or seed and/or shoots, and/or stem of eucalyptus;

at least one extraction with an organic solvent or a mixture of water and an organic solvent, miscible with water.

The extraction is carried out in respect of plant/solvent constituting from about 1/1 to about 1/20, and it can be repeated 2-3 times. The temperature of the solvent for extraction may be equal to the ambient temperature or higher, which can reach the boiling point of the used solvent. The time of contact of the plant with the solvent is from about 30 minutes to about 72 hours.

Preferably the solvent is selected from the group consisting of alkane (pentane, hexane, heptane, octane, cyclohexane), oxide of simple ether (tetrahydrofuran, dioxane, simple diethyl ether)of ester (ethyl acetate, isopropylacetate), alcohol (methanol, ethanol, propanol, isopropanol, butanol, octanol), ketone (methyl ethyl ketone, isobutyl ketone), halogen-substituted hydrocarbons (chloroform, dichloromethane) or a mixture of water and the PR is hanicheskih solvents, miscible with water (such as water-alcohol mixture).

Preferably the solvent for extraction is dichloromethane or isopropylacetate.

In the case of solvent extraction, mixed with water, the filtrate is dried, then dissolved in a solvent not miscible with water.

In case a solvent is not miscible with water, the filtrate is concentrated.

- Separation of solid/liquid separation methods known to the expert.

In a preferred method of carrying out the invention, one or more extraction liquid-liquid carried out by adding a base, preferably sodium carbonate (Na2CO3). The combined basic aqueous phase is acidified by adding an acid, preferably hydrochloric acid (HCl), then extracted with implementation of one or more extraction liquid-liquid made using a solvent not miscible with water. Preferably, the acidification leads to approximately pH 1.

The combined organic phase can be dried over sodium sulfate, and then concentrated in vacuum at a temperature ranging from ambient temperature to the boiling point.

The concentrate is dried using conventional means of drying (spray drying Cabinet, ...) at temperatures predpochtite is) not exceeding 60°C, he is the extract enriched macrocarpum L or macrocarpum M This extract can be stabilized by the addition of an antioxidant, such as ascorbic acid or citric acid, in amounts comprising from 0.05 to 1 g per 100 g of dry extract.

In the private embodiment of the invention the solvent for extraction can be a supercritical fluid.

Leaves, flowers, fruits, seeds, shoots or stems of eucalyptus (Eucalyptus sp.) or a mixture of these parts, pulverized or not, then extracted with a supercritical fluid, which can be carbon dioxide.

The first extraction supercritical CO2preferably carried out in the following conditions:

- liquid temperature from approximately 40°to approximately 80°C and preferably from approximately 40°to approximately 60°C;

- pressure from about 80 bar to about 250 bar and preferably from about 100 bar to about 200 bar;

the extraction time from about 1 hour to about 6 hours;

the fluid flow is determined by a specialist depending on the amount of substance that needs to be extracted, and the size of the autoclave. Preferably, the flow rate of CO2used in the method according to the present izobreteny is, is from 2 to 15 kg/hour, preferably from 8 to 12 kg/h;

• for the number of plants of 200 to 1000 g, preferably about 500 g,

• and for autoclave comprising from 2 to 10 liters, preferably about 5 litres.

During this first stage extraction is possible to add an organic co-solvent from the group of alcohols (including ethanol), oxides, ethers, esters or a mixture of two or more of these solvents.

Extracted so the plant can then be subjected to a second extraction. The extraction fluid preferably is a supercritical CO2with a co-solvent or without co-solvent. Operating conditions are as follows:

- liquid temperature from approximately 40°to approximately 80°C and preferably from approximately 40°to approximately 60°C;

- pressure from about 80 bar to about 250 bar and preferably from about 100 bar to about 200 bar;

the flow rate from 2 to 15 kg/hour, preferably from 8 to 12 kg/h;

• for the number of plants of 200 to 1000 g, preferably about 500 g,

• and for autoclave comprising from 2 to 10 liters, preferably about 5 litres.

Preferably extracti is carried out at a mass ratio plant/co-solvent, approximately from 1/0,1 to 1/5.

This second stage extraction can be repeated. The extraction time is from about 1 hour to about 3 hours one additional stage of extraction.

Then carry out the evaporation of the obtained extract.

The specialist can adapt operating conditions of the method using a supercritical fluid, to obtain more or less enriched extract of eucalyptus.

The final drying of the extract is carried out by lyophilization or more conventional drying means known to the expert (spraying, drying Cabinet, ...). Preferably the temperature of the drying does not exceed about 60°C.

The extract can be stabilized by the addition of an antioxidant, such as ascorbic acid, citric acid, in amounts comprising from about 0.05 to about 1 g per 100 g of dry extract.

Preferably these compounds (I), including macrocarpon L and macrocarpon M, can be selected on the basis of plant extract. Preferably plant extract is an extract of eucalyptus.

Ways to carry out their treatment, are common well-known specialist using chromatography. Extracts share n the preparative column, having as stationary phase, reverse phase, mainly phase Symetry Shield®, 5 μm (Waters), and as a mobile phase mixture of acetonitrile/water/triperoxonane acid in proportions 95/5/0,1%.

The purity of the compounds of formula (I) such fraction is greater than or equal to 90%.

Preferably the purity of macrocarpas L or macrocarpas M in such a fraction is greater than or equal to 90%.

The authors of the present invention showed the effect of the compounds of formula (I) according to the invention on the reuptake of neurotransmitters.

In the framework of the present invention under "neurotransmitters" understand dopamine and/or serotonin and/or norepinephrine.

Because of their pharmacological properties as inhibitors of reuptake of these neurotransmitters, these compounds of formula (I) are particularly suitable for the production of medicines or food additives intended for the treatment and/or prevention of many disorders or pathologies resulting from a deficiency of dopamine and/or serotonin and/or norepinephrine.

Among the disorders or pathologies that can be treated and/or prevention using at least one of the compounds of formula (I) according to the present invention, it is necessary to call as a non-restrictive and illustrative examples

- neurological diseases, disorders or Russ the device, such as neurodegenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson's disease, cerebral vascular disorders, traumatic brain injury), amyotrophic lateral sclerosis, senile dementia, fronto-temporal dementia, vascular dementia, migraine, neuropathic pain of Central origin;

psychiatric diseases, disorders or disorders, such as depression (endogenous resistant, reactive or iatrogenic), depressive status, schizophrenia, bipolar disorder, generalized anxiety, diseases associated with stress, panic attacks, obsessive-compulsive disorder, post-traumatic stress syndromes, disorders of attention and hyperactivity, eating disorders (particularly bulimia, anorexia), phobias (including agoraphobia), autism;

disorders of memory, attention and vigilance, associated with neurological and psychiatric diseases, disorders or disorders;

functional somatic disorders, such as chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, gastroesophageal reflux, decreased libido, erectile dysfunction, urinary incontinence;

- obesity, excess body weight;

- dependence on addictive substances, in particular is of icotine, alcohol, opiates, cannabinoids, stimulants.

Indeed, drug or food Supplement according to the invention is preferably intended:

• for the treatment of dependence on addictive substances, and especially during the preliminary stage stop Smoking, contributing, among other things, reduce consumption and/or reduce the associated symptoms, such as anxiety and/or depression;

• for the induction of withdrawal nicotine, alcohol, opiates, cannabinoids, stimulants, allowing, thus, to stop their consumption,

• for the prevention of relapse in abstinent and to maintain abstinence;

• to prevent and/or reduce the symptoms associated with the syndrome of nicotine, alcohol, opiates, cannabinoids, stimulants such as anxiety and/or depression.

The specialist can determine the other diseases for which treatment is required such inhibition. The applicant says here, not limiting way, some bibliographic references, which shows the relationship between pathologies and their treatment using a triple reuptake inhibitor of dopamine and/or serotonin and/or norepinephrine. Presents an example for each "group ".

Dopamine, serotonin and Nora is renalin contribute to the development and preservation of neurons (LAUDER J.M., Trends Neurosci, 1993, 16; 233). Some neurological diseases, such as Parkinson's disease (Hornykiewicz O., Adv Cytopharmacol. 1971, 1; 369) caused by deficiency of dopamine; monoamine oxidase inhibitors, which increase the level of dopamine, serotonin and norepinephrine, is used to treat Parkinson's disease and other neurological disorders (Ebadi M., Curr Drug Targets. 2006, 7; 1513). The compounds of formula (I) according to the present invention can be preferably used, therefore, in the treatment of these neurological diseases.

Depression is a common pathology of mood characterized by feelings of intense sadness, pessimistic thoughts, reduced self-esteem, often accompanied by loss of landmarks, decreased enthusiasm and libido. The inability to experience pleasure in normally enjoyable activities, also known as anhedonia, is also seen as a symptom often seen in depression. Depression cure at present, selective inhibitors of serotonin reuptake, such as fluoxetine, citalopram, or paroxetine, a selective reuptake inhibitors of norepinephrine, such as reboxetine, or mixed reuptake inhibitors of serotonin and norepinephrine, such as milnacipran or venlafaxine. Meanwhile an important role in IU is Anisman pleasure and motivation assign dopaminergic neurons, stretching in the brain called the nucleus accumbens (Koob G.F. Sem. Neurosci. 1992, 4, 139; J.D. Salamone Behav. Brain Res. 1994, 61, 117). Symptoms of depression can be, thus, is preferably subjected to treatment with the inhibitor of the reuptake of dopamine, serotonin and norepinephrine, such as the compound of formula (I) according to the present invention.

The absorbance of addictive substances, including nicotine, increases extracellular levels of dopamine in the ventral striatum in animals (Di Chiara G, Imperato et A., Proc Natl Acad Sci U S A. 1988, 85; 5274) and humans (Brody et al., Am J Psychiatry, 2004, 161; 1211). Deprivation of nicotine may be accompanied by a depressive syndrome (Wilhelm K, et al., Drug Alcohol Rev, 2006, 25; 97). The compounds of formula (I) according to the present invention can be preferably used, therefore, as a means for substitution therapy in the treatment of dependence on addictive substances such as nicotine, and for the prevention or treatment of depressive syndrome associated with the syndrome.

Functional disorders, also called somatotropic, are disorders that affect basic physiological functions and which are, apparently, not caused by organic damage, but related to the function of organs (liver, heart, etc.). Functional somatic disorders may underlie illness who evania, which will develop later. Among these disorders fibromyalgia is a disorder which combines the diffuse or localized pain, chronic fatigue, depressive symptoms, disorders of memory and concentration (ROOKS DS., Curr Opin Rheumatol. 2007, 19; 111). Fibromyalgia symptoms are treated mixed reuptake inhibitors norepinephrine/serotonin (Vitton O., Hum Psychopharmacol. 2004, 19 Suppl 1:S27). Add a component that promotes dopaminergic tone, such as a compound of formula (I) according to the present invention, it is preferable to obtain drugs, or dietary supplements intended for treatment and/or prophylaxis of functional somatic disorders.

Preferably the specified drug is oral, injectable or transdermal form.

Preferably oral form selected from the group consisting of tablets, gelatin capsules, capsules, liquid preparations such as syrups, drinkable solutions or powders for drinking suspensions.

Preferably specified food additive (which may be a nutraceutical or nutritional) are in the form of doses, and in such forms as capsules, tablets, pills and other similar forms, sachets of powder, and the pools of liquid, bottles with eyedropper, and other similar form of liquid preparations, or preparations in powder form, intended for reception in the form of measured units containing a small amount.

The invention will be better understood by the following examples, which however do not limit its scope.

Example 1.Getting macrocarpas L based on the extract of Eucalyptus globulus.

The leaves of Eucalyptus globulus were crushed, then was extracted with 5 volumes of dichloromethane. The extraction was carried out twice under reflux for 1 hour.

Then was carried out by filtration under vacuum. The combined filtrates were concentrated to 2 volumes.

Three extraction liquid-liquid was carried out by adding one volume of 0.1 M sodium carbonate (Na2CO3).

The combined basic aqueous phase was acidified by adding 1 M hydrochloric acid (HCl) to obtain a pH approximately equal to 1, then was extracted with 3 extraction liquid-liquid using dichloromethane. The organic phase was dried on sodium sulfate, then concentrated and dried under vacuum at 60°C max. The obtained dry residue contains a mass fraction of macrocarpas L of 1.5%. Thus obtained extract was separated on a column of silica gel with periodic gradient toluene/acetone, changing the following is roportaj: toluene 100%, toluene/acetone 99/1, acetone 100%. Fraction of toluene/acetone 99/1 containing macrocarpon L, evaporated, dried, then purified on a preparative column with the stationary phase reverse phase Symetry Shield®, 5 μm (Waters), and as a mobile phase mixture of acetonitrile/water/triperoxonane acid in proportions 25/75/0,1%.

The purity of macrocarpas L in the resulting fraction is approximately 97%.

These NMR selected molecules are as follows:

1H NMR (500 MHz, pyridine-d5), δ h/million: of 0.62 (t, J=8,54 Hz, 1H), 0,91 (DD, J=9,16, 5,80 Hz, 1H), 0,97 (d, J=6,41 Hz, 3H), 0,99-of 1.05 (m, 1H), of 1.06 (d, J=6,10 Hz, 3H), 1,10 (s, 3H), 1,11 (s, 3H), 1,24 (s, 3H), 1,42 of 1.46 (m, 1H), 1,44 (s, 3H), 1,50-of 1.65 (m, 3H), of 1.66-1.77 in (m, 2H), 1,90 (TD, J=13,12, to 3.36 Hz, 1H), 1,92-2,02 (m, 1H), 2,07 (dt, J=to 12.28, a 3.01 Hz, 1H), 2,13-of 2.24 (m, 2H), 2,74 (TD, J=12,21, of 3.05 Hz, 1H), 3,86 (dt, J=11,37, of 4.54 Hz, 1H), 10,56 (s, 1H), 10,57 (s, 1H).

13C NMR (125 MHz, pyridine-d5), δ, ppm: 16,3, 16,5, 17,1, 17,8, 19,2, 22,3, 22,4, 24,4, 25,0, 25,7, 27,8, 30,1, 32,3, 39,0, 39,3, 44,9, 45,4, 52,3, 54,0, 72,2, 107,0, 107,6, 107,8, 171,6, 172,1, 173,0, 192,2, 192,4.

Example 2.Determination of 50% inhibitory concentration (CI50) macrocarpas L, obtained according to example 1 regarding the reuptake of neurotransmitters in comparison with reverse grip hyperforin.

Tests for capture were carried outin vitroon the synapses of rats.

1) Evaluation of reuptake of serotonin (or 5-HT)

The Protocol used for this evaluation was described in Peovic, S. and W.E.G. MULLER, 1995 - Pharmacological profile of hypericum extract: effect on serotonin uptake by postsynaptic receptors, Arzneim-Forsch. Drug Res., 45: 1145-1148.

The principle consisted in the following.

Synapses obtained from rat brain were incubated for 15 min at 37°C with 0.1 MX [3H]-serotonin in the presence or in the absence (control) of the compound obtained according to example 1, or imipramine (standard) in buffer containing 118 mm NaCl, 5 mm KCl, 2.5 mm MgSO4, 1.2 mm NaH2PO4, 25 mm NaHCO3, 11 mm glucose, 10 μm EGTA and 50 μm ascorbic acid (pH=7,4).

Baseline activity was determined, incubare this mixture for 15 min at 37°C in the presence of 10 μm imipramine to block the reuptake.

After incubation, the samples were rapidly filtered under vacuum through a filter made of fiberglass (GB/B, Packard) and washed two times with ice-cold incubation buffer to remove free [3H]-serotonin. The filters were dried and the remaining radioactivity was measured with a scintillation counter (Topcount, Packard)using a scintillation cocktail (Microscint O, Packard).

2) evaluate the reuptake of dopamine (or DA)

The Protocol used for this evaluation was described in Janowsky A. Berger, P., Vocci F., R. Labarca, Skolnick P., and S.M. Paul, 1996 - Charcaterization of sodium-dependent [3H]GBR-12935 binding in brain: a radioligand for selective labelling of the dopamine transport complex, J. Neurochem., 46, 1272-1276.

The principle consisted in the following.

Synaptic environment (synapses striata is and rats) were incubated for 15 min at 37°C with 0.1 MX [ 3H]-DA in the presence or in the absence (control) of the compound obtained according to example 1 or GBR 12909 (standard) in buffer solution (see the reuptake of serotonin).

Baseline activity was determined, incubare this mixture for 15 min at 37°C in the presence of 10 μm GBR 12909, to block the reuptake.

After incubation, the samples were rapidly filtered under vacuum through a filter made of fiberglass (GB/B, Packard) and washed two times with ice-cold incubation buffer to remove free [3H]-dopamine. The filters were dried and the remaining radioactivity was measured with a scintillation counter (Topcount, Packard)using a scintillation cocktail (Microscint O, Packard).

3) evaluate the reuptake of norepinephrine (or NOT)

The Protocol used for this evaluation was described in Perovic, S. and W.E.G. MULLER, 1995 - Pharmacological profile of hypericum extract: effect on serotonin uptake by postsynaptic receptors, Arzneim-Forsch. Drug Res., 45: 1145-1148.

The principle consisted in the following.

Synaptic environment (the synapses of the rat hypothalamus) were incubated for 15 min at 37°C with 0.1 MX [3H]-NE in the presence or in the absence (control) of the compound obtained according to example 1 or protriptyline (standard) in buffer solution (see the reuptake of serotonin).

Baseline activity was determined, incubare this mixture for 20 min at 37°C in the presence of 10 μm protriptyline to block reverse C is the grip.

After incubation, the samples were rapidly filtered under vacuum through a filter made of fiberglass (GB/B, Packard) and washed two times with ice-cold incubation buffer to remove free [3H]-NE. The filters were dried and the remaining radioactivity was measured with a scintillation counter (Topcount, Packard)using a scintillation cocktail (Microscint O, Packard).

4) Results

The results were expressed as percent inhibition of reuptake of the estimated neurotransmitter.

These different protocols were repeated for different concentrations of the compound obtained according to example 1, and hyperforin.

The obtained curves of inhibition was possible to obtain values of CI50shown in the table.

Determination of 50% inhibitory concentration (CI50the connection according to the present invention and hyperforin in respect of the reuptake of serotonin, norepinephrine and dopamine
CI50(ág/ml)
TestMacrocarpon LHyperforin
Serotonin reuptake1,80,89
Noradrenaline reuptake3,10,79
Reuptake of dopamine1,00,23

These results demonstrated that the compound of formula (I) according to the present invention has inhibitory activity against reuptake of neurotransmitters.

1. The pharmaceutical composition comprising, as an active beginning at least one compound selected from
5-[(1'R)-1'-[(1S,3S,4S,7R,7R,7bS)-decahydro-7-hydroxy-1,1,3A,7-tetramethyl-1H-cyclopropa[A]naphthalene-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxole and
5-[(1'S)-1'-[(1aS,3S,4S,7R,7R,7bS)-decahydro-7-hydroxy-1,1,3A,7-tetramethyl-1H-cyclopropa[A]naphthalene-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxolyl,
in combination with an acceptable carrier, designed for the treatment and/or prevention of disorders or pathologies resulting from disorders reuptake of the following neurotransmitters: dopamine, serotonin and/or norepinephrine.

2. The pharmaceutical composition according to claim 1, characterized in that 5-[(1'R)-1'-[(1S,3S,4S,7R,7R,7bS)-decahydro-7-hydroxy-1,1,3A,7-tetramethyl-1H-cyclopropa[A]naphthalene-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxolyl or 5-[(1'S)-1'-[(1S,3S,4S,7R,7R,bS)-decahydro-7-hydroxy-1,1,3A,7-tetramethyl-1H-cyclopropa[A]naphthalene-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxole get from plant extract.

3. The pharmaceutical composition according to claim 2, characterized in that the plant extract obtained from eucalyptus selected from the species belonging to the subgenus Eudesmia, Symphomyrtus et Corymbia et les especes seq.: Eucalyptus globulus L., Eucalyptus pulverulenta Sims, Eucalyptus kartzoffiana L.A.S. Johnson 1 Blaxell, Eucalyptus macrocarpa Hook., Eucalyptus cinerea F.Mueli. ex Benth., Eucalyptus dorrigoensis (Blakely) L.A.S. Johnson 1 K.D.Hill Eucalyptus leptopoda Benth., Eucalyptus occidentalis Endl., Eucalyptus viridis R.T.Baker, Eucalyptus polybractea R.T.Baker et Eucalyptus smithii R.T.Baker.

4. The pharmaceutical composition according to claim 3, characterized in that the extract of eucalyptus selected from the group consisting of an extract of the leaves, flowers, fruits, seeds, shoots and stems of eucalyptus.

5. The pharmaceutical composition according to one of claims 1 to 4, characterized in that it comprises the extract of eucalyptus, in which the mass fraction of 5-[(1'R)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3A,7-tetramethyl-1H-cyclopropa[A]naphthalene-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxolyl or 5-[(1'S)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3A,7-tetramethyl-1H-cyclopropa[A]naphthalene-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxole exceed 0.05% and strictly less than 90%.

6. The use of at least one compound selected from
5-[(1'R)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3A,7-tetramethyl-1H-cyclopropa[A] naphthalene-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxole and
5-[(1'S)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3A,7-tetramethyl-1H-what ecoprobe[A]naphthalene-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzodioxolyl,
for obtaining a medicinal product intended for the treatment and/or prevention of dependency on addictive substances resulting from disorders reuptake of dopamine and/or serotonin and/or norepinephrine.

7. The use according to claim 6, characterized in that the treatment and/or prevention of these dependencies from addictive substances, is the inhibition of the reuptake of dopamine and/or serotonin and/or norepinephrine.

8. The use according to claim 6, wherein the addictive substance is selected from nicotine, alcohol, opiates, cannabinoids and stimulants.

9. The use according to claim 6, wherein the drug is an oral, injectable or transdermal form.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula used as herbicides, in which Q1 is H or F; Q2 is a halogen provided that when Q1 is H, Q2 is Cl or Br; R1 and R2 independently denote H, C1-C6-acyl; and Ar is a polysubstituted aryl group selected from a group consisting of

a) , b) , c) in which W1 is a halogen; X1 is C1-C4-alkyl, C1-C4-alkoxy, C1-C4-halogenalkyl, -NR3R4; Y1 is C1-C4-alkyl, C1-C4-halogenalkyl, halogen or -CN, or when X1 and Y1 are taken together denotes -O(CH2)nO-, in which n=1; and R3 and R4 independently denote H or C1-C4-alkyl; W2 is F or Cl; X2 is F, CI, -CN, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-alkylthionyl, C1-C4-alkylsulphonyl, C1-C4-halogenalkyl, C1-C4-halogenalkoxy, C1-C4-alkoxy-substituted C1-C4-alkyl, C1-C4-alkoxy-substituted C1-C4-alkoxy, -NR3R4 or fluorinated acetyl; Y2 is a halogen, C1-C4-alkyl, C1-C4-halogenalkyl or -CN, or when W2 is F, Xz and Y2, taken together, denote -O(CH2)nO-, in which n=1; and R3 and R4 independently denote H or C1-C6-alkyl; Y3 is a halogen or -CN; Z3 is F, CI, -NO2, C1-C4-alkoxy, -NR3R4; and R3 and R4 independently denote H; derivatives on the carboxyl group which are suitable for use in agriculture.

EFFECT: compounds are excellent herbicides with a wide range action against weeds and excellent selectivity towards agricultural crops.

19 cl, 7 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of extracting ortho-vanilin and iso-vanilin from aqueous solutions. The method involves addition of a salting-out agent - sodium chloride to aqueous solutions of ortho-vanilin and iso-vanilin and a solution of polyvinyl caprolactam prepared beforehand, having concentration of 5-15 wt % until achieving 34-35 wt % content of salt in the solution, with volume ratio of the aqueous phase to organic phase equal to 10:1. The organic phase is extracted and separated, analysed spectrophotometrically and the recovery ratio (R, %) of ortho-vanilin and iso-vanilin is calculated using the formula: R=D·100/(D+r), where D is coefficient of distribution of ortho-vanilin and iso-vanilin between the solution of polyvinyl caprolactam and the aqueous solution, r is the ratio of equilibrium volumes of the aqueous and organic phases.

EFFECT: method increases recovery ratio of ortho-vanilin and iso-vanilin from aqueous solutions.

1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: method of extracting vanillin, ethylvanillin, iso-vanillin and ortho-vanillin from water solutions is characterised by the following: preliminarily to water solutions of vanillin, ethylvanillin, iso-vanillin and ortho-vanillin added are; ammonium sulphate, until its content in solution is 42-43% to solution weight, and preliminary prepared mixture of solvents, consisting of 22-23 wt % acetone and 78-77 wt % diacetone alcohol, then extraction is carried out with molar ratio of water and organic phases 10:1, and degree of vanillins extraction (R,%) is calculated by formula: R=D-100/(D+r), where D is coefficient of vanillins distribution between solvent mixture and water-salt solution, r is ratio of equiweight volumes of water and organic phases.

EFFECT: increase of degree of vanillin, ethylvanillin, iso-vanillin and ortho-vanillin extraction from water solutions.

1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: vanillin is applied in confectionery, pharmaceutics and manufacturing of perfume and cosmetics, and lilac aldehyde is applied in manufacturing of trimetoprim, biseptol and other pharmaceutical drugs. Method involves extraction by oxygen-containing extraction agents at pH 6.0-8.0 and re-extraction by water alkaline solution at pH 10-14. Extraction stage involves use of tributhylphosphate, or kerosene solutions of tributylphosphate with 40-99 wt % of tributylphosphate, as extraction agents.

EFFECT: reduced volume of extraction agent required at extraction stage in comparison to existing technique.

7 ex

The invention relates to an improved process for the preparation of 2,3,4-trimethoxybenzaldehyde, which is used as an intermediate product to obtain drug - Trimetazidine

The invention relates to an improved process for the preparation of 2,3,4-trimethoxybenzaldehyde used as an intermediate product for the synthesis of medicinal substances
The invention relates to a method for products of fine organic synthesis of vanilla, lilac aldehyde, levulinate acid

The invention relates to a new method of obtaining 4-hydroxybenzaldehyde and its derivatives, in particular for the preparation of 3-methoxy-4-hydroxybenzaldehyde (vanilla) and 3-ethoxy-4-hydroxybenzaldehyde (ethylvanillin)
The invention relates to the field of fine organic synthesis, namely the method of selection of vanilla and lilac aldehyde from a solution obtained by oxidation lignindegrading raw materials by extraction of the high-boiling alcohols or esters having a boiling point of more than 130oSince at pH 6-8 with further reextracting aqueous-alkaline solution at pH 10 to 14 and the release of vanillin by acidification with sulfuric acid to pH 5

The invention relates to new naphtylpropionate F.-ly (I), where R1and R2- N, -HE or-O(C1-C4-alkyl); R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholinyl, dialkylamino - or 1-hexamethylen-aminogroup; n = 2 or 3, or pharmaceutically acceptable salts

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical and food industry, particularly producing compositions of biologically active substances applicable as biologically active additives. The pharmaceutical composition contains glycine enriched by crystal gamma-modification of glycin in amount 90-98 %, and an additive of non-toxic organic acids in amount 2-10 %. Gamma-modification of glycin makes up to 8-95 % of total amount of glycine. As additives of the organic acids, the non-toxic acids are specified as follows: malic, malonic, citric acid, citric acid hydrate or a mixture thereof. A method for preparing the pharmaceutical composition of glycine is implemented by the combined mechanical treatment of the ingredients in a vibrating mill for 6-60 minutes.

EFFECT: pharmaceutical composition of glycine under the invention is solid-stable.

2 cl, 6 dwg, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. What is described is an adhesive composition containing donepezil and a stabiliser. The stabiliser containing one or more compounds specified in a group consisting of ascorbic acid, metal salt or ester of such, isoascorbic acid or metal salt of such, ethylene-diamine-tetraacetic acid or metal salt of such, cysteine, acetylcysteine, 2-mercaptobenzimidazole, 3(2)-tert-butyl-4-hydroxyanisol, 2,6-di-tert-butyl-4-methylphenol, tetrakis[3-(3',5'-di-tert-butyl-4'-hydroxyphenyl)]propionate pentaerythrite, 3-mercapto-1,2-propanediol, tocopherol acetate, rutin, quercetin, hydroquinone, metal salt of hydroxymethansulphinic acid, metabisulphite metal salts, sulphite metal salt and thiosulphate metal salts; it is added to a layer of a pressure sensitive adhesive applied on at least one side of the substrate.

EFFECT: prepared high reliable and stable adhesive composition which inhibits formation of donepezil-related compounds in the layer of the pressure sensitive adhesive.

14 cl, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new substituted tertahydro-4H-tieno-pyrrolo[3,2- c] pyridines of general formula 1, their geometric isomers or a mixture whereof and their pharmaceutically acceptable salts. In the general formula 1 Th represents an annulated tien cycle; W represents an single bond (in this case R3 is immediately bonded to the pyrrole cycle nitrogen atom), methylene, 1,2-ethane, 1,2-ethylene, 1,2-acetylene, 1,3-propane or 1,3-allyl bridge, non-obligatorily substituted by a hydroxy group; R1 and R2 represent hydrogen, C1-C4alkyl, a halogen or -CH2OH; R3 represents hydrogen, non-obligatorily substituted phenyl, non-obligatorily substituted by azaheteroaryl; R4 represents C1- C4alkyl, CO2C2H5 or CO2C(CH3)3; R5, R6, R7 (independent of each other) represent hydrogen or C1- C4alkyl or R5 and R6 together form an ethylene bridge while R7 represents hydrogen or R5 and R7 together form an ethylene bridge while R6 represents a hydrogen atom, they representing substituted tetrahydro-4H-tieno-pyrrolo [3,2-c] pyridines pf general formula 1, their geometric isomers, a mixture of such geometric isomers, their pharmaceutically acceptable salts as per any of Items 1-5.

EFFECT: obtainment of compounds representing ligands with receptor activity with regard to alpha-oadrenoreceptors, dopamine receptors, histamine receptors and serotonin receptors which compounds may be used during prevention and treatment of central nervous system diseases and for study of peculiarities of physiologically active substances possession biological activity with regard to the said receptors.

11 cl, 3 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of indole with formula (I) or indole pharmaceutically acceptable salts: where: ring A stands for a benzene or a tiofen ring; R1 stands for a C1-.6 alkyl that may be substituted by one or several groups selected from among -OH, - O-C1-6 alkyl, an amino group that may be substituted by one or two C1-6 alkyls; -O-C1-6 alkyl; a halogen; CN; 5-6-membered cyclic amine; n is equal to 0 - 4 and to 0- 2 if ring A is a benzene or a tiofen ring accordingly; R2 stands for -H, -C1-6 alkyl; R3 stands for H, -C1-6 alkyl that may be substituted by phenyl, C3-6 cycloalkyl; R4 stands for C1-6 alkyl that may be substituted by one or several groups selected from among -OH, -O- C1-6 alkyl, an amino group that may be substituted by one or two C1-6 alkyls and 5-6-membered cyclic amine; C3-6 cycloalkyl, phenyl or-OH; X1 stands for -CH2-, -O-, -S-, -CH(R°)-; X2 stands for -C(RA)(RB)-, -O-; X3 stands for -C(RC)(RD)-; m is equal to 1 - 3; R° stands for -H, or R°, together with R4, form C3-6 alkylene; RA, RB, RC and RD are identical or different and stand for -H, C1-6 alkyl where, in case m is equal to 2 or 3, each RC and R° may be identical or different provided 1- methyl-4a-phenyl-2,3,4,4a,5,9b-hexahydro-1H-indeno [1,2-b] pyridine, 4a-phenyl-2,3,4,4a,5,9b-hexahydro-4aH-indeno [1,2-b] pyridine and 2-(1,2,3,4,5,9b-hexahydro-4aH-indeno [1,2-b] pyridine -4a-yl)-N,N-dimethylethanamine are excluded).

EFFECT: compounds possess antagonistic activity regarding NMDA receptor which enables their usage in pharmaceutical compositions for treatment of Alzheimer disease, vascular dementia, Parkinson disease, chronic depression, attention deficit hyperactivity disorder, migraines etc.

18 cl, 40 tbl, 84 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this group of inventions relates to medicine, namely - to neurology and deals with neurogenesis stimulation and depression treatment. For the said purpose one administers 2-(2-oxopyrrolidine-1-yl)-N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro (2,3-b)chinoline-4-yl) acetamide in quantities effective for generation of new nerve cells.

EFFECT: neurogenesis stimulation and depression treatment.

10 cl, 10 dwg, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, namely - to experimental pharmacology and can be used for physical endurance stimulation. For the said purpose one administers beta-cyclodextrin conjugated with p-amino-benzoic acid.

EFFECT: invention allows extending the range of medications for physical endurance stimulation.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to azaadamantane derivatives of formula (I), to their pharmaceutically acceptable salts possessing the properties of nAChR ligands, their application, a method of treating and based pharmaceutical compositions, and also to intermediate compounds of formula (VI) and (VII) and to application of the compound of formula (V) for preparing the compound (I). In general formulas

L1 represents -O- or -NRa-; A represents -Ar1 or -Ar2-L2- Ar3; Ar1 represents 5-9-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, carboxyalkyl, cyano, halogenalkoxy, halogenalkyl, halogen, hydroxy, nitro, -NH2, (NH2)carbonyl and oxido; Ar2 represents 5-6-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, carboxy alkyl, cyano, halogenalkoxy, halogenalkyl, halogen, hydroxy, nitro, -NH2 and (NH2) carbonyl; Ar3 represents aryl, optionally substituted alkoxy, alkoxyhalogenalkyl, alkyl, aryl, halogenalkoxy, halogen, hydroxy and -NH2; or Ar3 5-9-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, carboxy, carboxyalkyl, halogenalkyl, heterocyclyl and tritylaryl; L2 represents a bond, -O- or -C(O)NRa-; and Ra represents hydrogen.

EFFECT: preparing the pharmaceutically acceptable salts possessing the properties of nAChR ligands.

41 cl, 11 dwg, 162 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to N-(2-thiazolyl)amide derivatives of formula wherein R1 and R2 are independently selected from H, -NO2, fluorine, chlorine and iodine, provided at least one of R1 and R2 is different from H; m is equal to 1 or 2, or to its pharmaceutically acceptable salts.

EFFECT: invention refers to a method for preparing said compounds, based pharmaceutical composition and applying them for preparing a drug for treating or preventing GSK-3 mediated diseases or conditions, especially neurodegenerative diseases, such as Alzheimer's disease or insulin-independent diabetes.

24 cl, 3 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, particularly a composition for preventing or treating peripheral neuropathy. The pharmaceutical composition for preventing or treating peripheral neuropathy containing a therapeutically effective amount of a compound presented by formula 1, or its salt and a pharmaceutically acceptable carrier: [Formula 1]

wherein R is a hydrogen atom, alkyl group C1-C4 or saccharide. A food composition for preventing or treating peripheral neuropathy containing the compound presented by formula 1, or its salt as an active ingredient.

EFFECT: compositions described above for preventing or treating peripheral neuropathy.

6 cl, 9 dwg, 1 tbl, 15 ex

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