Use ones receptor antagonists tachykinin

 

(57) Abstract:

The invention relates to pharmacology. A new antagonist binding tachykinin with receptors tachykinin. Such proposed known antiestrogen formula (I), where R1and R3independently represent a hydrogen atom, methyl, (C1-C6-alkyl) or , where Ar is optionally substituted phenyl; R2selected from the group comprising pyrrolidinone and piperidino; or its pharmaceutically acceptable salt. The invention expands the Arsenal of tools specified destination. 3 C.p. f-crystals, 9 PL.

Tachykinins are a family of peptides that contain a common sequence with amidinophenoxy terminal carboxyl group,

Phe-Xaa-Gly-Leu-Met-NH2,

which is denoted as the Sequence with the identification number 1. The first selected peptide of this family was substance P, however, obtain it in pure form and the determination of its primary structure was carried out only in the early 1970

Substance P has the following amino acid sequence

Aro-Pro-Lys-Pro-Gln-Gln-Pne-Gly-Leu-Met-NH2< / BR>
which is hereinafter referred to as Consequently is the bookmark of two new mammalian tachykinins, received at the present time, the name of neurokinin A (also known as substance K, neuromedin I and neurokinin ) and neurokinin B (also known as neuromedin K and neurokinin ). Cm. an overview about these discoveries in the publication of J. E. Maggio, Peptides, 6 (Supplement 3): 237 - 243 (1985). Neurokinin A has the following sequence of amino acids

His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-HN2,

which is denoted as the Sequence ID number 3. Structure neirokinina B is described by the following sequence of amino acids

Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-HN2,

which is denoted as the Sequence ID number 4.

Tachykinin part of both Central and peripheral nervous system, stand out from nerves and possess a wide spectrum of biological effects, which in most cases is determined by the activity of specific receptors located on the membrane of target cells. Tachykinin also selects the next renewaling tissues.

Tachykinin mammals, such as substance P, neurokinin A and neurokinin B exert their action through three major receptor subtypes, which denote respectively as NK-1, NK-2 is Otsego, participates in the transmission of nerve impulses pain, including pain caused by migraines and arthritis. These peptides are involved in gastrointestinal diseases and diseases of the gastrointestinal tract, such as inflammation of the bowel. Tachykinin participate in other diseases, which are discussed next.

Due to the large number of clinical conditions associated with an excess of tachykinins or inappropriate stimulation of the receptors of tachykinins, development of receptor antagonists tachykinin will contribute to the management of these clinical conditions. The earliest receptor antagonists tachykinin were peptide derivatives. These antagonists, appear to have limited pharmacological use, because they are not metabolically stable.

In short, the present invention is to declare the class of potential ones receptor antagonists tachykinin. Due to their ones the nature of the compounds of the present invention are devoid of those disadvantages associated with metabolic instability that is inherent in the known receptor antagonists tachykinin-based peptides.

The present isob methods consist in the appointment of a mammal, in need of such treatment, a necessary and sufficient amount of the compounds of formula (I):

< / BR>
where R1and R3independently represent a hydrogen atom, methyl, (C1-C6- alkyl) or , where Ar is optionally substituted phenyl;

R2selected from the group including pyrrolidine group, hexamethyleneimino group and piperidino group; or its pharmaceutically acceptable salts and its MES.

The present invention relates to the discovery that a certain group of benzothiophenes, namely the compounds of formula I which are useful as antagonists of the receptor tachykinin. The invention captures such ways that put into practice by assigning a mammal in need of treatment, the dose of the compounds of formula (I) or its pharmaceutically acceptable salt or MES, which is necessary and sufficient for inhibition of physiological disorders caused by an excess of tachykinins. The term inhibition is used in its usual sense, which includes preventive medicine is prescribed to the mammal or human, subject to a specified disorder, and control and/or treatment already developing disease. Prov.bsem case, the compound is mixed with conventional fillers, diluents or carriers and pressed in the form of tablets or prepared in the form of elixirs or solutions that are convenient for oral use, or injected intramuscular or intravenous. Connection, you can enter through the skin or be prepared in the form of dosage forms for permanent preparation, etc.

The compounds used in the methods of the present invention, can be obtained by known or analogous methods, for example, described in detail in U.S. patent numbers 4133814, 4418068 and 4380635, which are given here for reference. In General, the synthesis begins, based on the benzo[b] thiophene, 6-hydroxyl group and 2-(4-hydroxyphenyl)group. The original connection protects, alkylate and remove the protection with the compounds of formula (I). Examples for such compounds are given in U.S. patents listed above and in the examples given in this description. Optionally substituted phenyl includes phenyl substituted once or twice (C1-C6)alkyl, (C1- C4)alkoxy group, a hydroxyl group, a nitrogroup, a chlorine atom, a fluorine atom, or three(chlorine or fluorine)/stands.

The invention includes a compound called raloxifene, FORMOSAT pharmaceutically acceptable salt of Association with an acid or base with a wide range of organic and inorganic acids and bases and include the physiologically acceptable salts, which are often used in pharmaceutical chemistry. Such salts are also part of the present invention. Typical inorganic acids used for the formation of such salts include hydrochloric, Hydrobromic, idiscovered, nitric, sulfuric, phosphoric, hypophosphorous acid, etc. Can also be used salts derived from organic acids such as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate acid and hydroxycarbonate acids, aromatic acids, aliphatic and aromatic sulfonic acids. These pharmaceutically acceptable salts thus include acetates, phenylacetate, triptoreline, acrylates, salts of ascorbic acid, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, acetoxybenzoic, salt, naphthalene-2-benzoic acid, bromides, isobutyrate, phenylbutyrate, beta-oxybutyrate, salt Butin-1,4-dinoboy acids, salts and hexyne-1,4-dinoboy acid, salts of capric acid, salts of Caprylic acid, chlorides, salts of cinnamic acid, citrate, formate, fumarate, salts of glycolic acid, salts of heptane acid, salt of hippuran is s, salts of malonic acid, salt, almond acids, salts meticilous acids, salts of nicotinic acid, salts of ISO-nicotinic acid, nitrates, oxalates, phthalates, terephthalate, phosphates, monohydrogenphosphate, dihydrophosphate, metaphosphates, pyrophosphates, salt propyl acid, salts of propionic acid, salts of phenylpropionic acid, salts of salicylic acid, salt sabatinovka acid, salts of succinic acid, salt, cork acid, sulphates, bisulfate, persulfate, sulfites, bisulfite, sulfonates, bansilalpet, p-bromophenylacetate, chlorobenzenesulfonate, econsultancy, 2-oxetanemethanol, methansulfonate, naphthalene-1-sulfonates, naphthalene-2-sulfonates, p-toluensulfonate, cellsurface, salts of tartaric acid, etc. are Preferred salts are the chlorides.

Pharmaceutically acceptable acid additive salts are usually obtained by the interaction of the compounds of formula I with an equimolar or excess amount of acid. The reagents are usually mixed in a suitable for both components a solvent such as diethyl ether or benzene. The salt normally precipitates out of solution within about one hour to 10 hours and can be isolated by filtration or solvent which are ammonium hydroxide and the hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals, as well as aliphatic and aromatic amines, aliphatic diamines and hydroxyethylamine. The Foundation is particularly useful for obtaining salts of joining include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, Ethylenediamine, cyclohexylamine and ethanolamine.

Pharmaceutically acceptable salts usually have high solubility in comparison with the connection from which they were formed, and often more than useful for preparing compounds in the form of liquids or emulsions.

The pharmaceutical compositions can be prepared by known methods. For example, the compounds can be mixed with conventional fillers, diluents, carriers and form in the form of tablets, capsules, suspensions, powders, etc., Examples of binders, diluents, and carriers that are suitable for the preparation of such compositions are the following: binders and inert fillers such as starch, sugars, mannitol, and derivatives of silicic acid; binders, such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; humectants, such kakaka as paraffin; substances that promote rapid absorption, such as Quaternary ammonium compounds; surface active agents such as cetyl alcohol and glycerol monostearate; sorbentia carriers such as kaolin and bentonite; and lubricants used in the preparation of tablets, such as talc, stearates of calcium and magnesium and glycols.

Compounds can also be in the form of elixirs or solutions suitable for oral use, or solutions for parenteral purposes, for example, intramuscular, subcutaneous or intravenous. Further compounds useful for preparing dosage forms, providing slow allocation of the drug, etc., Such compositions can be prepared in such a way that they release the active ingredients in a specific location in the gastrointestinal tract or through a certain period of time. Coatings, envelopes, and protective matrices for them can be made, for example, polymeric substances or waxes.

The specific dose of a compound according to formula (I) in accordance with the present invention will depend on the severity of the condition, the route of administration and other related factors will be Opredelitel 1000 mg/day, more typically from about 50 to about 200 mg/day. These doses can be assigned to a patient requiring such treatment, from one to three times daily, or more often if necessary.

Often desirable to assign the connection according to the formula /I/ in the form of an acid additive salt that is common with the introduction of pharmaceuticals containing group having the properties of a base, for example piperidine ring. For this there are the following dosage forms.

Compounds

The following compounds "active ingredient" means a compound according to the formula /I/.

Composition 1. Gelatin capsules (see tab. 1).

The ingredients are mixed, sieved through a sieve of 45 mesh and fill in a shell of solid gelatin.

Examples prepared with specific compositions in the form of capsules connections raloxifene presented in table. 2 - 5.

Part 2: raloxifene capsule (see tab. 2).

Part 3: raloxifene capsule (see tab. 3).

Part 4: raloxifene capsule (see tab. 4).

Part 5: raloxifene capsule (see tab. 5).

The specific formulations described above can be changed is gradient.

Part 6: tablets (see tab. 6).

The components are mixed and pressed to form tablets. Another way tablets containing from 0.1 to 1000 mg of active ingredient, are prepared as follows:

Part 7: tablets (see tab. 7).

The active ingredient, starch, talc and cellulose sieved through a sieve of 45 mesh and thoroughly mixed. To the resulting mixture of powders was added a solution of polyvinylpyrrolidone and again sieved through a 14 mesh sieve. The obtained granules are dried at 50 - 60oC and sieved 18 mesh. To the obtained granules was added sodium carboxymethyl cellulose, magnesium stearate and talc, previously sifted through a sieve of 60 mesh, and after the mixture is pressed in a special car, getting pills.

Suspensions, each of which contains 0.1 to 1000 mg medical devices in 5-ml dose, receive the following way:

Part 8: suspension (see tab. 8).

The drug is sieved through a sieve of 45 mesh and mixed with the sodium salt of carboxymethyl cellulose and syrup to form a homogeneous paste. Add with stirring a solution of benzoic acid, fragrance and dye, diluted with a little water. Then PR is dinani of the present invention appreciate that using primary tests that will allow you to quickly and accurately measure the binding of the tested compounds with known cellular receptors NK-1. The tests that can be used to assess receptor antagonists tachykinin, well known from the art. See, for example, J. Jukic et al. Life Science, 49: 1463 - 1469 (1991); N. Kucharczyk et al., Journal of Medical Chemistry, 36: 1654 - 1661 (1993); N. Roussi et al., Biochemical and Biophysical Research Communications, 176: 894 - 901 (1991).

Analysis of the binding of the receptor NK-1

Analysis of the binding of the receptor with the use of radioactive labels spend a few altered the previously known technique described in the publication of D. G. Payn et al, Journal of Immunology, 133; 3260 - 3265 (1984). To bring this analysis take aliquot sample of cells 1M9 (1 OF 106cells in the test tube with the medium RPM1 1640 containing 10% fetal serum cows) and incubated for 45 min at a temperature of 4oC in an incubator with 20 mm labeled with 125I substance P in the presence of increasing concentrations of competitor.

Cell line M well described and is easily accessible cell line human. See, in particular, Annals of the New York Academy of Science, 190: 221 - 234 (1972); Nature (London), 251: 443 - 444 (1974); Proceedings of the National Academy of Science USA) 71: 84 - 88 (1974). E. the fruit of the cow.

The reaction is interrupted by the filter in the sampler, equipped with a glass fiber filter, pre-soaked for 20 min in 0.1% solution of polyethylenimine. Specific binding containing the label substance P is determined in the presence of not containing the label of the ligand.

Analysis of the binding of the receptor NK-2

Cells CHO-hNK-2R, obtained from the cell line transformed with the receptor PC-2, containing about 400,000 of these receptors on the cell, grown in flasks or roller bottles with a capacity of 75 ml in a minimum quantity of the nutrient medium (alpha modification) with 10% fetal serum cows. The genetic sequence of the receptor NK-2 are presented in the publication N. P. Gerard et al., Journal of Biological Chemistry, 265, 20455 - 20462 (1990).

For preparation of membrane preparations share 30 confluent cultures in roller bottles by washing each roller bottle 10 ml of saline solution, Dulbecco containing phosphate buffer without calcium ions and magnesium, and then add 10 ml containing no enzyme solution separated cells (based salt solution containing phosphate buffer supplied by the firm "Specialty Media Inc"). After another 15 min OTDELENIE the drugs are prepared by homogenization for 10 15 tablets of cells in 380 ml of 40 mm Tris buffer pH 7.4 in a Tekmar homogenizerand then centrifuged for 30 min with a speed of 12,000 rpm (20000 g) on the rotor JA-14company "Beckman". Tablets are washed by the above mentioned method and re-suspended in 100 to 120 ml of 50 mm Tris buffer with a pH of 7.4, take an aliquot of 4 ml and store them frozen at minus 70oC. the Concentration of protein in these preparations is 2 mg/ml

To analyze the binding of one receptor 4-ml aliquot of membrane preparation CHO-hNK-2R suspended in 40 ml of the tested buffer solution containing 50 mm Tris pH 7.4 and add 3 mm of magnesium chloride, 0.02% of bovine serum albumin and 4 μg/ml of hemostatis. For analysis using 200 µl of homogenizate (40 μl protein) for each analysis. As containing radioactive labeled ligand using [125I]-itogether-neurokinin A (New England Nuclear", NEX-252) with an activity of 2200 CI/mmol; final concentration in each assay is 20 PM. The nonspecific binding determined using 1 μm eledoisin. To plot a standard curve of the axes of the concentration-response use ten different concentrations of e is 10 ál of dimethyl sulfoxide in the case of a tender or 5 ál of dimethyl sulfoxide in the case of determination of the value of the IC50. Order supplements when conducting incubation 190 or 195 ál used for analyzing buffer, 200 µl of homogenizate, 10, or 5 ál of sample in dimethyl sulfoxide, 100 μl of the ligand with a radioactive label. The sample was incubated for 1 h at room temperature, and then filtered in 48 cells cell sampler company "Brandel through filters, GF/B, which are pre-soaked for two hours in 50 mm Tris buffer with a pH of 7.4, containing 0.5% bovine serum albumin. The filter three times washed with approximately 3 ml of cold 50 mm solution of Tris buffer with a pH of 7.7. Then mugs filters perforined in 12 x 75 mm tubes made of polystyrene and is placed in the count of gamma radiation.

The usefulness of the described compounds is illustrated by activity in at least one of the above tests.

Since the compounds of formula I are effective antagonists of the receptor tachykinin, these compounds are of value in the treatment of a wide range of clinical conditions caused by excess tachykinin. Thus, in the present invention claimed methods of treatment or prevention of physiological disorders associated with an excess of tachykinins, which are destinations is asepticheski acceptable salt, the MES or predecessor medicines. The term "physiological disorder caused by excess tachykinin" includes disorders caused by inappropriate stimulation of the receptors tachykinin, regardless of the actual content tachykinin present in this place.

These physiological disorders can include Central nervous system disorders, such as pathological fear, depression, psychosis and schizophrenia; neurodegenerative diseases such as dementia, including senile dementia of the Alzheimer's type, Alzheimer's disease, dementia caused by AIDS, and the disease syndrome; diseases caused by destruction of the myelin nerve fiber layer, such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological diseases such as diseases of the peripheral nervous system, such as diabetic and chemotherapy caused by neuropathy and post herpetic and other neuralgia, diseases, associated with acute and chronic respiratory diseases, such as respiratory distress syndrome in adults, focal pneumonia, bronchial spasms, chronic bronchitis and asthma; inflammatory sanctifieth, vernal conjunctivitis, etc. ; skin diseases such as psoriasis, contact dermatitis, diffuse neurodermatitis, urticaria and other eczematoid dermatitis; drug diseases such as alcoholism; stress-induced somatic disease; reflex sympathetic dystrophy such as the syndrome of the shoulder-hand; estimatesa disorders; adverse immunological reactions such as rejection of transplanted tissues, disorders of the gastrointestinal tract and diseases associated with neural control of internal organs, such as ulcerative colitis, granulomatous disease and mucous colitis; disorders of bladder, such as hyperreflexia of the bladder and incontinence; disorders of the circulatory system associated with diseases involving the expansion and contraction of blood vessels, such as angina, migraine, symmetrical gangrene; and pain reception, for example, related to or associated with any of the previously mentioned conditions, in particular with the transmission of pain in migraine. For example, the compounds of formula (I) can be usefully applied in the treatment of Central nervous system diseases, such as pathological fear, d is a; respiratory diseases such as bronchial spasms and asthma; inflammatory diseases such as arthritis and inflammation of the intestine; adverse immunological reactions such as rejection of transplanted tissues; disorders of the gastrointestinal tract and diseases associated with neural control of internal organs, such as ulcerative colitis, granulomatous disease and mucous colitis; incontinence; disorders of blood circulation organs, accompanied by dilation of blood vessels; and pain reception, for example, related to or associated with any of the above conditions or the transmission of pain in migraine.

For example, antagonists of NK-1 is the most preferred in the treatment of pain, especially chronic pain, such as neuropathic pain, postoperative pain and migraine, pain caused by arthritis, pain caused by cancer, chronic lower back pain, migraine head, hermetic neuralgia, phantom of the disease, pain in the Central nervous system, dental pain, neuropathic pain, pain of internal organs, pain during surgery, pain in bone injuries, pain in childbirth, in pain from burns, postpartum pain, stenokardicheskie the texts NK-1 is especially preferred in the treatment and prevention of urinary incontinence; disorders of contractile function of the gastrointestinal tract, mucous colitis; diseases associated with acute and chronic respiratory diseases such as bronchial spasms, chronic bronchitis, asthma, and respiratory distress syndrome; inflammatory conditions, such as inflammation of the bowel, ulcerative colitis, granulomatous disease, neurogenic inflammation, Allergy, rhinitis, cough, urticaria, conjunctivitis, irritation, caused by the failure; the rejection of transplanted tissues; the allocation of plasma caused by chemotherapy with the use of cytokinins, etc.; spinal cord injuries; cerebral attacks; Alzheimer's disease; Parkinson's disease; multiple sclerosis; amyotrophic lateral sclerosis; schizophrenia; pathological fear, and depression.

Antagonists of NK-2 is most preferred in the treatment of urinary incontinence, acute bronchial asthma, respiratory distress syndrome in adults, disorders of contractile function of the gastrointestinal tract, such as mucous colitis, and pain.

1. The use of compounds having the formula

< / BR>
where R1and R3independently represent a hydrogen atom, methyl, (C1-C6-alkyl) or , where Ar is Gruppo,

or its pharmaceutically acceptable salt as antagonist binding tachykinin with receptors tachykinin.

2. Application under item 1, in which the specified connection is present in the form of its hydrochloric salt.

3. Application under item 1, where the specified destination is preventive.

4. Application under item 1, in which the specified connection represents a connection

< / BR>
or its hydrochloric salt.

 

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21 cl, 6 sch, 1 tbl, 153 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds including all its enantiomeric and diastereomeric forms, and to their pharmaceutically acceptable salts wherein indicated compound corresponds to the formula: wherein A represents a conformationally limited ring system chosen from the group comprising the following formulae: (a) (d) and (e) wherein carbon atoms labeled by asterisks can be in any stereochemical configuration or their mixtures wherein Y has a formula: -(CH2)b-R15 wherein index b = 1-4, and R15 represents -OH, -NH2, guanidine-group, and Z has a formula: wherein R represents hydrogen atom; R9 represents naphthylmethyl; R10 represents -C(X)N(R16)2 wherein each R16 represents independently hydrogen atom or (C1-C10)-alkyl; X represents oxygen atom; or Z represents naphthylmethyl wherein W has a formula: wherein R represents phenyl substituted optionally with halogen atom of OH-group wherein fragment L is chosen from the group comprising: -NH- or -NHC(O)-; B represents hydrogen atom of fragment of the formula: wherein fragments R2, R3 and R4 are chosen independently among the group comprising hydrogen atom, -NHC(O)CH3, benzyl substituted optionally with hydroxy-group or halogen atom, imidazolylmethyl; or fragments R2, R3 and R represent in common naphthalinyl or isoquinolinyl; or one radical among R2, R3 and R4 represents hydrogen atom and two radical among R, R3 or R4 chosen in common form piperidine ring or tetrahydroisoquinoline ring substituted optionally with the group -C(O)CH3. Also, invention relates to a pharmaceutical composition possessing the agonistic activity with respect to MC-3/MC-4 receptors based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of disorders mediated by function of MC-3/MC-4 receptors.

EFFECT: valuable medicinal properties of compounds and compositions.

17 cl, 14 tbl, 12 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzofuran of the formula (1): wherein R represents L; R1 represents 2-R2-5-R3-pyrrol-1-yl-carbonyl, -CON(C2H5)2, -CON(CH2C6H5)2, -CON[CO2C(CH3)2]2; L represents bromine atom (Br); R2 and R3 in each case and independently of one another represent alkyl comprising 1-6 carbon (C)-atoms, and to their salts also. These compounds are intermediate substances used in synthesis of medicinal preparations showing effect on the central nervous system, for example, 1-[4-(5-cyanoindole-3-yl)butyl]-4-carbamoylbenzofuran-5-yl)piperazine. Invention provides synthesis if new intermediate compounds allowing synthesis of medicinal preparations such as 1-[4-(5-cyanoindole-3-yl)butyl]-4-carbamoylbenzofuran-5-yl)piperazine by the available method.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

4 cl, 8 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

FIELD: pharmacy.

SUBSTANCE: invention proposes pharmaceutical compositions consisting of multiple particles with sustained-release of serotonin reuptake selective inhibitor (SRSI) with membrane cover comprising ammonium-methacrylate copolymer, or compositions comprising SRSI particles mixture, or compositions comprising SRSI particles mixture in form of sustained-release of SRSI, Also, invention relates to method for treatment of depression involving administration of these compositions. In particular, SRSI represents fluoxetine, fluvoxamine, sertraline or their salt. Proposed compositions provide a less index of fluctuations that reflects lower values of maximal concentrations of substance in plasma blood after multiple administrations, safety and good tolerance also.

EFFECT: improved medicinal and pharmaceutical properties of compositions.

11 cl, 5 dwg, 26 tbl, 6 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to heterocycle-substituted tricyclic compounds of the formula (I): or their pharmaceutically acceptable salts wherein R means hydrogen atom; R1 and R2 are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R3 means hydrogen atom; n1 and n2 = 0-3 independently under condition that they both do not mean 0; Het means pyridyl wherein pyridyl is added to B through cyclic carbon atom and it comprises from 1 to 4 substitutes (W) chosen independently from group comprising -NR4R5, -NHCOR26, -NHSO2R16; R21 means aryl and R21 means heteroaryl wherein heteroaryl represents furyl, thienyl, pyridyl, thiazolyl, pyrrolidinyl, azethidinyl; R4 and R5 mean hydrogen atom or alkyl comprising 1-6 carbon atoms, or R4 and R5 mean in common -(CH2)3-, -(CH2)4-, -(CH2)5- or -(CH2)2NR7-(CH2)2- wherein R7 means hydrogen atom or alkyl comprising 1-6 carbon atoms; R8, R, R10 and R11 mean hydrogen atom; B means -(CH2)n4CR12=CR12a(CH2)n5 wherein n4 and n5 = 0-2 independently; R12 and R12a are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R21 means from 1 to 3 substitutes chosen independently from group comprising hydrogen atom, trifluoromethyl, trifluoromethoxy, halogen atom, cyano, alkyl comprising 1-6 carbon atoms, alkoxy group comprising 1-6 carbon atoms, or -CR29(=NOR28); R22 means -COR23, -S(O)R31, -S(O)2R31 or -COOR27; R23 means cycloalkyl comprising 3-7 carbon atoms, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, cycloalkyl comprising 3-7 carbon atoms containing from 1 to 3 substitutes chosen from group comprising halogen atom, (C1-C3)-alkoxy-(C1-C3)-alkyl, hydroxy group and alkoxy group comprising 1-6 carbon atoms, aryl, aryl-(C2-C6)-alkyl; R27 means alkyl comprising 1-6 carbon atoms, phenyl or benzyl; R28 and R29 are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R31 means alkyl comprising 1-6 carbon atoms, halogenalkyl comprising 1-6 carbon atoms, aryl, aryl-(C1-C6)-alkyl. Also, invention relates to pharmaceutical compositions containing these substances and their using for preparing a drug used in treatment of thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, heart failure and cancer.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 11 tbl, 9 ex

FIELD: medicine; pharmacology.

SUBSTANCE: combined preparation includes an inhibitor of repeated absorption of the serotonin, representing fluoxetine, and the antagonist of a 5NT1a-receptor chosen from group, which make N-[2[4(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinilcyclohexancarboxamide and (R)-N-(2-methyl-(4-indolil-1-piperazinyl)ethyl)-N-(2-pyridinil) cyclohexancarboxamide, in therapeutically effective amounts.

EFFECT: treatment of thermoregulation function disorders at patients that cannot be exposed to ways of medical influence on the basis of steroids.

2 cl, 5 ex, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns compounds with inhibition effect on thrombocyte aggregation, their pharmaceutically acceptable salts, particularly compounds of general formula (I) (where R1 is C1-C6 alkyl etc., R2 is hydrogen, C2-C7 alkanoyl, C7-C11 arylcarbonyl, group of formula R4-(CH2)1- etc., R3 is C6-C10 aryl etc., X1, X2, X3, X4 and X5 are independently hydrogen, halogen etc., and n is an integer from 0 to 2), its pharmaceutically acceptable salts. Invention claims pharmaceutical compositions inhibiting thrombocyte activation and containing claimed compounds as agent.

EFFECT: obtaining compounds applicable as media of prevention and treatment of diseases related to thrombo- or embologenesis.

26 cl, 272 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula (I) , in which Ar is furanyl, thiophenyl, thiazolyl, pyridinyl; R1 is independently chosen from a group consisting of hydrogen, lower alkyl, lower alkoxy, halogen and nitro; R2 is independently chosen from a group consisting of hydrogen and halogen; R4 is hydroxyl or residue of pyrrolidine-2-carboxylic acid, piperidine-2-carboxylic acid or 1-aminocyclopentane carboxylic acid, bonded through a nitrogen atom of an amino acid residue; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; p is 0, and s is 0, or to their pharmaceutically acceptable salts, under the condition that, the compound is not S-1- [5-(biphenyl-4-yloxymethyl)furan-2-carbonyl]pyrrolidin-2-carboxylic acid, 5-(biphenyl-4-yloxymethyl)furan-2-carboxylic acid, 3-(biphenyl-4-yloxymethyl)benzoic acid, 2-(biphenyl-3-yloxymethyl)benzoic acid, 4-(biphenyl-3-yloxymethyl)benzoic acid, 4-(biphenyl-4-yloxymethyl)benzoic acid, 5-(biphenyl-4-yloxymethyl)thiophene-2-carboxylic acid. Invention also relates to a pharmaceutical composition based on formula (I) compounds, which stimulates glycogen synthase activity.

EFFECT: wider range of use of the compounds.

27 cl, 34 ex, 8 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered: the use of (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide (Ramelteon) in combination with one or more drug substances chosen from fluoxetine, sertraline, paroxetine, mianserine, milnacyprane, cytalopram, escytalopram, fluvoxamine, minaprine, duloxetine, venlafaxine, imipramine, clomipramine, doxepine, trazodone, nephazodone, amitriptyline, carbamazepine, mirtazapine, diazepam, flutazolam, lorazepam, buspirone, tandospirone, ethyl loflazepat, flutoprazepam, mexazolam, clothiazepam, ethizolam, hydroxysine, alprazolam, fludiazepam, chlorodiazepoxide, cloxazolam, clorazepat and oxazolam for making a pharmaceutical composition for prevention or treatment of depression or anxiety disorder, for prevention or treatment of depression or anxiety disorder in the patients with underlying diabetes, hyperlipidemia, hypertension or metabolic syndrome, as well as appropriate methods of treating.

EFFECT: intensified effect of diazepam or paroxetine in joint administration with Ramelteon with no adverse reactions.

4 cl, 14 dwg, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described 3,4-substituted piperidines applicable in diagnostics and drug therapy of a warm-blooded animal, preferentially for therapy of a disease which depends on renin activity; application of a compound of such kind for preparing a pharmaceutical composition for therapy of the disease which depends on renin activity; application of the compound of such kind for therapy of the disease which depends on renin activity; the pharmaceutical compositions containing 3,4-substituted piperidine, and/or a therapeutic mode involving administration of 3,4-substituted piperidine, a method for producing 3,4-substituted piperidine. The preferential compound (which also can be presented in the form of salts) are described by formula I' wherein R1, R2, T, R3 and R4 are such as described by the patent claim.

EFFECT: production of the compounds for therapy of the disease which depends on renin activity.

28 cl, 1 tbl, 375 ex

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