[(1h-indol-5-yl)-heteroaryloxy]-1-azabicyclo[3,3,1]nonanes as cholinergic ligands n-achr, applicable for psychotic and neurodegenerative disorders

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds in the form of a free base or a pharmaceutically acceptable acid addition salt specified in a group including: (4S,5R)-4-[5-(1H-indol-5-yl)-pyrimidin-2-yloxy]-1-azabicyclo[3.3.1]nonane, 5-{2-[(4S,5R)-(1-azabicyclo[3.3.1]non-4-yl)oxy]-pyrimidin-5-yl}-1,3-dihydroindol-2-one, (4S,5R)-4-[6-(1H-indol-5-yl)-pyridin-3-yloxy]-1-azabicyclo[3.3.1]nonane, (4S,5R)-4-[5-(1H-indol-5-yl)-pyridin-2-yloxy]-1-azabicyclo[3.3.1]nonane, (4S,5R)-4-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-1-azabicyclo[1.3.1]nonane and 5-{6-[(4S,5R)-(1-azabicyclo[3,3,1]non-4-yl)oxy]-pyridazin-3-yl}-1,3-dihydroindol-2-one, possess nAChR α7 agonist activity.

EFFECT: using them in pharmaceutical compositions and for preparing a drug applicable for preventing and treating a memory disorder.

21 cl, 2 ex

 

The invention relates to new derivatives of 1-azabicycloalkanes, to methods for their preparation, to their use as pharmaceuticals and to the containing pharmaceutical compositions.

The first variant of implementation of the present invention more preferably relates to a compound of formula (I)

in which

X denotes hydrogen or a hydroxy-group and

Y denotes one of the following groups:

in free base form or salt accession acid.

The preferred connection is proposed in the present invention, is (4S,5R)-4-[5-(1H-indol-5-yl)-pyrimidine-2-yloxy]-1-azabicyclo[3.3.1]nonan with the formula given below.

Another preferred compound proposed in the present invention is 5-{2-[(4S,5R)-(1-azabicyclo[3.3.1]non-4-yl)oxy]-pyrimidine-5-yl}-1,3-dihydroindol-2-he, having the formula given below.

Another preferred compound proposed in the present invention, is (4S,5R)-4-[6-(1H-indol-5-yl)-pyridine-3-yloxy]-1-azabicyclo[3.3.1] nonan with the formula given below.

Another Avenue is pactically connection proposed in this invention is (4S,5R)-4-[5-(lH-indol-5-yl)-pyridine-2-yloxy]-1-azabicyclo[3.3.1]nonan with the formula given below.

Another preferred compound proposed in the present invention, is (4S,5R)-4-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-1-azabicyclo[3.3.1]nonan with the formula given below.

Another preferred compound proposed in the present invention is 5-{6-[(4S,5R)-(1-azabicyclo[3.3.1]non-4-yl)oxy]-pyridazin-3-yl}-1,3-dihydroindol-2-he, having the formula given below.

The compounds of formula (I) exist in free base form or salt accession acid. In the present description, unless otherwise specified, the term "compounds of formula (I)" should be understood as including compounds in any form, for example, in free base form or salt accession acid. Also included are salts that are unsuitable for use in pharmaceuticals but which can be used, for example, for the isolation or purification of free compounds of formula (I), such as the picrate or perchlorate. For therapeutic purposes, use only the pharmaceutically acceptable salts or free compounds (if it is appropriate, in the form of farmacevticheskih drugs), and therefore they are preferred.

The compounds of formula (I) may exist in the form of various isomers, e.g., keto-enol tautomers. In the present description, unless otherwise specified, the term "compounds of formula (I)" should be understood as including compounds in any form, for example, keto-enol form or the form or in the form of any mixtures thereof.

If the compounds, salts, etc. specified in the plural, it also means one compound, salt, etc.

Another variant of implementation of the present invention also relates to methods of preparing compounds of formula (I).

The first method involves the following stages

i) reaction of compounds of formula (IX)

in which Y is as defined above, and z represents useplease group, such as CL, Br, I, tosylate with the compound of the formula (X)

in which R denotes H, C1-C4alkyl or both RO together with the atom to which they are attached, form a heterocyclic fragment, X is as defined above, and

ii) extract thus obtained compounds of formula (I).

The second method involves the following stages

i) reaction of compounds of formula (XI)

with the compound of the formula XII

in which X and Y are as defined above, and PG represents p chodawu protective group,

ii) subsequent removal of the protective group of the thus obtained compound and

iii) extracting the thus obtained compounds of formula (I) in free base form or salt accession acid.

This method is particularly suitable, if Y denotes the 3-peredelnyj fragment.

The original substances are known or can be obtained by known methods. Synthesis of the starting compounds is described, for example, in GB 123456, which is included in the present invention by reference.

The above-described individual stages of the reactions may include the following provisions:

A. One or more functional groups, for example, carboxypropyl, the hydroxy-group, the amino group or mercaptopropyl in the original substances may need to protect. Used protective groups may already be contained in the precursor and to protect the respective functional group from undesired secondary reactions, such as acylation, the formation of ethers, esters, oxidation, solvolysis and similar reactions. Themselves protective groups are different in that they are easily removed, i.e. without undesired secondary reactions, usually by means of solvolysis, recovery, photolysis or under the influence of enzymes, for example, under conditions similar to physiological conditions, the fact that they are not contained in the final products. The expert knows or can easily determine which protective groups are suitable for the reactions mentioned above and below in the present invention. The protection of such functional groups such protective groups are themselves protective group and the reaction of their removal are described, for example in standard reference manuals, such as J.F.W.McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T.W.Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981, in "The Peptidcs"; Volume 3 (editors: E.Gross and J.Meienhofer), Academic Press, London and New York 1981, in "Mcthoden der organischen Chemie" (Methods of organic chemistry), Houben Weyl, 4th edition, Volume 15/1, Gcorg Thieme Verlag, Stuttgart 1974, in H.-D.Jakubke and H.Jescheit, "Aminosaurcn, Peptide, Proteine" (Amino acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel, 1982, and in Jochen Lchmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of carbohydrates: monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.

b. Salt accession with acids can be obtained from the free bases by known methods, and Vice versa. Alternative you can use optically pure source materials. Salt accession with acids suitable for use in the context of the present invention include, for example, hydrochloride.

c. Mixture of stereoisomers, for example, a mixture of diastereoisomers can be divided into the respective isomers by methods in themselves known. For example, a mixture of diastereoisomers can be divided into separate d is stereoisomer using fractional crystallization, chromatography, the distribution between the solvent and using similar methodologies. This separation can be performed for the parent compounds or of compounds of formula I. the Enantiomers can be divided by education salts diastereoisomers, for example, by formation of a salt with an enantiomerically pure chiral acid, or by chromatography, for example, HPLC, using chromatographic substrates with chiral ligands. Alternative you can use optically pure source materials.

d. Diluents suitable for carrying out the above procedures, preferably are inert organic solvents. They include in particular aliphatic, alicyclic and aromatic, optionally halogenated hydrocarbons, such as, for example, benzine, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, and dimethyl ether of ethylene glycol and diethyl ether of ethylene glycol; ketones, such as acetone, butanone and methylisobutylketone; NITRILES, such as acetonitrile, propionitrile and butyronitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformamide, N-organic and Trini hexamethylphosphoric acid; esters such as methyl acetate and ethyl acetate; sulfoxidov, such as, dimethyl sulfoxide, alcohols, such as methanol, ethanol, n - and isopropanol, onomatology ether of ethylene glycol, monotropy ether of ethylene glycol, onomatology ether of diethylene glycol, monotropy ether of diethylene glycol. In addition, you can use a mixture of diluents. Depending on the starting compounds, the reaction conditions and excipients may be appropriate water or water-containing solvents. In addition, as a diluent at the same time you can use the original substance.

e. The temperature of the reaction can be varied within a relatively wide range. Typically, the methods carried out at temperatures from 0 to 150°C, preferably from 10 to 120°C. Conditions for deprotonation reactions can be varied within a relatively wide range. Typically, the methods carried out at temperatures from -150 to +50°C, preferably from -75 to 0°C.

f. The reaction is usually carried out at atmospheric pressure. However, the methods proposed in the present invention can also be carried out at elevated or reduced pressure is usually from 0.1 to 10 bar.

g. The original substances are generally used in approximately equimolar quantities. However, it is also possible to use a relatively large excess of one of the components. The reaction usually is about carried out in a suitable diluent in the presence of auxiliary substances for the reaction and the reaction mixture is typically stirred at elevated temperature for several hours.

h. The treatment of the reaction mixtures in accordance with the above methods and purification of the thus obtained compounds can be performed by known methods (see receipt).

Connections proposed in the present invention, according to studies in vitro and on animals have valuable pharmacological properties and are therefore applicable as pharmaceuticals.

So, found that the compounds proposed in the present invention, are cholinergic ligands nAChR. In addition, preferred compounds proposed in the present invention, showing selective activity against α7-nAChR. In particular, you may find that connections proposed in the present invention are agonists, partial agonists, antagonists or allosteric modulators of this receptor.

Due to its pharmacological profile, it is assumed that the compounds proposed in the present invention, applicable to the treatment of various diseases or pathological conditions, including diseases associated with CNS (Central nervous system)diseases associated with PNS (peripheral nervous system), diseases associated with inflammation, pain, and withdrawal symptoms caused by substance abuse. Diseases or disorders, wired the e with the Central nervous system, include generalized anxiety disorders, disorders of cognitive abilities, failure and impaired learning ability and memory, Alzheimer's disease (ad), prodromal AD, weak impaired cognitive ability in the elderly (SNP), amnestic SNP, memory impairment associated with age, attention deficit disorder with hyperactivity (ADHD), Parkinson's disease, Huntington's disease, BASS (amyotrophic lateral sclerosis), prion neurodegenerative disorders, such as disease of Creutzfeldt-Jakob disease and the disease Kuru, a disease Tourette's, psychosis, depression and depressive disorders, mania, manic depression, schizophrenia, the lack of cognitive ability in schizophrenia, obsessive-compulsive disorders, panic disorders, eating disorders, narcolepsy, nociception caused by AIDS-dementia, senile dementia, mild impaired cognitive abilities associated with age, autism, dyslexia, late dyskinesia, epilepsy and convulsive syndromes, post-traumatic stress disorder, a temporary anoxia, false dementia, pre-menstrual syndrome, late phase of luteinization, chronic fatigue syndrome and desynchronosis, developing when flying in a jet aircraft. In addition, the compounds proposed in the present invention, the can is about to be used for the treatment of endocrine disorders, such as thyrotoxicosis, programmazione, hypertension and arrhythmias, and angina, hyperkinesia, premature ejaculation and erection difficulties. In addition, the compounds proposed in the present invention, can be used to treat inflammatory disorders (Wang et al., Nature 2003, 421, 384; de Jonge et al., Nature Immunology 2005, 6, 844; Saeed et al., JEM 2005, 7, 1113), disorders or pathological conditions, including inflammatory skin disorders, rheumatoid arthritis, post-operative intestinal obstruction, Crohn's disease, inflammatory bowel disease, ulcerative colitis, sepsis, fibromyalgia, pancreatitis, and diarrhea. Connections proposed in the present invention can also be used for the treatment of withdrawal symptoms caused by termination of use creates dependence substances, such as heroin, cocaine, tobacco, nicotine, opioids, benzodiazepines and alcohol. In addition, the compounds proposed in the present invention, can be used to treat pain, for example, caused by migraine, postoperative pain, phantom pain in an amputated limb or pain associated with cancer. Pain can be an inflammatory or neuropathic pain, Central pain, chronic headaches, pain due to diabetic neuropathy, posttherapeutic neuralgia or peripheral ner is A.

In addition, degenerative eye disease that can be treated include eye diseases, which can directly or indirectly include degeneration of retinal cells, including ischemic retinopathy in General, internal ischemic neuropathy of the optic nerve, all forms of optic neuritis, age-related macular degeneration (SDT) in its dry form (dry TTP) and wet forms (wet TTP), diabetic retinopathy, racemose swelling yellow spots (SKIN), retinal detachment, pigmentary degeneration of the retina, macular degeneration, Stargardt, deltocephalinae macular degeneration best, Leber's congenital amaurosis and other types of hereditary retinal degeneration, pathologic myopia, retrolateral fibroplasia and hereditary neuropathy of the optic nerve's.

Found that exposure to a combination that includes at least one agonist of nicotinic alpha-7 receptor and at least one compound selected from the group comprising (a) conventional antipsychotics and (b) atypical antipsychotics in the treatment of mental disorders more than additive effect of the combined drugs. In particular, the combinations disclosed in the present invention, can be used for the treatment of schizophrenia, which is resistant as far as the structure to monotherapy using only one of the components of the combination.

Therefore, the present invention relates to a combination, such as a combined preparation or pharmaceutical composition, which includes at least one agonist of nicotinic alpha-7 receptor and at least one compound selected from the group comprising (a) conventional antipsychotics and (b) atypical antipsychotics, in which the active ingredients are contained in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier, designed for simultaneous, separate or sequential use.

The term "mental disorders" as used in this invention includes, but is not limited to, schizophrenia, anxiety disorders, depression and bipolar disorders. Preferably, if a mental disorder treated by the combination disclosed in the present invention, is schizophrenia, more preferably schizophrenia, which is stable with respect to monotherapy using only one of the components of the combination.

The term "conventional antipsychotics" when used in the present invention include, but are not limited to haloperidol, fluphenazine, thiothixene and flupentixol.

The terminology is "atypical antipsychotics" when used in the present invention includes, but not limited to, clozaril, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole.

In another embodiment, the compounds proposed in the present invention are used as diagnostic tools and/or ligands for PET, for example, for the identification and localization of nicotinic receptors in various tissues. Accordingly labeled with isotopes agents proposed in the present invention possess valuable characteristics when used as agents for labeling samples for histopathological studies, imaging agents and/or biomarkers, hereafter referred to as "markers" for the selective labeling of nAChR. The agents proposed in the present invention, it is preferable to use as markers for alpha-7 nAChR receptor in vitro or in vivo. In particular, the compounds proposed in the present invention, appropriately labeled with isotopes, applicable as markers for PET. Such markers for PET tagged with one or more atoms selected from the group including11C,13N15Oh,18F.

Therefore, the agents proposed in the present invention is applicable, for example, to determine the extent of employment receptor drug, effective at the nAChR, or for diagnostic purposes when the research the research Institute for diseases, caused by an imbalance or dysfunction of the nAChR, and for monitoring the effectiveness of medical treatment of such diseases.

In accordance with the above the present invention relates to an agent proposed in the present invention, intended for use as a marker to visualize when neyroissledovaniya.

In another embodiment, the present invention relates to compositions for labeling of brain structures and peripheral nervous system, containing nAChR in vivo and in vitro, including agent proposed in the present invention.

In yet another embodiment, the present invention relates to a method of labeling of brain structures and peripheral nervous system, containing nAChR in vivo and in vitro, which comprises the interaction of brain tissue with the agent proposed in this invention.

The method proposed in the present invention may include the additional step intended to establish that, had there been tagging the target structure of the agent proposed in the present invention. This additional step can be done through study of the target structure using positron emission tomography (PET) or single photon emission computed tomography (SPECT), or any other device, azuolausio register of radioactive radiation.

In particular, the agents proposed in the present invention are agonists of nicotinic acetylcholine α7 receptor (α7 nAChR).

For functional analysis of agents proposed in the present invention, detect high affinity to α7 nAChR, as evidenced by the following tests:

A. Functional analysis of affinity for α7 nAChR, make use of a line of pituitary cells of rats, stably expressing α7 nAChR. Briefly, the method consists in the following: GH3 Cells, recombinante expressing α7 nAChR, for 72 h prior to the experiment were seeded in black 96-well plates and incubated at 37°C in humidified atmosphere (5% CO2/95% air). On the day of the experiment, the medium is removed by shaking tablets and replaced with 100 μl of medium for the cultivation containing sensitive to calcium fluorescent dye, in the presence of 2.5 mm probenecid (Sigma). Cells are incubated at 37°C in humidified atmosphere (5% CO2/95% air) for 1 h Tablets shaken to remove excess Fluo-4, twice washed with buffered with Hepes (N-2-hydroxyethylpiperazine-N-2-econsultancy acid) salt solution (in mm: NaCl 130, KCl - 5,4, CaCl2- 2, MgSO4to 0.8, NaH2PO4to 0.9, glucose - 25, Hepes - 20, pH 7,4; CPX (balanced salt solution Hanks)) and put 100 ál of CPX, when the mu is the necessity of containing the antagonist. Incubation in the presence of antagonist spend 3-5 minutes Then the tablets are placed in the imaging reader and tablets record the fluorescence signal. In this assay, compounds proposed in the present invention have values RES50equal to from about 5 to about 9. In this study, preferred are partial and active agonists.

b. To evaluate the antagonistic activity of the compounds proposed in the present invention, in relation to neuronal nAChR α4β2 person have the same functional analysis using the line of epithelial human cells, stably expressing the α4β2 subtype of the person (Michelmore et al., Naunyn-Schmiedeberg''s Arch. Pharmacol. (2002) 366, 235). In this analysis, the preferred connection proposed in the present invention, detect the selectivity with respect to the subtype α7 nAChR.

c. To evaluate the antagonistic activity of the compounds proposed in the present invention, with respect to "ganglion subtype" (α3β4), nicotinic receptor muscle type (α1β1γδ) and the receptor 5-HT3conduct functional analyses, similar to those described above in section a), using the line of epithelial human cells, stably expressing ganglion subtype human cell line endogenously expressing cotinue the muscle-type receptors, or cell line expressing endogenous murine receptor 5-HT3(Michelmore et al. Naunyn-Schmiedeberg''s Arch. Pharmacol. (2002) 366, 235. Compounds which exhibit little activity or do not detect activity in relation to the α3β4 nAChR, nicotinic receptor muscle subtype, as well as receptor 5-HT3are particularly preferred.

In experiments on mice, characterized by insufficient capacity of the nervous system to modulate its sensitivity to incoming signals (mouse DBA/2), described in the publication S.Leonard et al., in Schizophrenia Bulletin 22, 431-445 (1996), compounds proposed in the present invention, significantly stimulate this ability at concentrations equal to from about 10 to about 40 microns.

It is possible to show that the compounds proposed in the present invention, improve attention in the study of attention in rodents (Robbins, J. Neuropsychiatry Clin. Neurosci. (2001) 13, 326-35), namely a 5-point study of the reaction time (5-CSRTT). In this study, rats have to look at the wall, containing 5 holes. If one of them goes light pulse, rat for 5 seconds have to touch the nose of the hole and then as a reward she gets a piece of food coming from the feeder in the opposite wall.

Compounds proposed in this of the Britanie, also can improve learning/memory in the study of group behavior in mice and rats (Ennaceur and Delacour, Behav. Brain Res. (1988) 31, 47-59).

Therefore, the compounds proposed in the present invention, applicable to the prevention and treatment (including attenuation and prevention of various disorders, preferably of the above. The applicability of agonists of α7 nAChR in the case of neurodegeneration described in the literature, for example, Wang et al., J. Biol. Chem. 275, 5626-5632 (2000).

Of course, in the treatment of the above and other violations of a suitable dose of a compound (active ingredient)proposed in the present invention, will vary depending on, for example, from the subject, route of administration and the nature and severity at treatment of pathological conditions as well as the relative activity of the specific tools used, proposed in the present invention. For example, the required number of active funds can be set using known techniques to study the in vitro and in vivo by determining how long the concentration of the active funds in the blood plasma is maintained at a value acceptable for therapeutic effect. Usually indicate that animal satisfactory results are achieved with daily doses equal to from about 0.01 to about 30.0 mg/kg personalnumber. For people prescribed daily dose is in the range from about 0.7 to about 1400 mg/day when administered orally, for example, from about 50 to 200 mg (for a person weighing 70 kg), which is usually administered once or in divided doses up to 4 times per day, or in the form of a delayed release means. Dosage forms for oral administration preferably include from about 1.75 or 2.0 to about 700 or 1400 mg of the compounds proposed in the present invention, in a mixture with an appropriate pharmaceutically acceptable diluent or carrier.

The pharmaceutical compositions contain, for example, from about 0.1 to about 99.9 percent, preferably from about 20 to about 60% of the active ingredient (ingredient).

Examples of compositions containing the compound proposed in the present invention include, for example, a solid dispersion, an aqueous solution, for example containing solubilizers agent, micro emulsion and suspension, for example, salts of the compounds of formula 1 or the free base of the compounds of formula I, in the range from 0.1 to 1%, for example 0.5%. Using a suitable buffer additives pH value of the composition can be set in the range, for example from 3.5 to 9.5, for example, 4,5.

Connections proposed in the present invention, are also used as chemicals for research

When applied in the context of the present invention the compound of formula I and/or its pharmaceutically acceptable salt can be entered in one active tools or in combination with one or more other active agents of the formula I and/or their pharmaceutically acceptable salts or, preferably, the other active agents are usually specially used for treating disorders described in the present invention, or additional other violations, in any usual manner, e.g. orally, e.g. in the form of tablets, capsules or nasal aerosol, or parenterally, e.g. in the form of solutions or suspensions for injection. Such other active tools used in such combinations, preferably selected from the group including benzodiazepines, selective inhibitors of reuptake of serotonin (SIPS, the camp maker), selective inhibitors of reuptake of serotonin and norepinephrine (SIPN), conventional antipsychotics, atypical antipsychotics, buspirone, carbamazepine, oxcarbazepine, gabapentin, pregabalin.

The SIPS, the camp maker, suitable for use in the present invention, preferably selected from the group including fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram and ESCITALOPRAM. SIPN, suitable for use in the present invention, site is preferably selected from the group including venlafaxine and DULOXETINE. The term "benzodiazepine" when used in the present invention includes, but is not limited to, clonazepam, diazepam and lorazepam. The term "conventional antipsychotics" when used in the present invention include, but are not limited to haloperidol, fluphenazine, thiothixene and flupentixol. The term "atypical antipsychotics" when used in the present invention means clozaril, risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole.

Buspirone can be entered in the form of free base or salt, for example, in the form of its hydrochloride, for example, in the form in which it is commercially available, for example, under the trade name of buspar™ or bespar™. It is possible to obtain and enter, for example, as described in US 3717634. Fluoxetine can be entered, for example, in the form of its hydrochloride, in which it is commercially available, for example, under the trade name prozac™. It is possible to obtain and enter, for example, as described in SA 2002182. Parasiten ((3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-forfinal)piperidine) can be entered, for example, in the form in which it is commercially available, for example, under the trade name paxil™. It is possible to obtain and enter, for example, as described in US 3912743. Sertraline can be entered, for example, in the form in which animalsa on sale, for example, under the trade name zoloft™. It is possible to obtain and enter, for example, as described in US 4536518. Clonazepam can be entered, for example, in the form in which it is commercially available, for example, under the trade name of antelepsin™. Diazepam can be entered, for example, in the form in which it is commercially available, for example, under the trade name diazepam designit™. Lorazepam can be entered, for example, in the form in which it is commercially available, for example, under the trade name Tavor™. Citalopram can be entered in the form of free base or salt, for example, in the form of its hydrobromide, for example, in the form in which it is commercially available, for example, under the trade name of cipramil™. ESCITALOPRAM can be entered, for example, in the form in which it is commercially available, for example, under the trade name cipralex™. It is possible to obtain and enter, for example, as described in AU 623144. Venlafaxine can be entered, for example, in the form in which it is commercially available, for example, under the trade name of traveler™. DULOXETINE can be entered, for example, in the form in which it is commercially available, for example, under the trade name of cymbalta™. It is possible to obtain and enter, for example, as described in SA 1302421. Carbamazepine can enter, for example, in the form in which it is commercially available, for example, under the trade name tegretol™ or egretol™. Oxcarbazepine can be entered, for example, in the form in which it is commercially available, for example, under the trade name trileptal™. Oxcarbazepine is well known from the literature [see for example, H. Schuetz et al., Xenobiotica (GB), 16(8), 769-778 (1986)]. Gabapentin can be entered, for example, in the form in which it is commercially available, for example, under the trade name neurontin™. Haloperidol can be entered, for example, in the form in which it is commercially available, for example, under the trade name haloperidol HERD™. Fluphenazine can be entered, for example, in the form of its dihydrochloride, in which it is commercially available, for example, under the trade name prolixin™. Citixen you can enter, for example, in the form in which it is commercially available, for example, under the trade name Navan™. It can be obtained for example as described in US 3310553. Flupentixol you can enter, for example, in the form of its dihydrochloride, for example, in the form in which it is commercially available, for example, under the trade name amaryl™ or as its decanoate, for example, in the form in which it is commercially available, for example, under the trade name depixol™. It can be obtained, for example, as described in BP 925538. Clozaril you can enter, for example, in the form in which it is commercially available, for example, under the trade name leponex™. It can be obtained for example as described in US 3539573. Resp ride you can enter, for example, in the form in which it is commercially available, for example, under the trade name of risperdal™. Olanzapine can be entered, for example, in the form in which it is commercially available, for example, under the trade name zyprexa™. Quetiapine can be entered, for example, in the form in which it is commercially available, for example, under the trade name seroquel™. Ziprasidone can be entered, for example, in the form in which it is commercially available, for example, under the trade name geodon™. It can be obtained for example as described in GB 281309. Aripiprazole can be entered, for example, in the form in which it is commercially available, for example, under the trade name of abilify™. It can be obtained for example as described in US 5006528.

The structure of the active ingredients, denoted by code numbers, generic or trade names that are listed in the latest edition of the standard reference book "The Merck Index" or in databases, for example, Patents International (e.g. IMS World Publications). Relevant their content is incorporated into the present application by reference. Any expert in the art may identify active agents and on the basis of these links can also be made to explore the pharmaceutical indications and characteristics using standard models, both in vitro and in vivo.

In the case of the combination pharmaceutical com is osili, intended for separate introduction of components of the combination and/or intended for insertion of components in a fixed combination, i.e. a single galenical composition comprising at least 2 components of the combination proposed in the present invention, can be obtained by the method, which is in itself known, and they are suitable for enteral, such as oral or rectal, and parenteral administration to mammals, including humans, and contain a therapeutically effective amount of at least one pharmacologically active component of the combination alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral administration. If applicable components of the combination administered in the form in which they are commercially available in the form of a particular drug, then, if the present invention is not specified, to provide described in the present invention benefit in their dosage and route of administration may be such as specified in the information provided in the leaflet of the corresponding commercially available medicines.

Pharmaceutical drugs for combination therapy for enteral or parenteral administration are, in the example, preparations in the form of a discrete dosage forms, such as tablets, coated in sugar, tablets, capsules or suppositories, and also ampoules. Unless otherwise indicated, are prepared by methods which are in themselves known, for example, using conventional methods of mixing, granulating, coating of sugar, dissolution or lyophilization. It should be understood that a single component quantity combinations contained in an individual dose of each dosage form in itself should not constitute an effective amount since the necessary effective amount can be achieved by introducing not only one dosage forms, but two or more dosage forms.

In particular, a therapeutically effective amount of each component of the combination can be administered simultaneously or sequentially and in any order, and the components can be entered separately (for example, sequentially through a constant or variable time intervals) or as a fixed combination. For example, the method of treatment (including impairment) violations in the context of the present invention may include (i) introduction of a component of the combination (a) (connections proposed in the present invention in free base form or pharmaceutically acceptable salt and (ii) the introduction of a component of the combination (b) (in the example, other compounds proposed in the present invention, or the active ingredient described by a formula) in free base form or pharmaceutically acceptable salt simultaneously or sequentially in any order, in amounts which together are therapeutically effective, preferably in synergistically effective amounts, e.g. in daily doses, containing the number described in this invention. The individual components of the combination can be entered separately at different times during the course of treatment, or both, in divided or single combination forms. In addition, the term "introduction" also includes the use of prodrugs of component combinations, which in vivo is converted in the component combination. Therefore, it should be understood that the present invention includes all such regimes of simultaneous and/or alternating treatment and the term "introduction" should be interpreted accordingly.

Effective used dose components of the combination may vary, for example, depending on the specific applying the compounds or pharmaceutical compositions, routes of administration, treated violations and/or severity undergoing treatment violations. Thus the dosing mode is selected in dependence the value of a number of factors, including route of administration, the compound's metabolism in the kidney and liver of the patient. A physician, Clinician or veterinarian with General training in the art can readily determine and prescribe the effective amount of one of the active ingredients needed for the prevention, reduction, prevention or suppression of a breach. Optimum accuracy when determining concentrations of active ingredients in the range in which the efficacy without toxicity requires a mode selection on the basis of the kinetics of receipt of the active ingredient in the appropriate area of the body.

In accordance with the above the present invention also applies to:

(1) to the Compound of formula 1 and/or salts thereof, intended for use in a diagnostic or therapeutic treatment of a mammal, preferably human; preferably for use as an agonist of the alpha-7 receptor, for example, for use for treatment purposes (including impairment) of any one or more violations, preferably any one or more of the specific violations identified above and below in the present invention.

(2) Pharmaceutical compositions comprising as active ingredient a compound of formula 1 and/or its pharmaceutically acceptable salt joint is with a pharmaceutically acceptable diluent or carrier.

(2') the Pharmaceutical composition intended for the treatment or prevention of disorders, in the treatment of which plays the role of activation of alpha 7 receptor or he participates and/or is the activity of the alpha-7 receptor, preferably any one or more of the violations listed above and below in the present invention, including the compound of formula 1 and/or its pharmaceutically acceptable salt and a pharmaceutically acceptable diluent or carrier.

(3) the Method of treatment of disorders, preferably any one or more of the specific violations listed above in the present invention, the subject in need of such treatment, comprising the introduction of a pharmaceutically effective amount of the compounds of formula 1 or its pharmaceutically acceptable salt.

(3') the Method of treating or preventing disorders, the treatment of which plays the role of activation of alpha 7 receptor or he participates and/or is the activity of the alpha-7 receptor, including the introduction needs it the mammal a therapeutically effective amount of the compounds of formula 1 and/or its pharmaceutically acceptable salt.

(4) the Use of the compounds of formula 1 and/or pharmaceutically acceptable salts, for preparing a medicinal product intended for the treatment or PR is to prevent disease or pathological condition, in the treatment which plays the role of activation of alpha 7 receptor or he participates and/or is the activity of the alpha-7 receptor, preferably one or more of the violations listed above.

(5) the Method described above comprising co-administration, e.g., simultaneous or sequential, a therapeutically effective amount of alpha-7 agonist of formula 1 and/or its pharmaceutically acceptable salt and a second pharmaceutically active compound and/or its pharmaceutically acceptable salt, a specified second pharmaceutically active compound and/or its salt is particularly suitable for use in the treatment of any one or more of the violations listed above and below in the present invention.

(6) a Combination comprising a therapeutically effective amount of alpha-7 agonist of formula 1 and/or its pharmaceutically acceptable salt and a second pharmaceutically active compound and/or its pharmaceutically acceptable salt, a specified second pharmaceutically active compound is particularly suitable for use in the treatment of any one or more of the specific violations listed above in the present invention.

The following examples are intended to illustrate the present invention without imposing restrictions on it in the volume. The following abbreviations are used:

AcOEtthe ethyl acetate
EtOHethanol
PFflash chromatography
BBhigh vacuum
MeonSon
TPLmelting point
MTBEmethyl tert-butyl ether
NHMDShexamethyldisilazane sodium
CTroom temperature
THFtetrahydrofuran

The temperature is measured in degrees Celsius. If not specified, the reaction was performed at room temperature. The structure of final products, intermediates and starting compounds confirmed using standard methods of analysis, e.g., microanalysis and spectroscopic characteristics (for example, MS (mass spectrometry), IR (infrared spectroscopy), NMR (nuclear magnetic resonator is (C)).

Example 1 (4S,5R)-4-[5-(1H-Indol-5-yl)-pyrimidine-2-yloxy]-1-azabicyclo[3.3.1]nonan

1-Azabicyclo[3.3.1]nonan-4-one (11,92 g, 85,6 mmole) is dissolved in 160 ml of Meon and cooled to -10°C. Portions added NaBH4(1,69 g, 42,9 mmole), so that the internal temperature did not exceed 0°C. the Reaction mixture is stirred at -10°C for 1 h was Added water and the solvent is evaporated. The remaining solid is dissolved in a mixture of MTBE/Meon, filtered through Hyflo and the filtrate is evaporated and get 19,28 g of the crude product, which was purified by chromatography on alumina (400 g, eluent: MTBE/Meon from 95:5 to 80:20) and get 10,96 g (91%) (4SR,5RS)-1-azabicyclo[3.3.1]nonan-4-ol.

To acetic anhydride (150 ml) under cooling portions add (4SR,5RS)-(1-azabicyclo[3.3.1]nonan-4-ol (21.34 g, 151 mmole). The reaction mixture is heated at 120°C for 2.5 h, evaporated and extracted with a mixture of THF/saturated solution of K2CO3. The aqueous layer was re-extracted with THF. The combined organic layers washed with brine, dried over Na2SO4, filtered and evaporated. The crude product is purified by distillation from a flask into the flask (BB, 90°C) and receive 24,07 g (87%) of 1-azabicyclo[3.3.1]non-4-silt ether (4SR,5RS)-acetic acid.

1-Azabicyclo[3.3.1]non-4-silt ether acetic acid (120,0 g, 655 mmole) is dissolved in 200 ml of absolute EtOH and 50 ml of water. Add the L(+)-tartaric acid (98.3 g, 655 mmole) and the mixture refluxed for 1 min. the Mixture is cooled to CT, then to 4°C. the Precipitate is filtered off, washed with EtOH and recrystallized three times from a mixture of EtOH/H2O 4:1 and get 41,16 g tartrate ([α]DKT=-14,72° (c=0,265, MeOH)), which after treatment with a saturated solution PA2CO3gives 22,6 g (123 mmole, 19%) 1-azabicyclo[3.3.1]non-4-silt ether (4S,5R)-acetic acid in the form of free base. Another 10.7 g (32.1 mmole, 5%) tartrate can be obtained from the mother solution by using another 3 recrystallization from a mixture of EtOH/H2O 4:1.

1-Azabicyclo[3.3.1]non-4-silt ester of acetic acid (of 5.45 g, and 29.7 mmole) dissolved in 10% aqueous NaOH solution and stirred for 1 h at 50°C. After cooling to CT the mixture is extracted with a mixture of THF/water. The organic layer is dried over Na2SO4, filtered and the filtrate is evaporated and get a 3.83 g (91%) of (4S,5R)-1-azabicyclo[3.3.1]nonan-4-ol, which is dissolved in 50 ml of THF and cooled to 0°C. are added dropwise NHMDS (35 ml of 1 M solution in THF), the reaction mixture was stirred at RT for 0.5 h and then added to pre-cooled (-15°C) solution of 5-bromo-2-chloropyrimidine (of 5.89 g, 30.5 mmole) in THF. The mixture is stirred for 15 h at RT, then diluted with THF and extracted with 1M aqueous NaOH solution and brine. Water layers twice re-extracted with the help of THF, the combined organic layers dried over Na2SO4, filtered and the filtrate is evaporated. The crude product (10,15 g) is recrystallized from a mixture of CH3CN/MeOH and get to 5.21 g (65%) of (4S,5R)-4-(5-bromopyrimidine-2-yloxy)-1-azabicyclo[3.3.1]nonane.

5,19 g a (17.4 mmole) of (4S,5R)-4-(5-Bromopyrimidine-2-yloxy)-1-azabicyclo[3.3.1]nonane dissolved in 200 ml of a mixture of toluene/tO 9:1. Add 5-indeliberately acid (3,47 g, 21.6 mmole), PD(h3)4(1.04 g, 0,873 mmole) and the solution PA2CO3(7,38 g, 69.6 mmole) in 35 ml of H2O. the Reaction mixture was stirred at 90°C for 15 hours After cooling to CT the mixture is filtered through Hyflo, the filtrate is extracted with water and brine. The aqueous layers are re-extracted with AcOEt and the combined organic layers dried over Na2SO4, filtered and the filtrate is evaporated. The crude product was then purified using PF (255 g of silica gel, eluent - AcOEt/MeOH/Et3N 70:27:3) and recrystallized from EtOH and get a 3.87 g (67%) of (4S,5R)-4-[5-(1H-indol-5-yl)-pyrimidine-2-yloxy]-1-azabicyclo[3.3.1]nonane. MS (ER+(electrospray ionization): m/e=335 (MN+), TPL 195-199°C.

Obtaining precursor, 1-azabicyclo[3.3.1]nonan-4-it is carried out in accordance with the publication .G.Kim et al., J. Med. Chem. (2003) 46, 2216.

Example 2 (Production of soft capsules)

5000 soft gelatin Capsules from each of them as the active ingredient contains 0.05 g of one of the compounds of formula (I), specified in the preceding examples, are prepared as follows:

250 g of Powdered active ingredient is suspended in 2 l of Lauroglykol® (propylene glycol laurate, Gattefosse S.A., Saint Priest, France) and ground in a wet milling to obtain a particle size of about 1 to 3 μm. Then use the machine for filling capsules servings mixture 0,419 g placed in capsules soft gelatin.

1. The compound in free base form or pharmaceutically acceptable salt of Association with an acid, and a specified compound selected from the group including:
(4S,5R)-4-[5-(1H-indol-5-yl)-pyrimidine-2-yloxy]-1-azabicyclo[3.3.1]nonan,
5-{2-[(4S,5R)-(1-azabicyclo[3.3.1]non-4-yl)oxy]-pyrimidine-5-yl}-1,3-dihydroindol-2-it,
(4S,5R)-4-[6-(1H-indol-5-yl)-pyridine-3-yloxy]-1-azabicyclo[3.3.1]nonan,
(4S,5R)-4-[5-(1H-indol-5-yl)-pyridine-2-yloxy]-1-azabicyclo[3.3.1]nonan,
(4S,5R)-4-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-1-azabicyclo[3.3.1]nonan and
5-{6-[(4S,5R)-(1-azabicyclo[3.3.1]non-4-yl)oxy]-pyridazin-3-yl}-1,3-dihydroindol-2-it.

2. The compound in free base form or pharmaceutically acceptable salt accession acid according to claim 1, which represents the (4S,5R)-4-[5-(1H-indol-5-yl)-pyrimidine-2-yloxy]-1-azabicyclo[3.3.1]nonan.

3. The compound in free base form or pharmaceutically acceptable salt accession acid according to claim 1, which represents 5-{2-[(4S,5R-(1-azabicyclo[3.3.1]non-4-yl)oxy]-pyrimidine-5-yl}-1,3-dihydroindol-2-it.

4. The compound in free base form or pharmaceutically acceptable salt accession acid according to claim 1, which represents the (4S,5R)-4-[6-(1H-indol-5-yl)-pyridine-3-yloxy]-1-azabicyclo[3.3.1]nonan.

5. The compound in free base form or pharmaceutically acceptable salt accession acid according to claim 1, which represents the (4S,5R)-4-[5-(1H-indol-5-yl)-pyridine-2-yloxy]-1-azabicyclo[3.3.1]nonan.

6. The compound in free base form or pharmaceutically acceptable salt accession acid according to claim 1, which represents the (4S,5R)-4-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-1-azabicyclo[3.3.1]nonan.

7. The compound in free base form or pharmaceutically acceptable salt accession acid according to claim 1, which represents 5-{6-[(4S,5R)-(1-azabicyclo[3.3.1]non-4-yl)oxy]-pyridazin-3-yl}-1,3-dihydroindol-2-it.

8. The connection according to one of claims 1 to 7 in free base form or pharmaceutically acceptable salt accession acid intended for use as pharmaceutical agents having agonistic activity against α7 nAChR.

9. Pharmaceutical composition having agonistic activity against α7 nAChR, including a connection according to one of claims 1 to 7 in free base form or pharmaceutically acceptable salt accession acid together with the pharmaceutical is a mini-carrier or diluent.

10. The use of compounds according to one of claims 1 to 7 in free base form or pharmaceutically acceptable salt accession acid as a pharmaceutical agent intended for the prevention and treatment of memory disorders.

11. The use of compounds according to one of claims 1 to 7 in free base form or pharmaceutically acceptable salt accession acid for preparing a medicinal product intended for the prevention, treatment or delay of progression of memory impairment.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), having antibacterial properties, a method for synthesis thereof, use thereof and a pharmaceutical composition based on said compounds. In general formula (I) R1 is a (CH2)n-NH2 or (CH2)n-NHR radical, where R is (C1-C6)alkyl and n equals 1 or 2; R2 is a hydrogen atom; R3 and R4 together form a nitrogen-containing aromatic 5-member heterocycle with 1, 2 or 3 nitrogen atoms, possibly substituted with one or more R' groups, where R' is selected from a group consisting of a hydrogen atom and alkyl radicals with 1-6 carbon atoms.

EFFECT: improved method.

13 cl, 4 ex

Liquid hardening // 2447114

FIELD: chemistry.

SUBSTANCE: invention relates to curing agents for air-drying alkyd-based resins, coating compositions, such as paint, varnish, wood stain, inks and linoleum floor coverings. Described is a curable liquid medium containing a) from 1 to 90 wt % of an alkyd-based resin and b) from 0.0001 to 0.1 wt % of a siccative in form of an iron or manganese complex with a tetradentate, pentadentate or hexadentate nitrogen donor ligand.

EFFECT: said siccative has high activity and enables hardening of compositions at relatively low concentration in a curable liquid medium.

19 cl, 8 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present application describes substituted bicyclic beta-lactams of formula I: which are class A and class C β-lactamase inhibitors wherein X, R1 and R2 are specified in the application, as well as a method for producing them. The compounds of formula I and their pharmaceutically acceptable salts are applicable for preparing a pharmaceutical composition and for producing a drug. The declared compounds are applicable for treating bacterial infections, optionally in a combination with a β-lactam antibiotic. Particularly, the compounds may be used with such β-lactam antibiotics, as e.g. imipenem, piperacillin or ceftazidime to control microorganisms resistant to β -lactam antibiotics due to the presence of β-lactamases.

EFFECT: preparing the composition for treating bacterial infections.

28 cl, 117 ex, 3 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (III) in form of a free base or an acid addition salt, use thereof as a pharmaceutical agent for preventing, treating and/or inhibiting progression of psychotic and neurodegenerative disorders, as well as pharmaceutical compositions based on said compound.

EFFECT: novel compound which can be used to prevent, treat or inhibit progression of diseases or a pathologic condition in which nAChR α7 activation participates or plays a role.

8 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to new 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazolyl derivatives of formula I or to their pharmaceutically acceptable salts; where Ar represents a phenyl group substituted by methylene dioxy or ethylene dioxy. Also, the invention refers to a pharmaceutical composition exhibiting cholinergic receptor activity on the basis of said compounds.

EFFECT: what is produced are new compounds and based pharmaceutical composition which can be effective for treating various diseases or disorders, such as those associated with the cholinergic system of the central nervous system, peripheral nervous system, diseases or disorders associated with smooth muscle contracture, endocrine diseases or disorders, neurodegenerative diseases or disorders, inflammatory diseases or disorders, pain and withdrawal syndromes caused by addictive chemical withdrawal.

10 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where the dotted line in the 6-member nitrogen-containing ring Z of formula (I) (said ring Z consists of ring atoms numbered 1 to 6) indicates that a double bond is either present in the 3,4-position of the ring Z of formula (I), or a double bond is absent in ring Z of formula (I); and where the double bond may be present in the 3,4-position of the ring Z of formula (I); or: the double may be absent in ring Z of formula (I) if: i) X denotes N or N+-O-, or ii) V denotes -O-CH2-Q-, or iii) W denotes para-substituted phenyl or para-substituted pyridinyl, and V denotes pyrrolidinyl of formula:

X denotes CH, N, or N+-O-; W denotes para-substituted phenyl or para-substituted pyridinyl; V denotes -O-CH2-Q-, where Q is bonded with a group U of formula (I), or V denotes pyrrolidinyl of formula:

U denotes mono-, di-, tri- or tetra-substituted aryl, where the substitutes are independently selected from C1-7-alkyl and halogen; Q denotes a five-member heteroaryl with two or three heteroatoms independently selected from O and N; R1 denotes C1-7-alkyl or cycloalky; R2 denotes halogen or C1-7-alkyl; R3 denotes halogen or hydrogen; R4 denotes C1-7-alkyl-O-(CH2)0-4-CH2-; R'R"N-(CH2)0-4-CH2-, where R' and R" are independently selected from a group consisting of hydrogen, C1-7-alkyl (optionally substituted with one-three fluorine atoms), cyclopropyl (optionally substituted with one-three fluorine atoms), cyclopropyl- C1-7-alkyl (optionally substituted with one-three fluorine atoms) and -C(=O)-R"', where R'" denotes C1-4-alkyl, C1-4-alkoxy, -CH2-CF3, or cyclopropyl; or R12NH-C(=O)·(O)0-1-(CH2)0-4-, where R12 denotes C1-4-alkyl or cyclopropyl; and n equals 0; and salts thereof. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having inhibiting effect on renin.

21 cl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds selected from a group comprising amides of peridine carboxylic acid of formula (I) , in which W denotes a phenyl ring or a six-member, non-benzocondensed aromatic ring, having one nitrogen atom, where said rings are substituted in the para-position through V; V denotes a bond; -A-(CH2)S- or -A-(CH2)v-B-; A and B independently denote -O-; U denotes mono-, di-, tri- or tetra-substituted aryl, in which substitutes are independently selected from a group consisting of halogen, alkyl and -CF3; Q denotes methylene; M denotes an aryl group, where the said group can be optionally mono- or di-substituted with substitutes independently selected from a group comprising alkyl; alkoxy; -CF3; halogen; alkyl-O-(CH2)0-4-CH2- and R'2N-(CH2)0-4-CH2-, where R' is independently selected from a group comprising hydrogen, alkyl (optionally substituted with one, two or three fluorine atoms), cyclopropyl, cyclopropylmethyl, -C(=O)-R", where R" denotes C1-C4-alkyl or -CH2-CF3; R1 denotes cycloalkyl; n equals 0 or 1; s equals 3; v equals 2; and substitutes in the ring, -CON(R1)-Q-M and -W-V-U, are in trans-position relative each other if n equals 1, and where configurations in positions 3 and 4 of the piperidine ring of formula (I) are 3R and 4R, respectively, if n equals 0; and optically pure enantiomers, mixture of enantiomers, such as racemates, diastereomers, mixture of diastereomers, diastereomer racemates, mixture of diastereomer racemates, and mesoforms, as well as to salts of such compounds. Invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having non-peptide rennin inhibiting activity.

12 cl, 27 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: described is a compound selected from formulae , , , , and , where X1 denotes CH; X2-X5 each independently denotes CH or C-, where -C represents the point where group B is bonded and where one of X2-X5 denotes -C; X7-X10 each independently denotes CH or CR2; X18-X21 each independently denotes CH or CR5; X22 and X23 each independently denotes CH or CR12, where at least one of X22 and X23 denotes CR12; X24 denotes CH; B denotes CH2 or C=O; B1 denotes CH; Y denotes oxygen or sulphur; Z denotes O; m equals 2; R denotes hydrogen or R denotes each indendently (C1-C6)alkyl, (C3-C8)cycloalkyl, halogen, imidazolyl substituted with (C1-C6)alkyl and/or an oxo group or OR9; R9 denotes hydrogen, (C1-C6)alkyl which is unsubstituted or substituted with once or several times with fluorine, or (C4-C8)cycloalkylalkyl; R12 denotes a (C1-C6)alkoxy group which is substituted once or several times with fluorine, unsubstituted thiazolyl, thiazolyl which is substituted with (C1-C6)alkyl, unsubstituted oxazolyl, dihydropyranyl, tetrahydropyranyl or tetrahydropyranyloxy, and pharmaceutically acceptable salts of the said compounds. Described also are pharmaceutical compositions containing the said compounds.

EFFECT: invention relates to ligands of nicotinic acetylcholine receptors (nAChR), activation of nAChRs and treatment of diseases associated with defective or with functional disorders of nicotinic acetylcholine receptors, especially in the brain.

69 cl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound or its salt of formula 1: , where A, E, D, R0, R1-R4 and a assume values given in the formula of invention. The invention also relates to an antioxidant medicinal agent.

EFFECT: effectiveness during treatment of ischemic diseases of organs, during treatment of diseases caused by oxidation cell disorders and when inhibiting disorders of the retina.

4 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-aza-bicyclo[3.3.0]octane derivatives of formula , where R1 and R2 are hydrogen, C1-4alkyl or fluorine; R3 is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl, trifluoromethoxy group and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxynyl; or isoxazolyl, pyridyl, indazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, pyrrolo[2,1b]thiazolyl, imidazo[ 1,2-a]pyridinyl or imidazo[2,1-b]thiazolyl, where said groups are unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, halogen and trifluoromethyl; A is or ; R4 is C1-4alkyl or -NR6R7; R6 is hydrogen or C1-4alkyl; R7 is hydrogen or C1-4alkyl; and D is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl and halogen; or a pharmaceutically acceptable salt of such a compound. 3-aza-bicyclo[3.3.0]octane derivatives or a pharmaceutically acceptable salt thereof are used as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: novel 3-aza-bicyclo[3,3,0]octane derivatives as nonpeptide antagonists of human orexin receptors.

9 cl, 1 tbl, 85 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel disubstituted phenylpyrrolidines of formula , any stereoisomers thereof or any mixtures of stereoisomers thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, where Ar denotes phenyl; R1 denotes F, Cl; R2 denotes F and Cl; R3 denotes H, Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec-Bu, tert-Bu, cyclopropylmethyl, CFH2CH2CH2-, CF2HCH2CH2-, CF3CH2CH2-, allyl and CH3OCH2CH2-; X denotes F, OH; under the condition that X denotes OH, R3 does not denote H.

EFFECT: compounds are capable of increasing levels of dopamine, norepinephrine and serotonin, which enables their use in treating central nervous system disorders.

16 cl, 21 dwg, 69 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. The method involves the administration of the preparation Venorm 1 teaspoon dissolved in warm water 100 ml 3 times a day 20 minutes before meals for 4 weeks.

EFFECT: method provides improving the functional state of the vegetative nervous system, ensuring higher body adaptation abilities and clinical effectiveness of the given pathology with the complete absence of side action.

6 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents a pharmaceutical composition for multiple sclerosis containing Teriflunomide as an agent and excipients in the following proportions, wt %: Teriflunomide - 3.0-13.5; Lactose and/or Ludipress LCE - 48.5-65.0; Starch - 7.0-16.0; Microcrystalline cellulose and/or Hypromeloza - 20.0-30.0; Collidone VA-64 - 3.5-4.5; Magnesium stearate - 0.8-1.2; Aerosil - 0.8-1.2; Benecel MP-824 - 13.5-15.5.

EFFECT: invention provides the extended range of effective drugs for multiple sclerosis.

7 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents a pharmaceutical composition for multiple sclerosis containing Teriflunomide as an agent and excipients in the following proportions, wt %: Teriflunomide - 3.0-13.5; Lactose and/or Ludipress LCE - 48.5-65.0; Starch - 7.0-16.0; Microcrystalline cellulose and/or Hypromeloza - 20.0-30.0; Collidone VA-64 - 3.5-4.5; Magnesium stearate - 0.8-1.2; Aerosil - 0.8-1.2; Benecel MP-824 - 13.5-15.5.

EFFECT: invention provides the extended range of effective drugs for multiple sclerosis.

7 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmacy, namely addictology and may be used for treating human addiction to alcohol, drugs and toxic substances. An intramuscularly injected prolonged-release pharmaceutical composition contains naltrexone as an active substance. Additionally, the composition contains a pharmaceutically acceptable solvent and excipients differing by the fact that the active substance is included in first and second microsphere fractions of polylactide coglycolide. The first microsphere fraction is characterized by the relation of lactide and glycolide monomer links 50 mole %:50 mole % and microsphere size 0.4 to 7 mcm. The second microsphere fraction is characterized by the relation of lactide and glycolide monomer links 75 mole %:25 mole % and microsphere size 20 to 90 mcm. A weight ratio of the first fraction of 0.01 to 0.15, while a weight ratio of the second fraction is 0.99 to 0.85.

EFFECT: preparing the composition for treating human addition to alcohol, drugs and toxic substances.

3 cl, 1 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, namely to orthopedics and neurosurgery. Electromyographic examination with making functional tests, assessing active amplitude of movements in joints, degree of arbitrary control of extremity, biomanual skills, is carried out. Data of examination are obtained before and after diagnostic blockage of median nerve with anesthetic. If amplitude of movements in joints increases, functional possibilities of extremity improve, and electrogenesis of forearm muscles reduces by more than 100 mcV, first neurosurgical treatment is performed with carrying out selective neurotomy of motor branches of median nerve. In case of insignificant impact of diagnostic blockage on examination results, first orthopedic treatment is performed.

EFFECT: method extends arsenal of means for determining type of surgical treatment of upper extremity in children with infantile cerebral paralysis.

2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel 2-substituted-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-ones and 2-substituted-2,3,5,6-tetrahydrooxazolo[3,2-a]pyrimidin-7-ones of formula (I): where p, n, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are described in the description. These compounds are modulators of metabotropic glutamate receptors (mGluR), particularly the mGluR2 receptor. Compounds in the present invention are therefore suitable for use as pharmaceutical agents, especially in treating and(or) preventing various disorders of the central nervous system (CNS), including, among others, acute and chronic neurodegenerative disorders, psychosis, convulsions, anxiety, depression, migraine, pain, sleep disorder and emesis.

EFFECT: improved method.

14 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 2-substituted-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-ones and 2-substituted-2,3,5,6-tetrahydrooxazolo[3,2-a]pyrimidin-7-ones of formula (I): where p, n, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are described in the description. These compounds are modulators of metabotropic glutamate receptors (mGluR), particularly the mGluR2 receptor. Compounds in the present invention are therefore suitable for use as pharmaceutical agents, especially in treating and(or) preventing various disorders of the central nervous system (CNS), including, among others, acute and chronic neurodegenerative disorders, psychosis, convulsions, anxiety, depression, migraine, pain, sleep disorder and emesis.

EFFECT: improved method.

14 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 2-substituted-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-ones and 2-substituted-2,3,5,6-tetrahydrooxazolo[3,2-a]pyrimidin-7-ones of formula (I): where p, n, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are described in the description. These compounds are modulators of metabotropic glutamate receptors (mGluR), particularly the mGluR2 receptor. Compounds in the present invention are therefore suitable for use as pharmaceutical agents, especially in treating and(or) preventing various disorders of the central nervous system (CNS), including, among others, acute and chronic neurodegenerative disorders, psychosis, convulsions, anxiety, depression, migraine, pain, sleep disorder and emesis.

EFFECT: improved method.

14 cl, 148 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are: composition, which contains β2-agonist, except formoterol and salmoterol, and antagonist of muscarinic receptors M3, which represents 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxy-propyl)-1-azoniumbicyclo[2.2.2]octane in form of salt with anion X, which represents pharmaceutically acceptable anion of mono- or polyvalent acid (aclinidium) and its application for obtaining medication for simultaneous, joined, separate or successive introduction for treatment of respiratory disease, reacting to M3 antagonism (versions), product, set, package, including said combination and respective treatment method.

EFFECT: claimed composition does not give traditional for combination of β2-agonist and antagonist of muscarinic receptors M3 side effects (tachycardia, palpitation, complaints of pains in angina pectoris, arrhythmias) and can be used for treating patient with earlier acquired heart disease or state, which can be aggravated by tachycardia).

19 cl, 4 dwg, 1 tbl

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