New 1,4-diaza-bicyclo[3,2,2]nonyl-oxadiazolyl derivatives and their medical application

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

 

The present invention relates to new 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivatives and their use in the manufacture of pharmaceutical compositions. As found, the compounds according to the invention are cholinergic ligands of nicotinic acetylcholine receptors.

Due to their pharmacological profile the compounds according to the invention may be useful for treatment of various diseases or disorders such as those associated with the cholinergic system of the Central nervous system (CNS), peripheral nervous system (PNS)diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases or disorders associated with inflammation, pain, and withdrawal symptoms caused by termination of use of chemical substances that are addictive.

Prior art

Endogenous cholinergic neurotransmitter acetylcholine carries out its biological effects through two types of cholinergic receptors: muscarinic acetylcholine receptors (mAChR) and nicotinic acetylcholine receptors (nAChR).

As is well established that muscarinic acetylcholine receptors predominate in quantitative terms over nicot the new acetylcholine receptors in the brain, important for memory and cognitive abilities, a large number of studies aimed at the development of agents for the treatment of disorders associated with memory, focused on the synthesis of modulators of muscarinic acetylcholine receptors.

Recently, however, have any interest in the development of nAChR modulators. Some diseases associated with degeneration of the cholinergic system, namely, senile dementia type, vascular dementia and impaired cognitive ability due to organic brain damage, disease, directly related to alcoholism. Indeed, some Central nervous system disorders can be explained by cholinergic deficiency, dopaminergic deficiency, adrenergic failure or serotonergic failure.

In WO 2004/029053 described 1,4-diazabicyclo derivatives, useful as modulators of nicotinic receptors. However, 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivatives of the present invention have not been described.

Summary of the invention

The present invention relates to the offering of new modulators of nicotinic receptors, are useful for treating diseases or disorders associated with cholinergic receptors.

Blagodarya pharmacological profile of the compounds according to the invention may be useful for treatment of various diseases or disorders, such as those related to the cholinergic system of the Central nervous system (CNS), peripheral nervous system (PNS)diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases or disorders associated with inflammation, pain, and withdrawal symptoms caused by termination of use of chemical substances that are addictive.

Compounds of the present invention may also be useful as diagnostic tools or monitoring agents in various diagnostic methods, and in particular, to visualize receptors in vivo (neuroimaging), and they can be used in labeled or unlabeled form.

In the first aspect of the present invention proposed new 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivatives of the formula I

or their pharmaceutically acceptable salts, where

Ar represents a phenyl group, substituted methylenedioxy or Ethylenedioxy.

In the second aspect of the invention proposed pharmaceutical composition containing a therapeutically effective amount of 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivatives according to the invention, or their pharmaceutically acceptable salts are also the organisations, or their prodrugs, together with at least one pharmaceutically acceptable carrier or diluent.

In an additional aspect this invention relates to the use of 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivatives according to the invention or their pharmaceutically acceptable salts accession for the production of pharmaceutical compositions/medicines for treating, preventing or alleviating disease or disorder or a condition of a mammal, including man, which is sensitive to modulation of cholinergic receptors.

In the last aspect of this invention, methods of treatment, prevention or relief of diseases, disorders or conditions of the body of the living animal, including humans, which is sensitive to modulation of cholinergic receptors, including the stage of introduction into the body of the living animal, in need thereof, a therapeutically effective amount of 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivatives according to the invention.

Other objectives of the invention will be obvious to a person skilled in the art from the following detailed description and examples.

Detailed description of the invention

1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivatives

In the first aspect of the proposed new 1,4-dia is a-bicyclo[3.2.2]nonyl-oxadiazoline derivatives; 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivatives according to the invention can be represented by the General formula I

or its pharmaceutically acceptable salt; where Ar represents a phenyl group, substituted methylenedioxy or Ethylenedioxy.

In a more preferred embodiment the 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention is a compound of formula I or its pharmaceutically acceptable salt, where Ar represents a phenyl group, substituted methylenedioxy.

In another more preferred embodiment the 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention is a compound of formula I or its pharmaceutically acceptable salt, where AG represents a phenyl group, substituted Ethylenedioxy.

In an even more preferred embodiment the 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention is a

4-(5-benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonan; or

4-[5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonan;

or its pharmaceutically acceptable salt.

In the most preferred embodiment the 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention is a

salt of 4-(5-b is the site, located between[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane with fumaric acid;

or salt of 4-[5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane with fumaric acid.

Any combination of two or more than two of the embodiments described herein are included in the scope of the present invention.

Pharmaceutically acceptable salt

1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention can be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre - or proletarienne forms of the compounds of the present invention.

Examples of pharmaceutically acceptable salts of the merger include, without limitation, non-toxic salt accession inorganic or organic acids, such as hydrochloride, obtained from hydrochloric acid, the hydrobromide obtained from Hydrobromic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, formate derived from formic acid, acetate derived from acetic acid, aconet obtained from amanitowoc acid, the ascorbate derived from ascorbic acid, bansilalpet obtained from benzosulfimide acid, the benzoate derived from benzoic acid, cinnamic obtained is from cinnamic acid, the citrate derived from citric acid, embanet obtained from monowai acid, enanthate, derived from enanthic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, malonate derived from malonic acid, mandelate obtained from almond acid, methanesulfonate, obtained from methanesulfonic acid, naphthalene-2-sulfonate derived from naphthalene-2-sulfonic acid, the phthalate derived from phthalic acid, the salicylate derived from salicylic acid, sorbate derived from sorbic acid, stearate derived from stearic acid, succinate derived from succinic acid, tartrate derived from tartaric acid, toluene-para-sulfonate obtained from pair-toluensulfonate acid and the like. Such salts can be obtained by methods well known and described in the art.

Other acids, such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in obtaining salts which are useful as intermediates in obtaining 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention or its pharmaceutically acceptable salt Ave the connections acid.

Examples of pharmaceutically acceptable cationic salts of 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention include, without limitation, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysine, ammonium salt and the like, the compounds according to the invention containing an anionic group. Such cationic salts can be obtained by methods well known and described in the art.

Additional examples of pharmaceutically acceptable salts of the merger include, without limitation, non-toxic salt accession inorganic or organic acids, such as, for example, hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconet, ascorbate, bansilalpet, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-para-sulfonate and the like. Such salts can be obtained by methods well known and described in the art.

Metal salts of 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention include alkali metal salts, such as, for example, the sodium salt of the compounds according to the invention containing a carboxy group.

In Conte, the CTE of the present invention "onevia salt" N-containing compounds are also considered as pharmaceutically acceptable salts. Preferred "onevia salts include alkyl-onieva salt, cycloalkyl-onieva salt and cycloalkenyl-onieva salt.

Labeled compounds

Compounds according to the invention can be used in their labeled or unlabeled form. In the context of the present invention labeled compound has one or more than one atom is replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Tagging will facilitate quantification of the specified connection.

Labeled compounds according to the invention can be useful as diagnostic tools, radioactive isotopes or monitoring agents in various diagnostic methods, as well as for visualization of the receptor in vivo.

Labeled isomer according to the invention preferably contains at least one radionuclide as a label. Positron-emitting radionuclides are candidates for use. In the context of this invention, the radionuclide is preferably selected from the2H (deuterium),3H (tritium),13C,14C,13I125I123I and18F.

Physical detection of labeled isomer of the present invention may be selected from positron emission tomography (PET), single photon emission computed Tomo is raffia (SPECT), magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI) and computerized transaxial tomography (CAT), or combinations thereof.

Methods of obtaining 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivatives

1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention can be obtained by conventional methods of chemical synthesis, such as those described in the working examples. Starting materials for the methods described in this invention are known or can be easily obtained by conventional methods from commercially available chemicals.

In addition, one connection according to the invention can be converted into another compound of the invention using conventional methods.

The final products of the reactions described herein may be selected traditional methods, such as extraction, crystallization, distillation, chromatography and the like.

Biological activity

The present invention relates to the proposal of new ligands and modulators of nicotinic receptors, are useful for treating diseases or disorders associated with cholinergic receptors, and, in particular, nicotinic acetylcholine receptor (nAChR). Preferred compounds according to the invention show a pronounced izberatelno the ü to nicotinic acetylcholine receptor subtype A7.

Due to their pharmacological profile the compounds according to the invention may be useful for treatment of various diseases or disorders, such as diseases associated with Central nervous system disease associated with the PNS disease associated with smooth muscle contraction, endocrine disorders, diseases associated with neurodegeneration, diseases associated with inflammation, pain, and withdrawal symptoms caused by termination of use of chemical substances that are addictive.

In the preferred embodiment of the compounds of the present invention may be useful for treating, preventing or alleviating disorders of cognition, human learning disorders and memory dysfunction, down syndrome, Alzheimer's disease, attention deficit, attention deficit disorder with hyperactivity disorder (AHDH), Tourette's syndrome, psychosis, depression, bipolar disorder, mania, manic depression, schizophrenia, impairment of cognitive abilities or attention related to schizophrenia, obsessive-compulsive disorders (OCD), panic disorders, eating disorders such as anorexia nervosa, bulimia and obesity, narcolepsy, nociception complex, AIDS-dementia, senile dementia, autism, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, is ravage, anxiety disorders that are not associated with OCD, convulsive disorders, epilepsy, neurodegenerative disorders, transient hypoxia-induced neurodegeneration, neuropathy, diabetic neuropathy, peripheral dyslexia, tardive dyskinesia, hyperkinesia, mild pain, moderate or severe pain, pain of acute, chronic or recurrent character, pain caused by migraine, postoperative pain, phantom pain, inflammatory pain, neuropathic pain, chronic headache, Central pain, pain related to diabetic neuropathy, with posttherapeutic neuralgia or damage to a peripheral nerve injury, bulimia, post-traumatic syndrome, social phobia, disorder sleep, pseudodementia, syndrome Ganzera, premenstrual syndrome, syndrome, late luteal phase, fibromyalgia, chronic fatigue syndrome, mutism, trichotillomania, circadian rhythm disorders of the body, arrhythmias, contractions of the smooth muscles, angina pectoris, premature labour, diarrhoea, asthma, tardive dyskinesia, hyperkinesia, premature ejaculation, erection difficulties, hypertension, inflammatory disorders, inflammatory skin disorders, acne, rosacea, Crohn's disease, inflammatory bowel disease, ulcerative colitis, diarrhoea, or xing the Roma cancel, caused by termination of use of substances, addictive, including nikotinsoderzhaschie products such as tobacco, opioids such as heroin, cocaine and morphine, benzodiazepines and benzodiazepinones drugs, and alcohol.

In a more preferred embodiment of compounds according to the invention can be useful for the treatment, prevention or alleviation of pain, mild or moderate or severe pain, pain of acute, chronic or recurrent character, pain caused by migraine, postoperative pain, phantom pain, inflammatory pain, neuropathic pain, chronic headache, Central pain, pain related to diabetic neuropathy, with posttherapeutic neuralgia, or to peripheral nerve damage.

In a more preferred embodiment of compounds according to the invention can be useful for the treatment, prevention or relief of diseases, disorders or conditions associated with contractions of smooth muscles, convulsive disorders, angina pectoris, premature labour, convulsions, diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation or erection difficulties.

In an even more preferred embodiment of compounds according to the invention can be useful for the treatment, prevention or relief of neurodegenerative t the tion, transient hypoxia or induced neurodegeneration.

In an even more preferred embodiment of compounds according to the invention can be useful for the treatment, prevention or relief of inflammatory disorders, inflammatory skin disorders, acne, rosacea, Crohn's disease, inflammatory bowel disease, ulcerative colitis or diarrhea.

In an additional preferred embodiment of the compounds according to the invention can be useful for the treatment, prevention or relief of diabetic neuropathy, schizophrenia, impairment of cognitive abilities or attention associated with schizophrenia, or depression.

Finally, the compounds according to the invention can be useful for the treatment of withdrawal symptoms caused by termination of use of substances that are addictive. Such substances, addictive, include nikotinsoderzhaschie products such as tobacco, opioids such as heroin, cocaine and morphine, benzodiazepines and benzodiazepinones drugs, and alcohol. Cancel substances, addictive, and is, in General, traumatic experience, characterized by anxiety and frustration, anger, anxiety, difficulty concentrating, restlessness, reduced heart rate and increased appetite and weight gain.

In this context, a "cured the e" includes treatment, warning, prevention and alleviate the condition of the withdrawal symptoms and abstinence, and treatment, leading to a voluntary reduction of consumption of a substance that causes addiction.

In another aspect of the compounds according to the invention are used as diagnostic agents, i.e. for the identification and localization of nicotinic receptors in various tissues. In the present invention, it is assumed that a suitable dosage of the active farmacevticheskogo ingredient (API) is in the range from about 0.1 to about 1000 mg API per day, more preferably from about 10 to about 500 mg API per day, most preferably from about 30 to about 100 mg API per day, depending, however, on the particular method of administration, the form in which it is introduced, provided evidence of the subject and, in particular, the body weight of the subject involved in the treatment, and, in addition, preferences and experience of the attending physician or veterinarian.

Preferred compounds according to the invention show a biological activity in submicromolar and molar range, i.e. of from below 1 to about 100 microns.

The pharmaceutical composition

In another aspect of the invention proposed new pharmaceutical compositions containing a therapeutically effective amount of 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazolidine is derived according to the invention.

While the 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention for use in therapy can be introduced in the form of the raw chemical compound, it is preferable to include the active ingredient, possibly in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more than one adjuvant, excipient, carrier, buffer, diluent and/or other conventional pharmaceutically auxiliary substance.

In the preferred embodiment of the present invention proposed pharmaceutical compositions containing 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention or its pharmaceutically acceptable salt or a derivative thereof together with one or more pharmaceutically acceptable carrier for him and, perhaps, other therapeutic and/or prophylactic ingredients, known and used in the art. The carrier(s) must be "acceptable" in the sense that it must be compatible with other ingredients of the drug and harmless to the recipient host.

The pharmaceutical composition according to the invention can be entered in any convenient way, which is suitable for the desired therapy. Preferred routes of administration include oral administration, in particular in the tablet, the cap is ule, in tablets, powder or liquid form, and parenteral administration, in particular cutaneous, subcutaneous, intramuscular or intravenous injection. The pharmaceutical composition according to the invention can be prepared by any expert using standard methods and traditional techniques appropriate to the desired preparation. If desired, can be used in compositions made with the possibility of prolonged release of the active ingredient.

The pharmaceutical compositions according to the invention can provide a composition suitable for oral, rectal, bronchial, nasal, pulmonary, local (including transbukkalno and sublingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or compositions in a form suitable for administration by inhalation or insufflation, including powders and the introduction of liquid aerosols or with prolonged release. Suitable examples of sustained release include semi-permeable matrices of solid hydrophobic polymers containing a compound according to the invention, which can be represented in the form of products of a particular FD is we, for example, films, or microcapsules.

1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention together with a conventional adjuvant, carrier or diluent can be represented in the form of pharmaceutical compositions and standard dosage forms. Such forms include solid forms, in particular tablets, filled capsules, powders and granules, and liquid forms, in particular an aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with them, all for oral administration; suppositories for rectal administration and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and their standard dosage forms may include common ingredients in standard proportions, with an additional active compounds or principles, and such a standard dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended range of daily dosage, which should be used.

1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention can be introduced in a wide variety of oral and parenteral dosage forms. The specialist should be obvious that the following dosage forms may be included as an asset of the CSO component or connection according to the invention, or a pharmaceutically acceptable salt of the compounds according to the invention.

For the manufacture of pharmaceutical compositions based on 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid dosage forms include powders, tablets, coated tablets, capsules, pills, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, corrigentov, soljubilizatory, lubricants, suspendresume agents, binders, preservatives, loosening agents for tablets or encapsulating material.

In powders, the carrier is a finely ground solid material, which is mixed with finely ground active component.

In tablets, the active ingredient is mixed with carrier having the necessary binding capacity in suitable proportions and compacted in the shape desired size.

The powders and tablets preferably contain from five or ten to about seventy percent of the active compounds. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, sodium carboxymethyl uloza, low-melting wax, cocoa butter and the like. Assume that the term "drug" includes the preparation of the active compound with encapsulating material as a carrier, forming a capsule, where the active ingredient with the carriers, or without them, is surrounded by carrier, which thus is in Association with him. In this way enabled the wafer and pellet. Tablets, powders, capsules, pills, wafers and cakes can be used as solid forms suitable for oral administration.

For the manufacture of suppositories low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, is first melted and the active component is homogeneous dispersed therein, for example, by stirring. The molten homogeneous mixture is then poured into molds of suitable size, allow to cool and then harden.

Compositions suitable for vaginal administration, can be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient suitable carrier materials known to specialists in this field of technology.

Liquid preparations include solutions, suspensions and emulsions, such as solutions in water or in water with propylene glycol. For example, liquid preparations for parenteral administration can be prepared in the form of races the thieves in an aqueous solution of polyethylene glycol.

1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative of the present invention may, therefore, be made in the form of a preparation for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in a standard dosage form in ampoules, pre-filled syringes, infusion of small volumes or in mnogochasovykh containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous carriers can contain agents for drugs, such as suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic selection of sterile solid or by lyophilization from solution, for dilution with a suitable solvent, such as sterile pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, corrigentov, stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be prepared by dispersing finely ground active the th component in water with viscous substance, such as natural and synthetic resins, gums, methylcellulose, sodium carboxymethylcellulose or other well-known suspendresume agents.

Also included are solid dosage forms that are designed to turn immediately before use in liquid dosage forms for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredient such preparations may contain colouring agents, corrigentov, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizing agents and the like.

For local injection into the epidermis 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention may be presented as ointments, creams or lotions, or as a transdermal patch. Ointments and creams can be prepared, for example, aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions can be prepared in water or oil-based, and, as a rule, they must also contain one or more than one emulsifying, stabilizing, dispersing, suspendisse, thickening agent or dye.

Compositions suitable for topical introduction into the oral cavity include pellet containing active the agent in the flavor basis, usually sucrose and Arabian gum or tragakant; tablets containing the active ingredient in an inert basis such as gelatin and glycerin or sucrose and Arabian gum; and a liquid for rinsing the oral cavity containing the active ingredient in a suitable liquid carrier.

The solutions or suspensions are injected directly into the nasal cavity using standard means, for example, a dropper, pipette or spray. The compositions can be presented in a single dose or mnogochasovykh forms.

Introduction to the respiratory tract may also be achieved using an aerosol formulation in which the active ingredient is in a sealed package with a suitable propellant such as a chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Aerosol acceptable may also contain a surfactant such as lecithin. The dose can be controlled using a metering valve.

Alternatively, the active ingredients can be represented in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives, for example, hypromellose and polyvinylpyrrolidone (PVP). For convenience powder novtel the need to form a gel in the nasal cavity. The powder composition may be presented in the form of a standard dose of, for example, capsules or cartridges, for example, from gelatin or blister packs from which the powder can be entered using the inhaler.

In compositions intended for administration to the respiratory tract, including intranasal compositions, the connection should generally have a small particle size, for example of the order of 5 microns or less. Particles of this size can be obtained by methods known in the art, for example by micronization.

At desire it is possible to apply compositions made with the possibility of prolonged release of the active ingredient.

Pharmaceuticals presents preferably in a standard dosage forms. In such form the preparation is divided into single standard doses containing appropriate quantities of the active component. Form single standard doses can be a drug in the package containing discrete quantities of preparation, such as packaging of tablets, capsules, and powders in vials or ampoules. The standard dosage may be itself a capsule, a tablet, wafer or cake, or the appropriate number of any of them in the package.

Tablets or capsules for oral administration and liquids for nutrion the th injection and continuous infusion are preferred compositions.

Additional details concerning methods of manufacture and introduction can be found in the latest edition Remington''s Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

A therapeutically effective dose refers to that amount of active ingredient that relieves the symptoms or condition. Therapeutic efficacy and toxicity, such as ED50and LD50can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is a therapeutic index and can be expressed by the ratio LD50/ED50. The pharmaceutical composition exhibiting a higher therapeutic indices are preferred.

Enter the dose, of course, must be carefully regulated in accordance with age, weight and condition of the individual, which are treated, as well as by injection, dosage form and scheme of administration and the desired result, and the exact dosage should, of course, be determined by the treating physician.

The actual dosage depends on the nature and severity of the disease, which is treatable and is at the discretion of the attending physician, and it can be varied by titration of the dosage for private embodiments of the present invention to obtain the desired therape the political effect. However, it is presently envisaged that the pharmaceutical compositions containing from about 0.1 to about 500 mg of the active ingredient on the individual dose, preferably from about 1 to about 100 mg, most preferably from about 1 to about 10 mg, are suitable for therapeutic treatment. The active ingredient can be introduced in one or several doses per day. Satisfactory results can sometimes be obtained in such low dosages as 0.1 µg/kg intravenous (i.v.) and 1 mg/kg oral (r.o.). The upper limit of the range of dosages provided currently as of approximately 10 mg/kg i.v. and 100 mg/kg r.o. Preferred ranges are from about 0.1 μg/kg to about 10 mg/kg/day i.v. and from about 1 μg/kg to about 100 mg/kg/day r.o.

The methods of treatment

1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivatives of the present invention are valuable nicotinic modulators, and therefore useful for the treatment of diseases involving cholinergic dysfunction as well as a number of disorders sensitive to the action of nAChR modulators.

In another aspect of the invention, a method for treatment, prevention or relief of disease and the and disorder or condition of the body of the living animal, including humans, which is sensitive to modulation of cholinergic receptors, including the introduction in the body of the living animal, including humans, in need thereof, an effective amount of 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention.

In the preferred embodiment the disease, disorder or condition refers to the Central nervous system.

Preferred medical conditions dealt with in accordance with the present invention are those listed above.

It is presently envisaged that suitable ranges of dosages range from 0.1 to 1000 milligrams daily, preferably 10-500 milligrams daily, and more preferably 30-100 milligrams daily, usually depending on the exact route of administration, form in which the introduction, indications for which this introduction is intended subject, which is treated and the body weight of the subject, and the preference and experience of the attending physician or veterinarian.

EXAMPLES

The invention is further illustrated with reference to the following examples, which in any case are not intended to limit the scope of the claimed invention.

Example 1

Example retrieve

All reactions involving sensitive to air reagents or PR is an interstitial compound, carried out in the nitrogen atmosphere and anhydrous solvents. Magnesium sulfate is used as a desiccant in the processing methods and the solvents evaporated under reduced pressure.

1.4-diaza-bicyclo(3.2.2)nonan (intermediate compound)

The connection specified in the header received in the following J. Med. Chem. 1993 36 2311-2320 (and in accordance with a slightly modified method described below).

1.4-diaza-bicyclo[3.2.2]nonan (intermediate compound)

To a solution of 1,4-diaza-bicyclo[3.2.2]nonan-3-one (15,8 g, 113 mmol) in absolute dioxane (130 ml) was added LiAIH4(4.9 g; 130 mmol) in argon atmosphere. The mixture was boiled under reflux for 6 hours and then allowed to reach room temperature. To the reaction mixture was added dropwise water (5 ml in 10 ml of dioxane), and the mixture was stirred for 0.5 hour and then was filtered through a glass filter. The solvent is evaporated and the residue was distilled using the apparatus Cuellar at 90°C (0.1 mbar (10 PA)) to give the 1,4-diaza-bicyclo[3.2.2]nonane (11.1 g; 78%) as a colorless hygroscopic material.

1,4-Diazabicyclo[3.2.2]nonan-3-one (intermediate compound)

To a solution of hydrochloride of 3-binucleation (45 g, 278 mmol) in 90 ml of an aqueous hydroxylamine hydrochloride (21 g, 302 mmol) was added sodium acetate (CH3COOH×3H2O; 83 g, 610 mmol), the mixture is eremetical at 70°C for 1 hour and then cooled to 0°C. Selected crystalline substance was filtered without washing and dried in vacuum to obtain 40,0 g of the oxime.

The oxime 3-binucleation (40,0 g) was added during 2 hours in small portions to a pre-heated up to 120°With polyphosphoric acid (190 g). The temperature of the solution during the reaction was maintained at 130°C. After adding all of the oxime solution was stirred for 20 minutes at the same temperature, then transferred in enameled vessel and allowed to reach room temperature. An acidic mixture was neutralized with potassium carbonate solution (500 g in 300 ml water)was transferred into a 2000-ml flask, diluted with 300 ml of water and was extracted with chloroform (3×600 ml). The combined organic extracts were dried with sodium sulfate, the solvent evaporated and the solid residue was dried in vacuum to obtain 30.0 g (77%) of a mixture of lactams.

Crystallization of the mixture of 1,4-dioxane (220 ml) gave to 15.8 g (40.5 percent) of 1,4-diaza-bicyclo[3.2.2]nonan-3-one as large colorless crystals with a melting point (TPL) 211-212°C.

Method And

Salt of 4-(5-benzo[1,3]dioxol-5-yl-[1.3.4]oxadiazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane with fumaric acid (Compound A1)

A mixture of 1,4-diaza-bicyclo[3.2.2]nonane (6,36 g of 50.4 mmol), 2-benzo[1,3]dioxol-5-yl-5-benzylmethyl-[1,3,4]oxadiazole (15.0 g, 48,0 mmol), dimethylformamide (DMF) (20 ml) and N,N-diisopropylethylamine (13,0 g, 100,8 mmol stirred at 100°C for 20 hours. Chromatography on silica gel with chloroform, 10% methanol and 1% aqueous ammonia as solvent gave the crude product (7.9 g). Repeated chromatography on silica gel with chloroform, 10% methanol and 1% aqueous ammonia as solvent gave the product as an amorphous solid. Yield 4.4 g (29%). The corresponding salt is obtained by adding a mixture of diethyl ether and methanol (9:1), saturated fumaric acid. Received fumarate salt was recrystallized from isopropanol. Output in the calculation of the free base 3.2 g (61%). Liquid chromatography and mass spectrometry high-resolution electrospray ionization (LC-ESI-HRMS) [M+H]+showed 315,1463 Yes. Designed 315,145716 Yes, reject (off.) 1.9 million-1.

Salt of 4-[5-(2,3-dihydro-benzo[1,tiokasin-6-yl[1,3,4]oxadiazol-2-yl-1,4-diaza-bicyclo[3.2.2]nonane with fumaric acid (Compound A2)

Received in accordance with the method And of the 1,4-diaza-bicyclo[3.2.2]nonane and 2-benzylmethyl-5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazole. LC-ESI-HRMS of [M+H]+showed 329,1616 Yes. Designed 329,161366 Yes, off. 0.7 million-1.

Method B

2-Benzo[1,31]dioxol-5-yl-5-benzylmethyl-[1,3,4]oxadiazole (Intermediate compound)

Benzylbromide (20.2 g, 118,1 mmol) was added over a 5 minute period to a mixture of 5-benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-thiol (25 g, 112,5 IMO the b) triethylamine (22,8 g, 225 mmol) and ethanol (200 ml, 99%). The reaction mixture was stirred at room temperature for 2 hours. Was added aqueous sodium hydroxide (150 ml, 1 M) and water (100 ml) followed by filtration. The product was isolated as solids. The output of 31.0 g (94%).

Method In

5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-thiol (Intermediate compound)

Hydrazide benzo[1,3]dioxol-5-carboxylic acid (45,8 g, 254 mmol) was added to a mixture of potassium hydroxide (15.7 g, 280 mmol) and methanol (350 ml). The mixture was stirred for 30 minutes at room temperature. Added carbon disulfide (38,7 g, 508 mmol). The mixture was stirred at the temperature of reflux distilled for 20 hours, followed by addition of another portion of the carbon disulfide (12.7 g, 167 mmol) and boiled under reflux for 4 hours. Was added water (300 ml) and an excess of carbon disulfide and methanol evaporated. The aqueous suspension was acidified by adding concentrated hydrochloric acid to pH 3-4. The product was besieged, was filtered and washed with water (50 ml). The output of 53.5 g (95%) as a yellow powder.

Method D

Hydrazide benzo[1,3]dioxol-5-carboxylic acid (Intermediate compound)

A mixture of benzo[1,3]dioxol-5-carboxylic acid (42.7 g, 257 mmol) and thionyl chloride (163 g of 1.36 mol) was stirred at 65°C for 6 days. A mixture of benzo[1,3]dioxol-5-carbonylchloride UE shall rivali, was dissolved in tetrahydrofuran (200 ml) and added to a mixture of hydrazine monohydrate (154.4 grams, is 3.08 mol) and tetrahydrofuran (250 ml) at -25°C., followed by stirring for 0.5 hours at -25°C. was Added water (200 ml) followed by filtration. Solid (35,0 g) was isolated by filtration and another portion of solid (10.8 g) was isolated by extraction of the filtrate with ethyl acetate, followed by drying and evaporation. The output of 45.8 g (99%).

Example 2

Inhibition of binding in vitro3N-α-bungarotoxin in the brain of the rat

In this example, the affinity of 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to the invention in relation to linking with octodiol nicotinic receptors was determined using the standard analysis performed essentially as described for example in WO 2006/087306.

The test value is represented as IR50(the concentration of test substance which inhibits the specific binding3N-α-bungarotoxin 50%).

The results of this experiment are presented in the Table below.

Table
Inhibition of binding3N-α-bungarotoxin
No. of connections IR50(µm)
A1<0,01

1. 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative represented by the formula I

or its pharmaceutically acceptable salt, where
AG represents a phenyl group, substituted methylenedioxy or Ethylenedioxy.

2. 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to claim 1 or its pharmaceutically acceptable salt, where AG represents a phenyl group, substituted methylenedioxy.

3. 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to claim 1 or its pharmaceutically acceptable salt, where AG represents a phenyl group, substituted Ethylenedioxy.

4. 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to claim 1, which represents a 4-(5-benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonan; or its pharmaceutically acceptable salt.

5. 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to claim 4, which represents a salt of 4-(5-benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane with fumaric acid.

6. 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to claim 1, which represents 4-[5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonan; or its pharmaceutically acceptable salt.

7. ,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to claim 6, representing salt of 4-[5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane with fumaric acid.

8. Pharmaceutical composition having activity against cholinergic receptors containing a therapeutically effective amount of 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to any one of claims 1 to 7 or its pharmaceutically acceptable salts joining together with at least one pharmaceutically acceptable carrier or diluent.

9. The use of 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to any one of claims 1 to 7 or its pharmaceutically acceptable salt accession for the production of pharmaceutical compositions/medicines for treating, preventing or alleviating disease or disorder or a condition of a mammal, which is sensitive to modulation of cholinergic receptors.

10. A method of treating, preventing or alleviating disease or disorder or condition of the body of the living animal, which is sensitive to modulation of cholinergic receptors, including the introduction in the body of the living animal, in need thereof, a therapeutically effective amount of 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazoline derivative according to any one of claims 1 to 7.



 

Same patents:

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 claims compound of the general formula (I) , where R is hydrogen atom or vinyl group; n is 1, X is a group of the formula CH or nitrogen atom, R1 is either phenyl or naphthyl group, or cyclohexyl group, or heteroaryl group, R2 is either hydrogen atom or one or more substitutes selected out of halogen atoms and trifluoromethyl, alkyl, alkoxyl phenyloxy, hydroxyl groups or group of the general formula -NR4R5, SO2NR4R5, or group of the formula -OCF2O-, each of R4 and R5 groups is hydrogen atom or alkyl group; and method of obtaining compound of the general formula (I), medicine, pharmaceutical composition. Compounds display special effect as specific inhibitors of glycine GlyT1 and/or GlyT2 transmitters and thus are applied in treatment of various diseases.

EFFECT: obtaining compounds with high specific inhibition effect.

13 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 3,4-dihydrobenzoxazine compounds of general formula [1] (where X denotes a nitrogen atom or CR3; R1 denotes a hydrogen atom or a halogen atom; R2 denotes a C1-6alkoxy group which can be substituted with 1-5 identical or different substitutes selected from a halogen atom and a hydroxyl group; and R3 denotes a halogen atom. However, R1 denotes a halogen atom when X denotes CR3). Said compounds are effective when treating diseases where activity of vanilloid receptors subtype 1 (VR1) is involved, e.g. pain.

EFFECT: more efficient use of pharmaceutical compositions based on said compounds, more effective treatment or pain killing.

19 cl, 4 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 3,4-dihydrobenzoxazine compounds of general formula [1] (where X denotes a nitrogen atom or CR3; R1 denotes a hydrogen atom or a halogen atom; R2 denotes a C1-6alkoxy group which can be substituted with 1-5 identical or different substitutes selected from a halogen atom and a hydroxyl group; and R3 denotes a halogen atom. However, R1 denotes a halogen atom when X denotes CR3). Said compounds are effective when treating diseases where activity of vanilloid receptors subtype 1 (VR1) is involved, e.g. pain.

EFFECT: more efficient use of pharmaceutical compositions based on said compounds, more effective treatment or pain killing.

19 cl, 4 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 3,4-dihydrobenzoxazine compounds of general formula [1] (where X denotes a nitrogen atom or CR3; R1 denotes a hydrogen atom or a halogen atom; R2 denotes a C1-6alkoxy group which can be substituted with 1-5 identical or different substitutes selected from a halogen atom and a hydroxyl group; and R3 denotes a halogen atom. However, R1 denotes a halogen atom when X denotes CR3). Said compounds are effective when treating diseases where activity of vanilloid receptors subtype 1 (VR1) is involved, e.g. pain.

EFFECT: more efficient use of pharmaceutical compositions based on said compounds, more effective treatment or pain killing.

19 cl, 4 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazoline derivatives of formula (I), where n equals 0 or 1, R1 denotes a saturated branched or straight unsubstituted C1-C4alkyl, saturated unsubstituted C3-C8cycloalkyl or unsubstituted phenyl bonded through a C1-C3alkyl chain, R2 denotes an unsubstituted or halogen atom-monosubstituted phenyl or thiophenyl, or unsubstituted phenyl bonded through a C1-C3alkyl chain, R3 denotes a saturated branched or straight C1-C8alkyl which is not substituted or contains one substitute selected from a group comprising -COO-methyl, thiomethyl or thiobenzyl, or a phenyl which is mono-substituted with a halogen atom and bonded through a C1-C3alkyl chain, R4 denotes a C1-C4alkyl, R5 and R6 independently denote a saturated branched or straight C1-C6alkyl, in form of a racemate, enantiomers, diastereomers, mixture of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method for synthesis of the compound of formula (I), intermediate compounds of formula B , a medicinal agent based on the compound of formula (I) or formula B and use of compounds of formula (I) or formula B to prepare a medicinal agent.

EFFECT: novel derivatives of imidazoline and substituted aldehyde of formula B, having µ-opiate receptor affinity, are obtained.

16 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are dietary and/or nutriceutic pharmaceutical composition for peroral application which contains S-adenosylmethi-onine-para-toluolsulfonate (SAMe) in combination with inositol and/or ino-sitol-1-phosphate and pharmaceutically acceptable excipients, in which at least one of and pharmaceutically acceptable excipients represents magnesium oxide in concentration from approximately 1.0 to approximately 10.0% of composition weight (versions), method of its obtaining, method of stabilisation of hard food and/or nutriceutic pharmaceutical composition based on SAMe-para-toluolsulfonate by application of inositol and/or inositol-1-phosphate, application of SAMe-para-toluolsulfonate in combination with inositol and/or inositol-1-phosphate for obtaining composition for treatment of depressive states and panic syndromes.

EFFECT: inclusion of magnesium oxide into composition increases SAMe-para-toluolsulfonate stability, inositol reduces SAMe-para-toluolsulfonate hygroscopicity and contributes to its soothing and antidepressant action.

27 cl, 41 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are dietary and/or nutriceutic pharmaceutical composition for peroral application which contains S-adenosylmethi-onine-para-toluolsulfonate (SAMe) in combination with inositol and/or ino-sitol-1-phosphate and pharmaceutically acceptable excipients, in which at least one of and pharmaceutically acceptable excipients represents magnesium oxide in concentration from approximately 1.0 to approximately 10.0% of composition weight (versions), method of its obtaining, method of stabilisation of hard food and/or nutriceutic pharmaceutical composition based on SAMe-para-toluolsulfonate by application of inositol and/or inositol-1-phosphate, application of SAMe-para-toluolsulfonate in combination with inositol and/or inositol-1-phosphate for obtaining composition for treatment of depressive states and panic syndromes.

EFFECT: inclusion of magnesium oxide into composition increases SAMe-para-toluolsulfonate stability, inositol reduces SAMe-para-toluolsulfonate hygroscopicity and contributes to its soothing and antidepressant action.

27 cl, 41 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry and deals with steroid compound of formula (I), in which one of R1 and R2 represents hydroxyl group, the other represents hydrogen atom; or R1 and R2 together represent oxogroup; R3 represents hydrogen atom or hydroxyl group; and broken lines represent single or double carbon-carbon bonds; or its pharmaceutically acceptable salt or ester for manufacturing medication for prevention or treatment of neuropathic pain, where derivative is selected from 11-hydroxy-Δ4-androsten-3,17-dione and 11-oxo-Δ4-androsten -3,17-dione.

EFFECT: formula (I) compound possesses higher efficiency in pain treatment.

7 cl, 2 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is composition in form of one-layer, without cavities film, which does not contain surface-active substances, gas-generating additives and taste-masking agents and contains at least two film-generators, one or several gel-generators and as active substance from group of neuroleptics - olanzapine. Film-generating agents are selected from the following group: sugars, sugar alcohols and their derivatives, low-molecular organic acids, polyethylene glycol, polyethylene glycol dioleate, 1,3-butanediol, propylene glycol, glycerol, isopropyl palmitate, dibutyl sebacynate, paraffin oil and castor oil, ethylcellulose, cellulose acetate, cellulose phthalate and their mixtures. At least one film-generating agent is water-insoluble. Composition by invention is applied for preparation of medication intended for treatment of central nervous system disorders.

EFFECT: composition in form of film by invention is characterised by high mechanical strength and ability to release active substance quickly, during several seconds.

26 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is composition in form of one-layer, without cavities film, which does not contain surface-active substances, gas-generating additives and taste-masking agents and contains at least two film-generators, one or several gel-generators and as active substance from group of neuroleptics - olanzapine. Film-generating agents are selected from the following group: sugars, sugar alcohols and their derivatives, low-molecular organic acids, polyethylene glycol, polyethylene glycol dioleate, 1,3-butanediol, propylene glycol, glycerol, isopropyl palmitate, dibutyl sebacynate, paraffin oil and castor oil, ethylcellulose, cellulose acetate, cellulose phthalate and their mixtures. At least one film-generating agent is water-insoluble. Composition by invention is applied for preparation of medication intended for treatment of central nervous system disorders.

EFFECT: composition in form of film by invention is characterised by high mechanical strength and ability to release active substance quickly, during several seconds.

26 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (A), where the whole of (A), except X, is denoted as MR36G-NR1R2-S; R1 is a linear or branched (C1-C10)-alkyl; R2 is hydrogen; R3 is a YR group. Y is oxygen, R is a linear or branched (C1-C6)-alkyl, provided that R3 is not O-CH3; X is hydrogen, a -S-R4-W radical or a MR36G-NR1R2-S radical, where R4 is (C1-C8)-alkyl, -(CH2)n-C(O)-NH-, or -(CH2)n-NH-C(O)-, where n is an integer ranging from 1 to 8; and W is naltrindole, as well as pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on said compounds for preparing a medicinal agent for curing pain, as well as use of said compounds to prepare a medicinal agent for curing pain.

EFFECT: more effective use of the compounds.

9 cl, 6 tbl, 4 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is composition in form of one-layer, without cavities film, which does not contain surface-active substances, gas-generating additives and taste-masking agents and contains at least two film-generators, one or several gel-generators and as active substance from group of neuroleptics - olanzapine. Film-generating agents are selected from the following group: sugars, sugar alcohols and their derivatives, low-molecular organic acids, polyethylene glycol, polyethylene glycol dioleate, 1,3-butanediol, propylene glycol, glycerol, isopropyl palmitate, dibutyl sebacynate, paraffin oil and castor oil, ethylcellulose, cellulose acetate, cellulose phthalate and their mixtures. At least one film-generating agent is water-insoluble. Composition by invention is applied for preparation of medication intended for treatment of central nervous system disorders.

EFFECT: composition in form of film by invention is characterised by high mechanical strength and ability to release active substance quickly, during several seconds.

26 cl, 3 ex

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