(1-azabicyclo[3,3,1]non-4-yl)-[5-(1h-indol-5-yl)-heteroaryl]-amines as cholinergic ligands nchar for treating psychotic and neurodegenerative disorders

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

 

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

n is 0, 1, 2, 3, 4 or 5,

R independently of one another denote a hydroxy-group, a cyano, a nitro-group, halogen, alkyl, alkoxygroup, alkylsulphonyl, alkoxycarbonyl, alkylamino, dialkylamino, alkylcarboxylic, allylcarbamate

Y denotes one of the following groups:

in free base form or salt accession acid.

Unless specified otherwise, the General terms used above and below in the present invention, in the context of the present description preferably have the following values:

The term "unsubstituted or substituted" when used in the present invention means that the radical contains one or more substituents, preferably up to 3, more preferably 1 or 2 substituent. The substituents are preferably selected from the group which Lucaya the amino group, With1-C4alkylamino, di(C1-C4alkyl)-amino group, With3-C5cycloalkylation, di(C3-C5)cycloalkylation, N-C1-C4alkyl-N-C3-C5cycloalkylation, halogen, C1-C4alkyl, C4-C6cycloalkyl, the hydroxy-group, With1-C4alkoxygroup,3-C5cycloalkylation,1-C4alkoxy-C1-C4alkoxygroup, di-(C1-C4alkyl)-amino-C1-C4alkoxygroup, carbarnoyl, N-C1-C4allylcarbamate, N,N-di(C1-C4alkyl)-carbarnoyl, a nitrogroup, cyano, carboxypropyl,1-C4alkoxycarbonyl,1-C4alkanoyl,1-C4alkanoyloxy, benzoyl, amedieval group, guanidine group, ureido group, mercaptopropyl,1-C4allylthiourea, pyridyl, phenyl, fenoxaprop,1-C4alkoxyphenyl, phenylthiourea, phenyl-C1-C4allylthiourea,1-C4alkylsulfonyl, phenylsulfonyl,1-C4alkylphenolates,1-C4alkenyl,1-C4alkanoyl,1-C4alkylenedioxy associated with the neighboring atoms of the ring, and With1-C4alkyl, which is substituted with halogen, hydroxy-group, With1-C4alkoxygroup, what Etnography, by cyano, carboxypropyl,1-C4alkoxycarbonyl, C1-C4alkanoyl or1-C4alkanoyloxy.

The terms "C5-C10aryl", "C5-C10heteroaryl" should be understood as aromatic residues, which in each case are unsubstituted or substituted by the above substituents, preferably in each case are unsubstituted or contain one or more substituents selected from the group including halogen, CN and alkyl which may be unsubstituted or substituted with halogen, such as trifluoromethyl; or (C1-C4alkoxygroup or condensed, for example, benzo[1,3]dioxole or 2,3-dihydrobenzo[1,4]dioxin and/or to another heterocyclic ring. With5-C10Heteroaryl means an aromatic heterocyclic system in which one or more carbon atoms are replaced by heteroatoms. Preferred are 5-9-membered ring system containing 1, 2 or 3 heteroatoms. Examples5-C10aryl and C5-C10heteroaryl residues above include phenyl, naphthyl, isobenzofuranyl, thienyl, indolyl.

The term "alkyl" means having a linear or branched chain alkyl group, preferably means having a linear or rasvet the feudal chain With 1-C7alkyl, particularly preferably means having a linear or branched chain With1-C4alkyl; for example, methyl, ethyl, n - or isopropyl, n-, ISO-, sec - or tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, and particular preference is given to the stands, ethyl, n-propylene and isopropyl.

Each alkyl fragment "alkoxygroup", "alkoxyalkyl", "alkoxycarbonyl", "alkoxycarbonyl" and "halogenoalkane" has the same values that are specified in the above definition of "alkyl". Alkoxygroup preferably represents C1-C4alkoxygroup, more preferably methoxy, ethoxy - or n-propoxylate.

"Heteroatoms" are the atoms which are not carbon and hydrogen, preferably nitrogen (N), oxygen (O) or sulfur (S).

"Halogen" means fluorine, chlorine, bromine or iodine, preferably denotes fluorine, chlorine or bromine and particularly preferably means chlorine.

Due to the presence of asymmetric atom (atoms) of carbon in the compounds of formula (I) and their salts of the compounds can exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures. All optical isomers and their mixtures, including racemic mixtures, form part of this invention.

Connect the Oia 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 connections, 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 pharmaceutical preparations) 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.

Due to the high affinity of the new compounds in free base form with compounds in the form of their salts, including salts, which can be used as intermediates, for example, in the purification and identification of novel compounds, any reference to the compounds in free base form, above and below in this image the shadow, it should be understood, as referring also to the corresponding salts, if they are appropriate or acceptable.

If for compounds, salts, etc. used the plural, it means also a single compound, salt, etc.

Preferred substituents, preferred ranges of numeric values and preferred ranges of the radicals contained in the formula (I)and the corresponding intermediate compounds defined below. These substituents, preferred ranges of numeric values, and the preferred ranges are preferred independently, collectively or in any combination or subcombination:

Preferably, if n is 0 or 1.

Particularly preferably, if n is 0.

R preferably denotes a hydroxy-group, With1-C4alkyl, C1-C4alkylcarboxylic.

The preferred connection is proposed in the present invention, is (4SR,5RS)-(1-azabicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)-pyridine-2-yl]-amine, having the formula given below.

Another preferred compound proposed in the present invention, is (4SR,5RS)-(1-azabicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)-pyrimidine-2-yl]-amine, having the formula given below.

Other before occhialini connection proposed in this invention is (4SR,5RS)-(1-azabicyclo[3.3.1]non-4-yl)-[6-(1H-indol-5-yl)-pyridin-3-yl]-amine, having the formula given below.

Another preferred compound proposed in the present invention, is (4SR,5RS)-(1-azabicyclo[3.3.1]non-4-yl)-[5-(1H-indol-4-yl)-pyridine-2-yl]-amine, having the formula given below.

Another preferred compound proposed in the present invention, is (4SR,5RS)-(1-azabicyclo[3.3.1] non-4-yl)-[5-(1H-indol-4-yl)-pyrimidine-2-yl]-amine, having the formula given below.

Another preferred compound proposed in the present invention, is (4SR,5RS)-(1-azabicyclo[3.3.1]non-4-yl)-[6-(1H-indol-5-yl)-pyridazin-3-yl]-amine, having the formula given below.

Another preferred compound proposed in the present invention, is (4SR,5RS)-(1-azabicyclo[3.3.1]non-4-yl)-[5-(1H-indol-6-yl)-pyridine-2-yl]-amine, having the formula given below.

Another preferred compound proposed in the present invention, is (4SR,5RS)-(1-azabicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)-pyridin-3-yl]-amine, having the formula given below.

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 (VIII)

in which R stands for

Y denotes one of the following fragments

and Z denotes useplease group, such as CL, Br, I or tosylate, with the compound of formula (IX)

,

in which X denotes indaily fragment is substituted with Rn(for example, 5-indolyl, 4-indolyl, 5-1,3-dihydroindol-2-IMT), and R denotes H or C1-C4alkyl or the two groups RO together with the boron atom to which they are attached, form a heterocyclic ring;

ii) extract thus obtained compounds of formula (I) in free base form or salt accession acid;

iii) optional separation of stereoisomers by known methods, for example using chiral HPLC (high performance liquid chromatography).

The second method involves the following stages

i) reaction of compounds of formula (X)

with the compound of the formula (XI)

in to the ora R and n are as such as defined for (I), and

ii) extract thus obtained compounds of formula (I) in free base form or salt accession acid;

iii) optional separation of stereoisomers by known methods, for example, chiral HPLC.

The original substances are known or can be obtained by known methods.

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, and the fact that they are not contained in the final products. The expert knows or can easily determine which protective groups are suitable for reactions specified what's 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 Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in "Methods der organischen Chemie" (Methods of organic chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Acids, Peptide, Proteine" (Amino acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel, 1982, and in Jochen Lehmann, "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 diastereoisomer using fractional crystallization, chromatography, distribution between solvents and using similar methodologies. This separation can be performed for the source connection is on or for the 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 triamide 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 is usually carried out in a suitable diluent in the presence of auxiliary substances for the reaction and the reaction mixture is typically stirred at an elevated temperature in the course is e few 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, pheochromocytoma, 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, intended 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, p is permitted to register radioactive radiation.

In particular, the agents proposed in the present invention are agonists of nicotinic actylcholine of the 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 neo is needed 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 of 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 oral is doing. 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 compounds of formula I or a free base of the compounds of formula I, in the range from 0.1 to 1%, for example 0.5%. Using a suitable buffer additive, the 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 scientific research is.

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 busparTMor busparTM. 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 prozacTM. 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 paxilTM. It is possible to obtain and enter, for example, as described in US 3912743. Sertraline can be entered, nab is emer, in the form in which it is commercially available, for example, under the trade name zoloftTM. 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 antelepsinTM. Diazepam can be entered, for example, in the form in which it is commercially available, for example, under the trade name diazepam desinitTM. 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 AU623144. 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 Eesa on sale, for example, under the trade name tegretol™ or tegretol™. 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 is. It can be obtained for example as described in US 3539573. Risperidone can be entered, 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 the different models, both in vitro and in vivo.

In the case of the combination pharmaceutical compositions 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 preparations for combiner the tub therapy for enteral or parenteral administration are, for example, drugs 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 (s) introduction component combin, the tion (b) (for 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 I 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 the formula I 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 the formula I 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 I 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 I and/or its pharmaceutically acceptable salt.

(4) the Use of the compounds of formula I 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 I 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 I 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
MeonMeon
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 resonance)).

(4SR,5RS)-1-azabicyclo[3..1]non-4-ylamine receive in accordance with the publication of Frank D. King et al., J. Med. Chem. (1993) 36, 683.

Example 1 (4SR,5RS)-(1-azabicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)-pyridine-2-yl]-amine

The mixture 2,59 g (10.9 mmole) of 2,5-dibromopyridine, of 1.57 g (to 16.4 mmole) of tert-butoxide sodium, 0.20 g Pd2(dba)3and 0.38 g xantphos [9,9-dimethyl-4,6-bis-(diphenylphosphino)-xanthene] dissolved in 40 ml of dry toluene and treated with a solution of 1.53 g (10.9 mmole) (rat)-1-azabicyclo[3.3.1]non-4-ylamine in 10 ml of toluene. After heating at 95°C for 60 min, the reaction mixture was poured on ice and diluted with AcOEt. The aqueous phase is extracted with AcOEt and the combined organic phases are washed with water and brine, dried over powdered PA2CO3and evaporated. The residue is purified by medium pressure chromatography on silica gel using a mixture of AcOEt/MeOH/NEts 50:45:5 and receive 2,09 g (4SR,5RS)-(1-azabicyclo[3.3.1]non-4-yl)-(5-bromopyridin-2-yl)-amine as a beige powder. MS (mass spectrometry) (ER+(electrospray ionization): m/e=296/298 (MN+).

In the vessel for a microwave reactor containing the rod for mixing, placed 148 mg (0.5 mmole) (4SR,5RS)-(1-azabicyclo[3.3.1]non-4-yl)-(5-bromopyridin-2-yl)-amine, 98 mg (0,61 mmole) indole-5-Bronevoy acid and 29.7 mg of tetrakis(triphenylphosphine)palladium, close and after pumping purge with argon. After addition of 9 ml of toluene, 1 ml of EtOH and 1 ml of 2 M solution of PA2CO3Mas at 120°C for 45 min irradiated in a microwave reactor (Initiator Exp, Biotage). The reaction mixture was filtered through Hyflo and diluted with AcOEt. The aqueous phase is extracted with AcOEt, the combined organic phases are washed with water and brine, dried over Na2SO4and evaporated. The residue is purified by medium pressure chromatography on silica gel using a mixture of AcOEt/MeOH/NEt350:45:5 and receive a foamed substance, which after trituration with pentane gives 73 mg (4SR,5RS)-(1-azabicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)-pyridine-2-yl]-amine as a beige powder. MS (ER+): m/e=333 (MN+).

Preparative separation of enantiomers:

Column: Chiralpak AD 20 μm; 5×(75×21,2 mm)

Eluent: n-hexane: l3: Meon 50:25:25+0.1% diethylamine

Flow rate: 40 ml/min

Detector: UV at 254 nm

Peak 1: 9-13 min; peak 2: 17-30 minutes

Analysis:

Column: Chiralpak AD 10 μm; a 4.6×250 mm

Eluent: n-hexane: l3: Meon 50:25:25+0.1% diethylamine

Flow rate: 1.5 ml/min

Detector: UV at 254 nm

Peak 1: 6,65 min=(4R,5S)-(1-azabicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)-pyridine-2-yl]-amine; peak 2: 19,12 minutes=(4S,5R)-(1-azabicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)-pyridine-2-yl]-amine

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 mentioned in the preceding examples, are prepared as follows clicks the zoom:

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 of formula (I)

in free base form or salt accession acid.

2. The compound according to claim 1 in free base form or pharmaceutically acceptable salt accession acid intended for use as pharmaceutical agents having agonistic activity against α7-nAChR.

3. The compound according to claim 1 in free base form or pharmaceutically acceptable salt accession acid intended for use for the prevention, treatment or delay of progression of psychotic or neurodegenerative disorders.

4. Pharmaceutical composition having agonistic activity against α7-nAChR, including a connection according to claim 1 in free base form or pharmaceutically acceptable salt accession acid, together with a pharmaceutical carrier or diluent.

5. The use of compounds according to claim 1 in free base form or formats whitesky acceptable salt accession acid as pharmaceuticals, intended for prevention, treatment and/or delay of progression of psychotic or neurodegenerative disorders.

6. The use of compounds according to claim 1 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 psychotic or neurodegenerative disorders.

7. The compound according to claim 1 in free base form or pharmaceutically acceptable salt accession acid intended for use for the prevention, treatment and/or delay progression of the disease or pathological condition involving or plays the role of activation of the α7 nAChR.

8. The use of compounds according to claim 1 in free base form or pharmaceutically acceptable salt accession acid as a pharmaceutical agent intended for preventing, treating and/or delaying progression of the disease or pathological condition involving or plays the role of activation of the α7 nAChR.



 

Same patents:

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 a method for synthesis of 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3.2.1]octanes with general formula: The method involves reacting aliphatic aldehyde (acetic, propionic, butyric, valerianic, caproic) saturated with hydrogen sulphide with 1,2-diaminoethane in molar ratio diamine:aldehyde:hydrogen sulphide equal to 1:3:2, at 0°C for 3 hours. 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3.2.1]octanes can be used as selective sorbents and extraction agents of precious metals, as antibacterial, antiviral, fungicidal and acaricidal agents.

EFFECT: stereoselective synthesis of one conformationally pure 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3,2,1]octane isomer; the method is also distinguished by simplicity of carrying experiments and availability of initial reagents.

1 cl, 1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: there described are diazabicyclic aryl derivatives of general formula I , their enantiomers or any mixture of those enantiomers, or their pharmaceutically acceptable salts, where radical values A, L, B and n are given in the description, and pharmaceutical composition containing the above diazabicyclic aryl derivatives.

EFFECT: new compounds represent cholinergic ligands of nicotinic receptors of acetylcholine and modulators of receptors and carrying agents of monoamines, and can be used for treatment of diseases and illnesses related to cholinergic system of central nervous system and periphery nervous system, which are related to activity of muscles, endocrine diseases, inflammatory diseases, and neurodegenerative diseases.

12 cl, 2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: there are described new diazabicyclic aryl derivatives of general formula (I), where A', A", L and B, n possess the values as specified in the description which are cholinergic ligands to nicotinic acetylcholine receptors, as well as a based pharmaceutical composition. Owing to their pharmacological profile, the compound according to the invention, can be effective in treating such various diseases or disorders, as those associated with the cholinergic system of central nervous system (CNS), peripheral nervous system (PNS), as those associated with plain muscle contraction, endocrine diseases or disorders, neurodegenerative diseases or disorders, diseases or disorders involving inflammation, pain and abstinence symptoms caused by termination of abusing the chemical substances.

EFFECT: effective with regard to various diseases.

16 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a pharmaceutical composition having activity for stimulating formation of nerve tissue and (or) inhibiting neuron degeneration, containing a compound of formula , where each R1 is independently selected from a group consisting of H, F, CI, Br, R7 and -O-R7, where R7 denotes substituted alkyl containing 1-6 carbon atoms or an aralkyl or aryl group containing 6-14 carbon atoms; R2 is selected from O or S; R3 is selected from alkyl containing 1-6 carbon atoms or an ether containing 1-6 carbon atoms and R4 is selected from an aryl containing 6-14 carbon atoms, an aralkyl substituted with an aromatic group, substituted with a heteroatomatic group or substituted with a heteroaromatic-alkyl group, or R4 is selected from a substituted 3-quinolinylmethyl, 2-pyridyl, 2-pyridylmethyl, 2- or 4-pyrimidinyl, benzo[1,3]dioxol-5-yl or benzoxazolyl. The invention also relates to methods of stimulating formation of nerve tissue and/or inhibiting neuron degeneration, based on use of said compounds and specific compounds.

EFFECT: novel compositions and methods containing compounds which are useful for stimulating formation of nerve tissue.

23 cl, 5 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of compounds of formula I where R1 denotes a hydrogen atom, a tritium atom, hydroxy, lower alkyl, lower alkoxy, a halogen atom, nitro, aminor or lower alkyl substituted with a halogen atom; R2 denotes a hydrogen atom, hydroxy or lower alkyl; X denotes N and Y denotes CH or CH2 or CH-lower alkyl, or X denotes CH and Y denotes N; Q denotes CH2,O, NH, N-alkyl, N-SO2-alkyl or N-SO2-tolul-4-yl; W denotes CH2 or a bond; m and n are independently equal to 1, 2 or 3; when m equals 2 or 3, R2 can be identical or different, when n equals 2 or 3, R1 can be identical or different; each dotted line, independently from another dotted line, may or may not denote a bond; and their pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomeric forms of compounds of formula I in preparing medicines for treating bipolar disorder, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, eating disorders, diabetic complications, dyslipidaemia, energy assimilation and consumption disorders, temperature homeostasis disorders, sleep and circadian rhythm disorders. The invention also relates to use of a compound of formula IA, compound of formula I and medicine based on the compound of formula I.

EFFECT: obtaining novel 2-midazole derivatives having useful biological properties.

63 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel malonamide derivatives of formula and their pharmaceutically suitable acid addition salts, optically pure enantiomers, racemates or diastereomer mixtures, where A1 denotes -CHR- or -C(O)-; A2 denotes -C(O)-; and R2/R3 independently denote hydrogen, lower alkyl, halogen, hydroxy or lower alkoxy; or A2 denotes -O-C(O)-, and R2/R3 independently denote hydrogen or lower alkyl; R denotes hydrogen or lower alkyl substituted with a halogen; R1 denotes hydrogen, lower alkyl or -(CH2)n-aryl, optionally substituted with halogen; R4 denotes lower alkyl substituted with a halogen; n equals 0, 1 or 2. The invention also relates to a method of producing a compound of formula I, a medicinal agent based on the compound of formula I and use of the compound of formula I.

EFFECT: obtaining novel malonamide derivatives of formula I, having inhibiting action on γ-secretase and are useful in treating Alzheimer's disease.

13 cl, 72 ex

FIELD: medicine.

SUBSTANCE: invention relates to applications of compound 11-deoxyprostaglandin of general formula (IV) for obtaining composition for treatment of central nervous system disorder and for obtaining composition for protection of endothelial cells of brain vessels, to pharmaceutical composition based on said compounds, to method of treating central nervous system disorder, as well as to method of treating central nervous system disorder, as well as to compounds of general formula (IV) or their pharmaceutically acceptable salts, esters or amides, on condition that compound is not 11-desoexy-13,14-dihydro-15-keto-16,16-difluor- PGE1. , where L represnts hydroxy, lower alkanoyloxy or oxo; A represents -COOH or its pharmaceutically acceptable salt, ester or amide; B represents -CH2-CH2 or -CH=CH-; Z represents , or , where R4 and R5 represent hydrogen or hydroxy. R4 and R5 cannot represent hydroxy simultaneously; X1 and X2 represent similar or different halogen atoms; R1 represents saturated or unsaturated bivalent lower or middle aliphatic hydrocarbon; R2 represents single bond or lower alkylene and R3 represents linear lower alkyl.

EFFECT: increase of treatment efficiency.

14 cl, 7 ex, 6 tbl, 20 dwg

FIELD: medicine.

SUBSTANCE: invention relates to applications of compound 11-deoxyprostaglandin of general formula (IV) for obtaining composition for treatment of central nervous system disorder and for obtaining composition for protection of endothelial cells of brain vessels, to pharmaceutical composition based on said compounds, to method of treating central nervous system disorder, as well as to method of treating central nervous system disorder, as well as to compounds of general formula (IV) or their pharmaceutically acceptable salts, esters or amides, on condition that compound is not 11-desoexy-13,14-dihydro-15-keto-16,16-difluor- PGE1. , where L represnts hydroxy, lower alkanoyloxy or oxo; A represents -COOH or its pharmaceutically acceptable salt, ester or amide; B represents -CH2-CH2 or -CH=CH-; Z represents , or , where R4 and R5 represent hydrogen or hydroxy. R4 and R5 cannot represent hydroxy simultaneously; X1 and X2 represent similar or different halogen atoms; R1 represents saturated or unsaturated bivalent lower or middle aliphatic hydrocarbon; R2 represents single bond or lower alkylene and R3 represents linear lower alkyl.

EFFECT: increase of treatment efficiency.

14 cl, 7 ex, 6 tbl, 20 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine. A method involves application of IL-31 antagonist for IL-31 induced signal transduction inhibition in dorsal root ganglion cells. The IL-31 antagonist inhibits IL-31 polypeptide binding containing amino acid residues 27-164 SEQ ID NO:2 with its heterodimeric receptor containing IL-31RA and OSMR-beta. The antagonist represents a humanized monoclonal antibody or a chimeric antibody.

EFFECT: use of the method effectively relieves inflammation, pain and itching.

8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine, in particular to pharmacy. A composition for injections exhibiting tranquilising action contains the ingredients in the following proportions, wt %: crystalline β-modification of 7-brom-1,3-dihydro-5-(2-chlorphenyl)-2H-1,4-benzodiazepin-2-one - 0.05-0.15, polyvinylpyrrolidone - 0.50-1.20, "Tween-80" - 2.00-10.00, glycerine - 5.00-15.00, sodium pyrosulphite - 0.30-1.20, sodium hydrate solution - to pH 6.0-7.5, water - the rest. A method for preparing the composition consist in the fact that "Tween-80" and glycerine are mixed, heated to 70-90°C, and crystalline β-modification of 7-brom-1,3-dihydro-5-(2-chlorphenyl)-2H-1,4-benzodiazepin-2-one is dissolved. The prepared mixture is poured in the mixed aqueous solution of sodium pyrosulphite and polyvinylpyrrolidone heated to 40-90°C, cooled to room temperature, filtered, reduced to pH 6.0-7.5 with sodium hydrate solution, bottled and sterilised.

EFFECT: presented group of inventions provide a composition exhibiting improved anxiolytic action and decreased sedation in comparison with the composition based on pharmacopoeial phenazepam.

2 cl, 2 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is application of O-(3-piperidino-2-hydroxy-1-propyl)-nicotinamidoxime or its pharmaceutically acceptable salt for preparing a pharmaceutical composition applicable for preventing or reducing a side effect represented by overweight or obesity in treating by an antipsychotic drug, and the pharmaceutical composition possess said action and contains the antipsychotic agent which when taken causes overweight or obesity, and O-(3-piperidino-2-hydroxy-1-propyl)-nicotinamidoxime or its pharmaceutically acceptable salt mixed with more than one common carrier.

EFFECT: reducing the declared side effect ensured by olanzapine, clozapine and risperidon is shown with metformin and rosiglitazone failed to prevent olanzapine-induced weight gain.

8 cl, 3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical agents and concerns an delayed-release oral tablet containing: (a) 10-80 wt % 1-{[(α-isobutanoyloxyehtoxy)carbonyl]aminomethyl)-1-cyclohexane acetic acid, and (b) 1-30 wt % of a fatty compound, such as glycerine ester, lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol, cytostearyl alcohol, palmitoyl alcohol, ouricury wax, hydrated vegetable oil, candelilla wax, esparto wax, stearic acid, hard wax, beeswax, glyco wax, hydrated castor oil and carnauba wax or their combination, where the value wt % is calculated by total dry weight of the dosage form which when taken by a human patient on an empty stomach per 1-{[(α-isobutanoyloxyehtoxy)carbonyl]aminomethyl)-1-cyclohexane acetic acid 1100-1300 mg provides the plasma gabapentin concentration profile Cmax 3-6 mcg/ml at Tmax 4-7 hours and AUC 30-70 mcgh/ml; when taken by a human patient after meal per 1-{[(α-isobutanoyloxyehtoxy)carbonyl]aminomethyl)-1-cyclohexane acetic acid 1100-1300 mg provides the plasma gabapentin concentration profile Cmax 5-8 mcg/ml at Tmax 6-11 h and AUC 60-110 mcgh/ml. What is also offered is application of 1-{[(α-isobutanoyloxyehtoxy)carbonyl]aminomethyl)-1-cyclohexane acetic acid for preparing a delayed-release tablet for treating restless leg syndrome and postherpetic neuralgia.

EFFECT: tablets under the invention provide improved pharmacokinetic profile of gabapentin.

17 cl, 8 dwg, 2 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine and concerns methods of treating, relieving symptoms and prolonging a remission interval of autoimmune diseases of peripheral nervous system, particularly Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), neuropathy accompanying vasculitis. An effective amount of a sphingosine-1-phosphate receptor agonist, particularly FTY720, FTY720-P, AAL(R), AFD(R) or SEW2871 is introduced in a patient.

EFFECT: group of inventions provide extending the range of methods for treating autoimmune diseases of the peripheral nervous system.

20 cl, 10 dwg, 1 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: there are offered a pharmaceutical composition for treating a overactive bladder (OAB) containing a therapeutically effective amount of a first compound (being an antimuscarinic or anticholinergic agent) and a therapeutically active amount of a second compound (causes salivary gland stimulation), and (i) the first compound is oxybutynin or its acceptable salt, and the second compound is pilocarpin or its salt; or (ii) the first compound is tolterodine or its salt, and the second compound is pilocarpin or its salt, and a relevant method of treating a patient involving introduction of the pharmaceutical composition described above. It is shown that antimuscarinic activity of oxybutynin, responsible for its therapeutic effect on OAB, remains unchanged after introduction of the composition after its adverse side effect - dry mouth - completely neutrolised.

EFFECT: invention leads to more tolerable, effective and profitable treatment.

15 cl, 7 dwg, 3 tbl

Up!