Novel chroman-2-one derivatives and use thereof as monoamine neuromediator reuptake inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula or to any isomer thereof, or mixture of isomers thereof, or pharmaceutically acceptable salt thereof, where R1 represents hydrogen or alkyl; R2 and R3 together form -(CH2)2-, and R2' and R3' represent hydrogen, m equals 1; n equals 1; X represents -O-; and Q represents chroman-2-on-7-yl, which is possibly substituted with one or more substitutes independently selected from a group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl. The invention also relates to a pharmaceutical composition, as well as to use of chemical compound in any of paragraphs 1-4.

EFFECT: obtaining novel biologically active compounds having monoamine neuromediator reuptake inhibitory activity.

8 cl, 10 ex, 1 tbl

 

The scope of the invention

This invention relates to new chromen-2-novym derivative, useful as inhibitors of reuptake monoamine neurotransmitters.

In other aspects the invention relates to the use of these compounds in a method of therapy and to pharmaceutical compositions containing the compounds according to the invention.

Prior art

Currently, selective inhibitors of serotonin reuptake (SSRIs) ensure the effectiveness of the treatment of some disorders of the Central nervous system (CNS), including depression and panic disorder. Psychiatrists and physicians first aid often take SSRIs as an effective, well-tolerated and light in the introduction. However, they are accompanied by a number of undesirable properties.

Therefore, still there is a strong need for compounds with optimal pharmacological profile in relation to the activity reuptake monoamine neurotransmitters serotonin, dopamine and norepinephrine, such as the ratio of the activity of serotonin reuptake to be active reuptake of norepinephrine and dopamine.

In Bioorganic & Medicinal Chemistry (Jackson, Sharon A. et al., 13 (2005) 2723-2739) reviewed the structure, synthesis and characterization of a new class of inhibitors based on coumarin, or the inducible synthase is nitric oxide. Among the disclosed compounds include salt triperoxonane acid and 6-bromo-4-(piperidine-4-yloxy)-1-benzopyran-2-it. The same compound disclosed in WO 2005/026143.

A brief description of the invention

In the first aspect of the invention features a compound of formula I

or any of its isomers or any mixture of its isomers, or pharmaceutically acceptable salt,

where R1, R2, R2, R3, R3', m, n, X and Q are defined below.

In the second aspect of the invention features a pharmaceutical composition comprising a therapeutically effective amount of the compounds according to the invention or any of its isomers or any mixture of its isomers, or its pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier, excipient or diluent.

In an additional aspect of the invention features the use of compounds according to the invention or any of its isomers or any mixture of its isomers, or its pharmaceutically acceptable salt for the manufacture of pharmaceutical compositions for the treatment, prevention or relief of a disease or disorder, or condition of a mammal, including humans, and the disease, disorder or condition responsive to the inhibition of the reuptake of monoamine the output of neurotransmitters in the Central nervous system.

In yet another additional aspect of the invention relates to a method of treating, preventing or alleviating disease or disorder, or condition of a living animal body, including a human, the disease, disorder or condition responsive to the inhibition of the reuptake monoamine neurotransmitters in the Central nervous system, and this method includes a step of introducing such needs it for a living organism to an animal a therapeutically effective amount of the compounds according to the invention or any of its isomers or any mixture of its isomers, or its pharmaceutically acceptable salt.

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

Detailed description of the invention

Chromen-2-about derivatives

In the first aspect of the present invention features a compound of formula I

or any of its isomers or any mixture of its isomers,

or its pharmaceutically acceptable salt,

where

R1represents hydrogen or alkyl;

where the alkyl possibly substituted by one or more substituents independently selected from the group consisting of: halogen, trifloromethyl, triptoreline, cyano, hydroxy, amino, nitro, alkoxy, CEC is alkoxy, of alkyl, cycloalkyl, cycloalkenyl, alkenyl and quinil;

each of R2, R2', R3and R3'independently from each other represents hydrogen or alkyl; or R2and R3together form -(CH2)pand R2'and R3'independently from each other represent hydrogen or alkyl; where R is 1, 2 or 3;

m is 0, 1 or 2;

n is 0, 1 or 2;

X represents-O - or-NR4-;

where R4represents hydrogen, alkyl, -C(=O)R5or-SO2R5;

where R5represents hydrogen or alkyl; and

Q represents chromen-2-about the group which may substituted by one or more substituents independently selected from the group consisting of halogeno, trifloromethyl, triptoreline, cyano, hydroxy, amino, nitro, alkoxy, cycloalkane, alkyl, cycloalkyl, cycloalkenyl, alkenyl and quinil.

In one embodiment R1represents hydrogen. In the second embodiment R1represents alkyl.

In an additional embodiment, R2and R3together form -(CH2)p-. In yet another additional embodiment, R2and R3together form -(CH2)p-, and R2'and R3'each represents hydrogen. In a specific embodiment R2and R3together form

-(CH2)2 -. In an additional specific embodiment R2and R3together form -(CH2)2-,

and R2'and R3'represent hydrogen.

In yet another additional embodiment, R2, R2', R3and R3'each represents alkyl. In a specific embodiment R2, R2', R3and R3'each represents methyl. In an additional embodiment, R2, R2', R3and R3'each represents hydrogen.

In a further embodiment m is 1. In yet another additional embodiment n is equal to 1. In a particular embodiment m is 1 and n is equal to 1.

In an additional embodiment X represents-O-.

In yet another additional embodiment, R2, R2', R3and R3'each represents alkyl, such as methyl, m is 1 and n is equal to 1.

In an additional embodiment, R2, R2', R3and R3'each represents hydrogen, m is 1 and n is equal to 1.

In an additional embodiment, R2and R3together form -(CH2)2-, R2'and R3'represent hydrogen, m is 1 and n is equal to 1.

In yet another additional embodiment Q represents chromen-2-he-4-yl, chromen-2-on-6-yl or chromen-2-one-7-yl. In a particular embodiment Q represents chromen-2-he-4-yl. In an additional embodiment the Q submitted is chromen-2-on-6-yl. In yet another additional embodiment Q represents chromen-2-one-7-yl. In an additional embodiment Q represents chromen-2-he, substituted alkyl, such as methyl. In a particular embodiment Q is a 4-methyl-chromen-2-on-6-yl.

In a particular embodiment of a chemical compound according to the invention is not 6-bromo-4-(piperidine-4-yloxy)-1-benzopyran-2-it.

In a particular embodiment of a chemical compound according to the invention is

Exo-7-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-he;

Exo-4-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-he;

Exo-6-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-4-methyl-chromen-2-he;

Exo-6-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-he;

7-(1-methyl-piperidine-4-yloxy)-chromen-2-he;

7-(1,2,2,6,6-pentamethyl-piperidine-4-yloxy)-chromen-2-he;

7-(2,2,6,6-tetramethyl-piperidine-4-yloxy)-chromen-2-he;

Exo-7-(8-H-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-he;

Exo-6-(8-H-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-he;

or their pharmaceutically acceptable salt.

Any combination of two or more of the above-described embodiments are considered within the scope of the present invention.

The definition of the substituents

In the context of this invention, halogen is a fluorescent, chloro, bromo or iodine.

In the context of this invention alkyl group means a monovalent us is on an unbranched or branched hydrocarbon chain. The hydrocarbon chain preferably contains from one to six carbon atoms (C1-6-alkyl), including pentyl, isopentyl, neopentyl, tertiary of pentyl, hexyl and isohexyl. In the preferred embodiment the alkyl represents a C1-4is an alkyl group, including butyl, isobutyl, secondary butyl and tertiary butyl. In another preferred embodiment of this invention the alkyl represents a C1-3-alkyl group, which may be, in particular, stands, ethyl, propylene or isopropyl.

In the context of this invention Alchemilla group means a carbon chain containing one or more double bonds, including dieny, triene and a polyene. In the preferred embodiment Alchemilla group according to the invention contains from two to six carbon atoms (C2-6alkenyl) together with at least one double bond. In the preferred embodiment Alchemilla group according to the invention is atenolol; 1 - or 2-propanolol; 1-, 2 - or 3-butanolom or 1,3-butadienyl; 1-, 2-, 3-, 4 - or 5-hexenyl or 1,3-hexadienyl, or 1,3,5-hexatriene.

In the context of this invention Alchemilla group means a carbon chain containing one or more triple relations, including dieny, triinu and Polyany. In the preferred embodiment Alchemilla group according to the invention contains from two to six at the MOU carbon (C 2-6-quinil) together with at least one triple bond. In its most preferred embodiment Alchemilla group according to the invention is atenolol; 1 - or 2-PROPYNYL; 1-, 2 - or 3-butanolom or 1,3-butadienyl; 1-, 2-, 3-, 4-pentinum or 1,3-pentadienyl; 1-, 2-, 3-, 4 - or 5-geksanalem or 1,3-hexadienyl, or 1,3,5-hexatriene.

In the context of this invention cycloalkyl group means a cyclic alkyl group, preferably containing from three to seven carbon atoms (C3-7-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Alkoxy represents O-alkyl, where alkyl is defined above.

Cycloalkane means O-cycloalkyl where cycloalkyl defined above.

Cycloalkenyl means above cycloalkyl and the above alkyl; for example, means cyclopropylmethyl.

Amino represents NH2or NH-alkyl, or N(alkyl)2, where alkyl is defined above.

In the context of this invention, the aryl group means a carbocyclic aromatic ring system such as phenyl, naphthyl (1-naphthyl or 2-naphthyl) or fluorenyl.

Pharmaceutically acceptable salt

Chemical compound according to the invention can be provided in any form suitable for the scheduled introduction. Suitable forms include pharmaceutical is key (i.e. physiologically) acceptable salts, and pre - or proletarienne form chemical compounds according to the invention.

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

Examples of pharmaceutically acceptable cationic salts chemical compounds according to the invention include, without limitation, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, salt, choline, lysine salt and ammonium salt (and the like) of a chemical compound according to the invention containing an anionic group. Such cationic salts can be formed by well known and described in the art methods.

In the context of this invention "onevia salt" N-containing compounds are also provided as pharmaceutically acceptable salts. Preferred "onevia salts include alkyl-onieva salt, cycloalkyl-onieva salt and cyclea killkill-onieva salt.

Examples of pre - and proletarienne forms of chemical compounds according to the invention include examples of suitable prodrugs of the substances according to the invention include compounds which are modified by one or more than one reactive or capable of derivatization the original connection. Of particular interest are compounds modified at the carboxyl group, hydroxyl group or amino group. Examples of suitable derivatives are the esters or amides.

Chemical compound according to the invention can be presented in a soluble or insoluble forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Soluble forms may also include hydrated forms, such as the monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like. In General, for the purposes of this invention are soluble forms are recognized as equivalent to insoluble forms.

Spatial isomers

Specialists in the art it will be clear that the compounds of the present invention can contain one or more chiral centres, and that such compounds exist in the form of isomers.

Some chemical compounds according to the invention, having the-C=C - double bond can exist in two forms, SYN - and anti-forms of the (Z - and E-form), depending on the arrangement of the substituents around the double bond. Chemical compound according to the present invention may thus be in the SYN or anti form, or may represent a mixture.

Moreover, the chemical compounds of the present invention can exist as enantiomers (+) and (-) forms as well as in racemic forms (±).

The invention includes all such isomers and any mixtures thereof, including racemic mixtures.

The racemic forms can be separated into the optical antipodes known methods and ways. One of the ways to separate the isomeric salts is the use of an optically active acid and isolation of the optically active amine compound by treatment with base. Another method of separation of racemates on the optical antipodes based on chromatography on optically active matrix. Racemic compounds of the present invention thus can be separated into their optical antipodes, for example, by fractional crystallization of d - or l-salts (tartratami, mandelate or camphorsulfonate), for example.

Chemical compounds of the present invention can also be separated through the formation of diastereomeric amides by the reaction of chemical compounds of the present invention with an optically active activated carboxylic acid, Taco is as derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) campanulas acid, or through the formation of diastereomeric carbamates by the reaction of a chemical compound according to the present invention with an optically active chloroformate or the like.

Additional methods of separation of optical isomers are known in the art. Such methods include described Jaques J, Collet A & Wilen's in the "Enantiomers, Racemates, and Resolutions" (John Wiley and Sons, New York (1981)).

Optically active compounds can also be prepared from optically active starting materials.

Labeled compounds

Compounds according to the invention can be applied 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. The label provides the ability to easily quantify the specified connection.

Labeled compounds according to the invention can be used as diagnostic tools, radioactive indicators or control agent in various diagnostic methods for the visualization of receptors in vivo.

Labeled isomer according to the invention preferably contains at least one radionuclide as IU is key. All 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,131I125I123I and18F.

Physical detection of labeled isomer of the present invention may be selected from positron emission tomography (PET), single photon imaging computed tomography (SPECT), magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI) and computed axial x-ray tomography (CAT) or combinations thereof.

Ways to get

Chemical compounds according to the invention can be obtained by conventional methods of chemical synthesis, for example, described in the working examples. Starting materials for the methods described in this application are known or can be easily obtained by using common methods from commercially available chemicals.

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

The final products described herein reactions can be isolated by standard methods, for example, extraction, crystallization, distillation, chromatography and so on.

Biological activity

Compounds according to the invention can be tested for their ability to inhibit the reuptake of the monoamines dopamine, noradrenaline and serotonin in the uptake, for example, as described in WO 97/30997 (NeuroSearch A/S). Based on a balanced activity observed in these tests, the compound according to the invention are considered useful for treatment, prevention or relief of a disease or disorder, or condition of a mammal, including humans, which are sensitive to inhibition of reuptake monoamine neurotransmitters in the Central nervous system.

In a particular embodiment of the compounds according to the invention are considered useful for treatment, prevention or relief: mood disorders, depression, atypical depression, secondary depression due to the pain, major depressive disorder, estimatesare disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, mood disorders due to a General medical condition, mood disorders, caused by substances, pseudodementia, syndrome Ganzera, obsessive-compulsive disorder, panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without paycheck the th disorders in history, acute anxiety with panic reaction, memory deficits, memory loss, attention deficit disorder with hyperactivity disorder, obesity, anxiety disorders, generalized anxiety, eating disorders, Parkinson's disease, parkinsonism, dementia, senile dementia, senile dementia, Alzheimer's disease, dementia and acquired immunodeficiency syndrome, senile memory dysfunction, specific phobia, social phobia, posttraumatic stress disorder, acute stress disorder, drug addiction, drug abuse, cocaine abuse, nicotine abuse, tobacco abuse, chronic alcoholism, alcoholism, pain, chronic pain, inflammatory pain, neuropathic pain, migrainebuy pain, headache busy type headache chronic type of pain associated with depression, fibromyalgia, arthritis, osteoarthritis, rheumatoid arthritis, back pain, cancer pain, pain in irritable bowel, irritable bowel syndrome, post-operative pain, postmastectomy pain syndrome (PMPS), pain after stroke, neuropathy caused by medication, diabetic neuropathy, simpaticeskii supported pain, trigeminal neuralgia, dental pain, mifa the social pain, phantom pain, bulimia, premenstrual syndrome, syndrome, late luteal phase, post-traumatic syndrome, chronic fatigue syndrome, urinary incontinence, stress incontinence, failure, nocturnal incontinence, sexual dysfunction, premature ejaculation, erectile difficulty, erectile dysfunction, premature female orgasm, syndrome restless legs, eating disorders, mental anorexia, sleep disorders, profound developmental disorders, autism, Asperger syndrome, rett syndrome, disintegrative disorders of childhood, neobhodimosti, disorders of motor skills, mutism, trichotillomania, narcolepsy, depression after stroke, brain damage caused by stroke, neuronal damage resulting from stroke, or disease, Gilles de La Tourette. In the preferred embodiment of the compounds are considered useful for treatment, prevention or relief of depression.

This provides that the appropriate dosage of the active pharmaceutical ingredient (API) is 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 p the wrong route of administration, forms of introduction, consider the testimony of the subject and, in particular, body mass affected subject, 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 micromolar range, i.e. below 1 to about 100 microns.

The pharmaceutical composition

In another aspect of the invention offers new pharmaceutical compositions containing a therapeutically effective amount of a chemical compound according to the invention,

Although chemical compound according to the invention for use in therapy can be introduced in the form of the raw chemical compound, it is preferable to make the active ingredient, possibly in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical additives.

In the preferred embodiment of the invention offers a pharmaceutical composition comprising a chemical compound according to the invention or its pharmaceutically acceptable salt or a derivative thereof together with one or more pharmaceutically acceptable carriers and, possibly, other therapeutic and/or prophylactic phrases is Tami, known and used in the art. The carrier(s) need(s) to be acceptable(and)" in the sense of compatibility with other ingredients of the composition and safety for the recipient.

The pharmaceutical compositions according to the invention can be suitable for oral, rectal, bronchial, nasal, pulmonary, local (including transbukkalno and sublingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, vnutricherepnuyu, intraocular injection or infusion) administration, or to be in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol introduction, or slow release. Suitable examples of sustained-release include semi-permeable matrices of solid hydrophobic polymers containing a compound according to the invention, which (matrix) can be in the form of particles of a certain shape, e.g. films, or microcapsules.

Thus, a chemical compound according to the invention together with a conventional adjuvant, carrier or diluent can be placed in the form of pharmaceutical compositions and their standard dosage forms. Such forms include solids, in particular tablets, capsule filler with, p is rockabye shape and form granules, and liquids, in particular aqueous and non-aqueous solutions, suspensions, emulsions, elixirs and filled capsules, all for oral administration, suppositories for rectal administration and sterile solutions for injection for parenteral use. Such pharmaceutical compositions and their standard dosage forms may contain conventional ingredients in conventional proportions, with or without additional active compounds or active principles, and such a standard dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dose range for use.

Chemical compound according to the present invention can be introduced in a wide variety of oral and parenteral dosage forms. For specialists in the art it will be obvious that the following dosage forms may contain as an active ingredient or chemical compound according to the invention, or pharmaceutically acceptable salt of a chemical compound according to the invention.

For preparing pharmaceutical compositions from a chemical compound according to the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Drugs in solid form include powders, tablets, pills, capsules, about what ADI, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, corrigentov, solubilization, lubricants, suspendida agents, binders, preservatives, baking powder, tablets or encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.

In tablets, the active ingredient in suitable proportions mixed with carrier having the necessary binding capacity, and pressed to the desired shape and 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, methyl cellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. The term "drug" means including the composition of the active compound with encapsulating material as carrier providing a capsule in which the active ingredient with the carriers, or without them, is surrounded by carrier, which is thus associated with him. Similarly includes a wafer and pellet. Tabla is key, powders, capsules, pills, wafers and cakes can be used as solid dosage forms suitable for oral administration.

For preparing suppositories first melted low-melting wax such as a mixture of fatty acid glycerides or cocoa butter, and there is homogeneous distribute the active ingredient, for example, by stirring. The molten homogeneous mixture is then poured into forms with common dimensions, leave to cool and thereby solidify.

Compositions suitable for vaginal administration, can be represented by pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers, which in the art it is known that they are appropriate.

Liquid preparations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, liquid preparations for parenteral injection can be prepared as solutions in aqueous solution of polyethylene glycol.

Chemical compound according to the present invention can thus be prepared for parenteral administration (e.g. by injection, for example bolus injection or prolonged infusion) and may be presented in a standard dosage form in ampoules, prajapatih syringes, infusion Malyshev or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous solvents, and may include forming agents, such as suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for Association with a suitable solvent, such as sterile pyrogen-free water, before use.

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

Aqueous suspensions suitable for oral use can be obtained by dispersing finely divided active component in water with viscous material such as natural or synthetic resins, polymers, methylcellulose, sodium carboxymethylcellulose or other commonly known suspendresume agents.

Also included preparations in solid form intended for fast transformation before applying the medication in liquid form for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the active component still the preparations may contain colouring agents, the corrigentov, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizing agents and the like.

For local injection into the epidermis chemical compound according to the invention can be prepared in the form of ointments, creams or lotions, or transdermal patch. Ointments and creams can be prepared, for example, aqueous or oily base with the addition of suitable thickeners and/or gelling agents. Lotions can be prepared in water or oil based and usually also contain one or more than one emulsifier, a stabilizing agent, a dispersing agent, suspendisse agent, thickening agent or dye.

Compositions suitable for local injection in the mouth include pellet containing the active agent on a taste basis, usually sucrose and gum Arabic or tragana; tablets containing the active ingredient in an inert basis such as gelatin and glycerol or sucrose and gum Arabic; and a liquid for rinsing the oral cavity containing the active ingredient in a suitable liquid carrier.

Directly in the nasal cavity solutions or suspensions are applied using traditional means, for example, with a dropper, pipette or spray. The composition can be provided in single or multi-dose form.

Put the e in the respiratory tract may also be achieved by means of an aerosol drug in which the active ingredient is provided in the package under pressure with a suitable propellant such as a chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may also traditionally contain a surfactant such as lecithin. The dose of the drug can be controlled by providing a metering valve.

Alternatively, the active ingredients can be provided 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, such as hypromellose and polyvinylpyrrolidone (PVP). Powder media traditionally forms a gel in the nasal cavity. The powder composition may be presented in a standard dosage form such as capsules or cartridges of, for example, gelatin or blister packs from which the powder may be introduced through the inhaler.

In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size, for example of the order of 5 microns or less. This particle size can be obtained by methods known in the art, for example micron is the situation.

If necessary, can be applied composition adapted for slow release of the active ingredient.

The pharmaceutical preparations are preferably in a standard dosage forms. In such form the preparation is divided into standard doses containing appropriate quantities of the active component. Standard dosage form can be a packaged preparation, where the package contains discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Standard dosage form itself can be a capsule, tablet, wafer or bread or can be an appropriate number of any of these in packaged form.

The preferred compositions are tablets or capsules for oral administration and fluids for intravenous and prolonged infusions.

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

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

The dose for administration, of course, should be carefully matched by age, weight and condition of the person under treatment, as well as on the method of administration, dosage form and mode, and the desired result and the exact dosage should, of course, determined by the practitioner.

The actual dosage depends on the nature and severity of the disease, which is treatable and remains at the discretion of the physician, and may vary by dose titration in relation to specific cases of the present invention to obtain the desired therapeutic effect. This, however, provided that suitable for therapeutic treatment are pharmaceutical compositions containing from about 0.1 to about 500 mg of the active ingredient in the individual dose, preferably from about 2 to about 100 mg, most preferably from about 1 to about 10 mg.

The active ingredient can be introduced in one or in multiple doses per day. In some cases, satisfactory results can be obtained already the ri dose of 0.1 mg/kg intravenous (I.V) and 1 mg/kg oral (P.O.). The upper limit of the range of the dose is now considered to be approximately 10 mg/kg I.V and 100 mg/kg P.O. Preferred ranges are from about 0.1 μg/kg to about 10 mg/kg/day centuries and from about 1 μg/kg to about 100 mg/kg/day P.O.

Treatment

In another aspect of the invention features a method of treating, preventing or alleviating disease or disorder, or condition of a living animal body, including a human, the disease, disorder or condition responsive to the inhibition of the reuptake monoamine neurotransmitters in the Central nervous system, and this method includes the introduction of such a need in him to the living animal body, including a human, an effective amount of a chemical compound according to the invention.

This is provided that a suitable dosage ranges are from 0.1 to 1000 milligrams per day, 10-500 milligrams daily, and especially 30-100 milligrams per day, depending, as usual, from the correct route of administration, forms of administration, indications for the purpose of introduction, the affected subject and body mass affected subject, and, in addition, preferences and experience of the responsible attending physician or veterinarian.

Examples

Further, the invention is illustrated with reference to the trail of the following following examples, are not intended to be any limitation of the scope of the claimed invention.

General provisions: All reactions involving sensitive to air reagents or intermediate compounds were carried out in nitrogen atmosphere and anhydrous solvents. As a dewatering agent in the working methods used magnesium sulfate, the solvents evaporated under reduced pressure.

Method And

Exo-7-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-about salt fumaric acid

A mixture of triphenylphosphine (17.6 g, 67 mmol) and dioxane (150 ml) was stirred and cooled to 8°C. and then slowly added diethylazodicarboxylate (10.4 ml, 67 mmol) at a temperature below 15°C. the Cooling was removed, was added according to (7.9 g, 56 mmol) and 7-hydroxy-coumarin (10 g, 62 mmol) and the reaction mixture was left to mix for 15 hours. The reaction mixture was stirred at 65°C for 5 hours. Was added aqueous sodium hydroxide (100 ml, 1 M) and was extracted with diethyl ether (2×100 ml). Phase diethyl ether was washed with water (50 ml). Chromatography of the crude mixture on silica gel with dichloromethane, methanol and concentrated ammonia (96:3:1) gave specified in the title compound in free base form in the form of oil. Yield 2.0 g (13%). The corresponding salt was obtained by adding a mixture of diethyl ether and met the Nola (9:1), rich fumaric acid. TPL (melting point) 252°C.

Exo-4-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-about free base

Was obtained from 4-hydroxycoumarin according to method A. TPL 143,5-146,5°C.

Exo-6-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-4-methyl-chromen-2-about salt of hydrochloric acid

Was obtained from 6-hydroxy-4-methylcoumarin according to method A. TPL >250°C (decomp.).

Exo-7-(8-tert-butoxycarbonyl-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-about the free base (intermediate compound)

Received in the form of oil according to the method of A.

Exo-6-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-about salt of hydrochloric acid

Was obtained from 6-hydroxycoumarin according to method A. TPL 278°C.

7-(1-Methyl-piperidine-4-yloxy)-chromen-2-about salt fumaric acid

Obtained from 7-hydroxycoumarin and 4-hydroxy-1-methylpiperidine according to method A. TPL 205-210°C.

Method B

7-(1,2,2,6,6-Pentamethyl-piperidine-4-yloxy)-chromen-2-about salt of hydrochloric acid

A mixture of triphenylphosphine (9.4 g, 36 mmol) and dioxane (100 ml) was stirred at room temperature, and then was slowly added diethylazodicarboxylate (5.6 ml, 36 mmol). Was added 4-hydroxy-1,2,2,6,6-pentamethyl-piperidine (5.1 g, 30 mmol) (obtained from 1,2,2,6,6-pentamethyl-piperidine-4-it by restoring borage is the home of sodium) and 7-hydroxycoumarin (5,2 g, 32 mmol) and the reaction mixture was left to mix for 15 hours at room temperature, and then stirred at 40°C for 4 hours. Was added aqueous sodium hydroxide (100 ml, 1 M) and diethyl ether (2×50 ml) was extracted with the mixture. Phase diethyl ether was washed with water (50 ml). The volume of the ether phase was reduced to 30 ml and was filtered crystalline triphenylphosphine oxide. The filtrate was mixed with hydrochloric acid (30 ml, 1 M) and twice washed with diethyl ether (2×50 ml). The aqueous mixture was brought to an alkaline state by the addition of concentrated ammonia. The product precipitated in the form of free base, and it was collected by filtration. The free base was dissolved in ethyl acetate (40 ml) was added hydrochloric acid (2 ml, 3 M). The product precipitated as a salt of hydrochloric acid, and filtered. The product was subjected to recrystallization from isopropyl alcohol (50 ml). The output of 1.05 g (10%). TPL 273°C.

Method In

7-(2,2,6,6-Tetramethyl-piperidine-4-yloxy)-chromen-2-about salt of hydrochloric acid

A mixture of 7-(1,2,2,6,6-pentamethyl-piperidine-4-yloxy)-chromen-2-it (0,69 g, 2.2 mmol), diethylazodicarboxylate (1.0 ml, 6.6 ml) and toluene (50 ml) was stirred at 115°C for 15 hours. To the mixture was added hydrochloric acid (10 ml, 2n.) and boiled under reflux for 1 hour. The mixture was cooled, and the product issue is made in the precipitate as a salt of hydrochloric acid. Yield 0.26 g (37%). TPL >300°C.

Method D

Exo-7-(8-H-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-about salt of hydrochloric acid

A mixture of Exo-7-(8-tert-butoxycarbonyl-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-it (of 0.60 g, 1.6 mmol) and hydrochloric acid (10 ml, 1 M) in acetic acid was stirred for 1 hour. Added diethyl ether, the precipitate was filtered and washed with diethyl ether (10 ml). Yield 0.28 g (57%). TPL >300°C.

Method D

Exo-6-(8-H-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-about salt of hydrochloric acid

A mixture of Exo-6-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-it (0,90 g and 3.15 mmol), 2,2-trichloroethyl-chloroformate (2.00 g, 9.4 mmol) and toluene (20 ml) was stirred at reflux for 15 hours. Was added water (20 ml), the organic phase was separated and washed with water (20 ml). Toluene phase was evaporated. Was added acetic acid (5 ml), water (5 ml) and zinc powder (1,03 g, 15,77 mmol) and was stirred for 70 hours. Was added aqueous sodium hydroxide (10 ml, 1 M) and diethyl ether (2×30 ml) was extracted with the mixture. Allocated free base output 0,86 g (94%). Besieged salt of hydrochloric acid. TPL >280°C.

In vitro inhibition of reuptake3H-dopamine (3H-DA) in the veins uptake

Obtaining tissue drug: Obtaining a tissue preparations is carried out and at 0-4°C, if not stated otherwise. Striatum of male Wistar rats (150-200 g) were gamogenetically for 5-10 seconds in 100 volumes of the cooled in ice of 0.32 M sucrose solution containing 1 mm of pargyline, using a homogenizer Ultra-Turrax. The activity of monoamine oxidase is inhibited in the presence of pargyline. The homogenate was centrifuged at 1000×g for 10 minutes. The resulting supernatant is then centrifuged at 27000×g for 50 minutes and the supernatant discarded. The residue after centrifugation (R2) resuspending in oxygendemand (balanced in an atmosphere of 96% O2: 4% CO2for at least 30 minutes) incubation buffer Krebs-ringer (8000 ml per g of original tissue) at pH of 7.2, containing 122 mm NaCl, 0,16 mM EDTA (ethylenediaminetetraacetic acid), 4.8 mm KCl, 12.7 mm Na2HPO4, 3.0 mm NaH2PO4, 1.2 mm MgSO4, 1 mm CaCl2, 10 mm glucose and 1 mm ascorbic acid.

Analysis: Aliquots of 4.0 ml tissue suspension are added to 100 μl of test solution and 100 µl of the3H-DA (1 nm, final concentration), mixed and incubated for 25 minutes at 37°C. non-specific reuptake determined using benzotropine (10 μm, final concentration). After incubation, the sample was poured directly onto a glass-fiber filters Whatman GF/C under vacuum. These filters are then washed three times 5 is l cooled in ice with 0.9% (wt./about.) NaCl solution. The amount of radioactivity on the filters define the conventional method of registering a liquid scintillation. Specific reuptake calculated as the difference between total return capture and nonspecific reverse grip.

Must be achieved 25-75% inhibition of specific binding, and then calculate IC50.

The test value is given as IC50(the concentration (μm) test substance which inhibits the specific binding3H-DA at 50%).

In vitro inhibition of reuptake3H-norepinephrine (3H-NA) in hippocampal uptake

Obtaining tissue drug: Obtaining a tissue preparations were performed at 0-4°C, unless otherwise noted. Hippocampi of male Wistar rats (150-200 g) homogenized for 5-10 seconds in 100 volumes of the cooled in ice to 0,32M sucrose solution containing 1 mm of pargyline, using a homogenizer Ultra-Turrax. The activity of monoamine oxidase is inhibited in the presence of pargyline. The homogenate cetrifugation at 1000×g for 10 minutes. The resulting supernatant is then centrifuged at 27000×g for 50 minutes and the supernatant discarded. The residue after centrifugation (R2) resuspending in oxygendemand (balanced in an atmosphere of 96% O2: 4% CO2over on the men is her least 30 minutes) incubation buffer Krebs-ringer (2000 ml per g of original tissue) at pH 7,2, containing 122 mm NaCl, 0,16 mM EDTA, 4.8 mm KCl, 12.7 mm Na2HPO4, 3.0 mm NaH2PO4, 1.2 mm MgSO4, 1 mm CaCl2, 10 mm glucose and 1 mm ascorbic acid.

Analysis:Aliquots of 4.0 ml of the suspension fabric is added to 100 μl of test solution and 100 µl of the3H-NA (1 nm, final concentration), mixed and incubated for 90 minutes at 37°C. non-specific reuptake determined with the use of desipramine (10 μm, final concentration). After incubation, the sample was poured directly onto a glass-fiber filters Whatman GF/C under vacuum. These filters are then washed three times with 5 ml chilled in ice with 0.9% (wt./about.) NaCl solution. The amount of radioactivity on the filters define the conventional method of registering a liquid scintillation. Specific reuptake calculated as the difference between total return capture and nonspecific reverse grip.

Must be achieved 25-75% inhibition of specific binding, and then calculate IC50.

The test value is given as IC50(the concentration (μm) test substance which inhibits the specific binding3H-NA 50%).

In vitro inhibition of reuptake3H-5-hydroxytryptamine (3H-S-HT, serotonin) in cortical uptake

Obtaining tissue preparations/u> : Obtaining a tissue preparations were performed at 0-4°C, unless otherwise noted. The cerebral cortex of male Wistar rats (150-200 g) homogenized for 5-10 seconds in 100 volumes of the cooled in ice of 0.32 M sucrose solution containing 1 mm of pargyline, using a homogenizer Ultra-Turrax. The activity of monoamine oxidase is inhibited in the presence of pargyline. The homogenate cetrifugation at 1000×g for 10 minutes. The resulting supernatant is then centrifuged at 27000×g for 50 minutes and the supernatant discarded. The residue after centrifugation (R2) resuspending in oxygendemand (balanced in an atmosphere of 96% O2: 4% CO2for at least 30 minutes) incubation buffer Krebs-ringer (1000 ml per g of original tissue) at pH of 7.2, containing 122 mm NaCl, 0,16 mM EDTA (ethylenediaminetetraacetic acid), 4.8 mm KCl, 12.7 mm Na2HPO4, 3.0 mm NaH2PO4, 1.2 mm MgSO4, 1 mm CaCl2, 10 mm glucose and 1 mm ascorbic acid.

Analysis:Aliquots of 4.0 ml of the suspension fabric is added to 100 μl of test solution and 100 µl of the3H-5-1-HT (1 nm, final concentration), mixed and incubated for 30 minutes at 37°C. non-specific reuptake determined with the use of citalopram (10 μm, final concentration). After incubation, the sample was poured directly onto a glass-fiber filters Whatman GF/PAYG pressure. These filters are then washed three times with 5 ml chilled in ice with 0.9% (wt./about.) NaCl solution. The amount of radioactivity on the filters define the conventional method of registering a liquid scintillation. Specific reuptake calculated as the difference between total return capture and nonspecific reverse grip.

Must be achieved 25-75% inhibition of specific binding, and then calculate IC50.

The test value is given as IC50(the concentration (μm) test substance which inhibits the specific binding3H-5-HT by 50%).

The results of testing the compounds of the present invention are listed in the following next table.

Test connectionReuptake DA IC50(µm)Reuptake NA IC50(µm)The reuptake of 5-HT IC50(µm)
Exo-7-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-he0,150,690,0059
Exo-7-(8-H-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-he0,300,089 0,00052

Presented in the table results show that the compounds according to the invention effectively inhibit the reuptake of dopamine, norepinephrine and serotonin in the uptake.

1. The compound of the formula I

or any of its isomers or any mixture of its isomers,
or its pharmaceutically acceptable salt,
where R1represents hydrogen or alkyl;
R2and R3together form -(CH2)2-, and R2'and R3'represent hydrogen;
m is 1;
n = 1;
X represents-O-; and
Q represents chromen-2-one-7-yl, which is possibly substituted by one or more substituents independently selected from the group consisting of halogeno, trifloromethyl, triptoreline, piano, hydroxy, amino, nitro, alkoxy, cycloalkane, alkyl, cycloalkyl, cycloalkenyl, alkenyl and quinil.

2. Chemical compound according to claim 1, where R1represents hydrogen.

3. Chemical compound according to claim 1, where R1represents alkyl.

4. Chemical compound according to claim 1, which is a
Exo-7-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-he;
Exo-7-(8-H-8-Aza-bicyclo[3.2.1]Oct-3-yloxy)-chromen-2-he;
or its pharmaceutically acceptable salt.

5. Pharmaceutical composition having activity of inhibitors of reverse is the NAP monoamine neurotransmitters containing a therapeutically effective amount of a compound according to any one of claims 1 to 4 or any of its isomers or any mixture of its isomers, or its pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier, excipient or diluent.

6. The use of chemical compounds according to any one of claims 1 to 4 or any of its isomers or any mixture of its isomers, or its pharmaceutically acceptable salt for the manufacture of drugs, active reuptake inhibitors monoamine neurotransmitters.

7. The use according to claim 6 for the manufacture of pharmaceutical compositions for the treatment, prevention or relief of a disease or disorder, or condition of a mammal, including humans, and the disease, disorder or condition responsive to the inhibition of the reuptake monoamine neurotransmitters in the Central nervous system.

8. The use according to claim 7, where the disease, disorder or condition is a mood disorder, depression, atypical depression, secondary depression due to the pain, major depressive disorder, discomycetes disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, mood disorder due to General medical is skogo state, a mood disorder caused by substances, pseudodementia, syndrome Ganzera, obsessive-compulsive disorder, panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without panic disorder in disorder, acute anxiety condition, panic reaction, memory deficits, memory loss, attention deficit disorder with hyperactivity disorder, obesity, anxiety disorder generalized anxiety, eating disorder, Parkinson's disease, parkinsonism, dementia, senile dementia, senile dementia, Alzheimer's disease, dementia complex and acquired immunodeficiency syndrome, age-related memory dysfunction, specific phobia, social phobia, post-traumatic stress disorder, acute stress disorder, drug addiction, drug abuse, cocaine abuse, nicotine abuse, tobacco abuse, chronic alcoholism, alcoholism, pain, chronic pain, inflammatory pain, neuropathic pain, migrainebuy pain, headache busy type headache chronic type pain associated with depression, fibromyalgia, arthritis, osteoarthritis, rheumatoid arthritis, back pain, raculously, pain in irritable bowel, irritable bowel syndrome, post-operative pain, postmastectomy pain syndrome (PMPS), pain after stroke, neuropathy caused by medication, diabetic neuropathy, simpaticeskii supported by pain, trigeminal neuralgia, dental pain, myofascial pain, phantom pain, bulimia, premenstrual syndrome, syndrome, late luteal phase, post-traumatic syndrome, chronic fatigue syndrome, urinary incontinence, stress incontinence, nederzhanyem, nocturnal incontinence, sexual dysfunction, premature ejaculation, erectile difficulty, erectile dysfunction, premature female orgasm, a syndrome of "restless legs", disorders eating, mental anorexia, sleep disorders, profound developmental disorders, autism, Asperger syndrome, rett syndrome, disintegrative disorder of childhood, neobhodimosti, disorders of motor skills, mutism, trichotillomania, narcolepsy, depression after stroke, brain damage caused by stroke, neuronal damage due to impact, or disease, Gilles de La Tourette.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of diaryl compounds with formulae given below ,

.

, in which M is S(O)2, Rx represents alkyl, R1, R2, R3 and R4 are each independently selected from OH and -NR7S(O)2R8, R5 and R7 each independently represents hydrogen or alkyl, R8 is alkyl; and their pharmaceutically acceptable derivatives, as well as to pharmaceutical compositions containing said compounds and their use in making a medicinal agent with inhibitory activity on Aβ, IAPP amyloid fibrils or synuclein fibrils.

EFFECT: substituted n-arylbenzamide and related compounds for treating amyloid diseases and synucleinopathy are disclosed.

11 cl, 19 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new 8-aza-bicyclo[3.2.1]octane derivatives of formula I or any its isomer or mixed isomers, or their pharmaceutically acceptable salt, where Ra represents hydrogen; X represents -O-; Rb represents aryl or heteroaryl group chosen from phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl or quinazolinyl substituted with one or two substitutes independently chosen from group including: halogeno, trifluoromethyl, trifluoromethoxy, cyano, hydroxy and alkoxy provided that compound is not 3-(3-trifluoromethylphenoxy)-8-azabcyclo[3.2.1]octane, 3-(4-trifluoromethylphenoxy)-8-azabcyclo[3.2.1]octane, 3-(2-bromphenoxy)-8-azabcyclo[3.2.1]octane, 3-(4-chlorophenoxy)-8-azabcyclo[3.2.1]octane or 3-(4-fluorophenoxy)-8-azabcyclo[3.2.1]octane. Besides invention refers to pharmaceutical composition and application thereof.

EFFECT: production of new biologically active compounds characterised with monoamine recapture inhibiting activity.

6 cl, 1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention pertains to new hetero-aryl derivatives of 8-azabicyclo-[3.2.1]-octan-3-ol with general formula I where R-R4 represent hetero-aryl. The hetero-aryl is in form of a cyclic aromatic group with C5-C6 or a bicyclic group with C9-C10, which contain 1, 2 or 3 hetero atoms, independently O, S or N, or a residue of , R1-H, C1-C6-akyl, R2 and R3 independently CH3, -OCH3, F, Cl, Br, J, R4 - from 1 to 4 substitutes, -H, halogen, C1-C6alkyl, -CF3, -OCF3, -(CH2)n-OR5, -(CH2)n-NR5R6, -(CH2)n-NHSO2R5, -(CH2)n-NH(CH2)2NR5R6, -(CH2)n-NHC(O)NR5R7, -(CH2)n-NH(CH2)2OR5, or 1-piperazinyl; n - 0, 1, 2, 3; R5 and R6 - H, C1C3alkyl, R7-H, C1-C3alkyl, aminoalkyl C1-C3, or to their pharmaceutical salts. The compounds are antagonists of the nociceptin ORL-1 receptor.

EFFECT: obtaining of compounds that are useful in the treatment of cough.

10 cl, 22 ex, 1 tbl

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

The invention relates to therapeutic active usacycling or azabicyclic compounds, method of their preparation and to pharmaceutical compositions comprising these compounds

The invention relates to a derivative (azetidin-1-illlil)lactams of the formula (I) and their pharmaceutically acceptable salts, where R - (C1-C6)-alkyl, optionally substituted by-COOH, -COO((C1-C4)-alkyl), (C3-C7-cycloalkyl, aryl or het1and (C3-C7-cycloalkyl, optionally substituted with 1-2 substituents selected from (C1-C4)-alkyl and fluorine; R1is phenyl, optionally substituted by 1-2 halosubstituted; R2- -CONR3R4, -CONR5((C3-C7-cycloalkyl), -NR3R4that gets3or a group of formula (a), (b), (C); X - (C1-C4-alkylene; X1- directional communication, X2- directional communication or CO; m = 1; used in the treatment of diseases by producing antagonistic action on tachykinin, working in human NK1-, NK2- and NK3the receptor or in their combinations

The invention relates to derivatives of 3-(piperidinyl-1)-chroman-5,7-diol and 1-(4-hydroxyphenyl)-2-(piperidinyl-1)alkanol General formula I or their pharmaceutically acceptable salts accession acid, in which (a) R2and R5taken individually and R1, R2, R3and R4independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7and R5represents methyl; or (b) R2and R5taken together form a ring chroman-4-ol, a R1, R3and R4each independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7; R7represents methyl; and R6represents a substituted piperidinyl or 8-azabicyclo[3,2,1]octenidine derived; provided that (a) if R2and R5taken separately, at least one of R1, R2, R3and R4is not hydrogen; and (b) if R2and R5taken together, at least one of R1, R3and R4is not hydrogen, with the property that the NMDA antagonist

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of common formula (I) , in which: A, if available, means (C1-C6)-alkyl; R1 means group NR6R7, (C4-C7)-azacycloalkyl, (C5-C9)-azabicycloalkyl, besides, these groups, unnecessarily, are substituted with one or more substituents, selected from (C1-C5)-alkyl or halogen; A-R1 is such that nitrogen of radical R1 and nitrogen in position 1 of pyrazole are necessarily separated at least by two atoms of carbon; R3 means radical H, OH, NH2, ORc, NHC(O)Ra or NHSO2Ra; R4 means phenyl or heteroaryl, unnecessarily, substituted with one or more substituents, selected from halogen, CN, NH2, OH, ORc, C(O)NH2, phenyl, polyfluoroalkyl, linear or ramified (C1-C6)-alkyl, besides these substituents, unnecessarily, are substituted with halogen, and moreover, heteroaryl radicals are 3-10-member, containing one or more heteroatoms, selected from sulphur or nitrogen; R5 means radical H, linear or ramified (C1-C6)-alkyl; Ra means linear or ramified (C1-C6)-alkyl; Rc means linear or ramified (C1-C6)-alkyl, (poly)fluoroalkyl or phenyl; R6 and R7, independently from each other, means hydrogen, (C1-C6)-alkyl; R6 and R7 may create 5-, 6- or 7-member saturated or non-saturated cycle, which includes one heteroatom, such as N, and which, unnecessarily, substituted with one or more atoms of halogen; to its racemates, enantiomers, diastereoisomers and their mixtures, to their tautomers and their pharmaceutically acceptable salts, excluding 3-(3-pyridinyl)-1H-pyrazole-1- butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine. Invention is also related to methods for production of compounds of formula (I) and to pharmaceutical composition intended for treatment of diseases that appear as a result of disfunction of nicotine receptors α7 or favorably responding to their modulation, on the basis of these compounds.

EFFECT: production of new compounds and pharmaceutically acceptable composition on their basis, which may find application in medicine for treatment, prophylaxis, diagnostics and observance over development of psychiatric or neurological disorders or diseases of central nervous system, when cognitive functions deteriorate or quality of sensor information processing drops.

16 cl, 106 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new ester derivatives of 2-amino-bicyclo[3,1,0]hexane-2,6-dicarboxylic acid, with formula [I] or [II] and their pharmaceutical salts, with antagonistic properties towards II group metabotropic glutamate receptors. In general formulae [I] or [II] R1 and R2 are identical or different, and each stands for a C1-10alkyl group, or one of R1 or R2 is a hydrogen atom, and the other is a C1-10alkyl group, C2-10alkenyl group, C2-10alkynyl group, C1-10alkyl group, substituted with a phenyl group, possibly substituted with halogen atoms, C1-4alkyl group, C1-4 alkoxyl group; hydroxyC2-10alkyl group, halogenC1-10alkyl group, azidoC1-10alkyl, aminoC2-10alkyl, C1-10alkoxycarbonylC1-10alkyl group, farnesyl group, 4-morpholinyl-C1-10alkyl group, C1-10alkyl group, substituted with a group with formula -C(O)NRaRb (where Ra and Rb are identical or different and each represents a hydrogen atom or a C1-10alkyl group), or with a group with formula -CHRcOC(O)ZRd (where Z is an oxygen atom or a single bond; Rc represents a hydrogen atom, C1-10alkyl group or aryl group, chosen from phenyl and naphthyl, which can be substituted with a C1-4alkyl group or C1-4alkoxyl group), or substituted with a group with formula [i] [ii], (where Rd denotes the same as described above), or by a group with formula [ii]; X is a fluorine atom; and Y represents -OCHR3R4, -SR3, -S(O)nR5, -SCHR3R4, -NHCHR3R4, -N(CHR3R4)(CHR3'R4'), -NHCOR3 or -OCOR5 (where R3, R3', R4 and R4' are identical or different, and each represents a hydrogen atom, C1-10alkyl group, phenyl group, naphthyl group, phenyl group substituted with one-five substitutes, chosen from a group, consisting of a halogen atom, R5 represents a phenyl group, or a phenyl group substituted with one-five substitutes, chosen from a group, consisting of a halogen atom, and n is 1 or 2).

EFFECT: invented compounds can be used in treating and preventing mental illnesses, such as schizophrenia, anxiety and anxiety related diseases, depression, bipolar disorders and epilepsy, invention also pertains to a medicinal preparation.

30 cl, 5 tbl, 19 ex

FIELD: medicine, pharmacology.

SUBSTANCE: pharmaceutical mode of injection through mucosa has plain configuration comprising solid solution of bioactive substance in phosphatidylcholine fraction, in which residues of fatty acids are saturated at least for 90% and contain at least 80 wt % of phosphatidylcholine fraction.

EFFECT: regulated emission of great range of bioactive sunstances in oral mucosa.

10 cl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

EFFECT: obtaining solutions, which ca be used for treatment and prevention of diseases, mediated by activity of neuropeptide FF receptor.

6 cl, 4 tbl, 106 ex

FIELD: medicine.

SUBSTANCE: medicine containing eicosapentaenoic acid (EPA) is introduced in effective amount. Besides, EPA is applied to produce medicine for neuropsychic anorexia or bulimia.

EFFECT: possibility to use eicosapentaenoic acid in treatment of neuropsychic anorexia or bulimia.

22 cl, 1 tbl, 9 ex, 5 dwg

FIELD: medicine; psychiatry.

SUBSTANCE: method includes complex treatment of pathological drive to gaming. Electrophysiological examination and electroencephalography are carried out. Background record of electroencephalography (EEG) and electrooculography is performed while electrodes are arrayed under international scheme 10-20. After that patient plays computer game simulating slot for 5 minutes. Record is repeated, registered results are compared to those before game. Focus of paroxysmal activity is detected after specific load. If focus of paroxysmal activity is detected, antiparoxysmal therapy is prescribed as follows - Clonazepamum up to 2 mg a day, Finlepsin up to 600 mg a day, Depakine Chrono up to 1000 mg a day. Evident change of alpha activity after specific load detected is considered to be reason for choice of psychotherapy method.

EFFECT: method enables to develop readaptation and rehabilitation programs and to increase therapy efficiency; provides medical aid individualisation.

1 ex

FIELD: medicine; veterinary science.

SUBSTANCE: invention refers to application of compounds with common structural formula

R1=-H, -NH2, -Br, -Cl, -ОН, -СООН,

B=-N=, -CH=, Z=-CH=, -N=,

A=-CH- at B=-N=, Z=-CH-,

A=-CH- at В=-СН=, Z=-CH=,

A=-N= at B=-N=, Z=-CH-,

A=-CH- at B=-N=, Z=-N=,

A=-CH= at В=-СН=, Z=-N=.

Structures of specified formula are active for nitrergic and dopaminergic systems of mammal body including human body. These compounds can be applied as neuroprotectors, to improve cognitive function and to normalise psychophysiologic state, to treat consequences of substance abuse, as well as to treat wide range of diseases including neuropsychic, cardiovascular, immune, inflammatory and gastro-intestinal disorders.

EFFECT: application of new and well-known compound to effect nitrergic and dopaminergic systems for treatment purposes.

4 ex, 3 tbl, 8 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: invention group refers to compositions containing hapten-carrier conjugate within arranged and repeating matrix, and method of related composition production. Offered hapten-carrier conjugate used for induction of agent-specified immune reaction in case of addiction or abuse, contains cortex particle including at least one first apposition site, where specified cortex particle is virus-like particle of RNA-phage, and at least one nicotine hapten with at least one second apposition site, where specified second apposition site is associated by at least one covalent non-peptide bond with specified first apposition site, thus forming arranged and repeating hapten-carrier conjugate. Offered conjugates and compositions under this invention can include virus-like particles connected to various haptens including hormones, toxins and agent, especially agents causing addiction, as nicotine and can be applied for induction of hapten immune reaction for therapeutic, preventive and diagnostic purposes.

EFFECT: vaccines can induce stable immune reactions for nicotine and fast reduce nicotine availability for brain absorbing.

31 cl, 6 dwg

FIELD: medicine.

SUBSTANCE: invention refers to application of 17 alpha-acetate-21-pivaloat 17alpha, 21-dihydroxipregn-4-en-3.20 dion as an agent reducing pathological attraction to cocaine.

EFFECT: agent has high efficiency.

3 dwg, 2 ex

FIELD: medicine, narcology, pharmacy.

SUBSTANCE: invention proposes using flumazenil representing 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester for production of drug used in treatment of cocaine abuse, abstinence syndrome from cocaine and relapse of cocaine abuse. Agent is administrated in time periods from 1 to 15 min providing administration of from 0.1 to 0.3 mg of flumazenil that represents the therapeutically effective dose for treatment of cocaine abuse (variants), corresponding drugs (variants) of flumazenil and methods for treatment (variants). In this regimen in the dose 2 mg of flumazenil for less 1 h above 55% of gamma-glutamic acid receptors are occupied. Invention provides attenuation or removing symptoms of cocaine abuse and rapid recovery of psychophysiological functions.

EFFECT: valuable properties of drug and enhanced effectiveness of treatment.

29 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to an acid addition dopenzil salt [(±)-2-[(1-benzyl-4-piperidinyl)mathyl]-5,6-dimehoxy-1-indanone] of general formula (II), where X stands for a radical of fumaric acid prepared by reaction of dopenzil base and fumaric acid in ethanol or 2-propanol as a solvent, separation of dopenzil salt produced thereby and optionally washings with an organic solvent. The invention also concerns a pharmaceutical composition, the method of preparing the pharmaceutical compositions, application of acid addition dopenzil salt, and also the method for prevention or treatment of the diseases.

EFFECT: preparation of new acid addition dopenzil salt which is applicable for prevention or treatment of the diseases associated with acetylcholine lack in brain, Alzheimer's disease or senile psychosis.

8 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

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