Non-peptide antagonists gnrh

FIELD: chemistry.

SUBSTANCE: invention pertains to non-peptide antagonists GnRH, with general formula 1 , where each of A1, A2 and A3 are independently chosen from A5 and A6; and A4 represents either a covalent bond, or A5; under the condition that, if A4 is a covalent bond, then one of A1-A3 represent A6, and the other two represent A5, and that, if A4 represents A5, then all of A1-A3 represent A5; A5 is chosen from C-R13 and N; A6 is chosen from N-R14, S and O; R1 is chosen from H, NHY1 and COY2, and R2 represents H; or and R1, and R2 represents methyl or together represent =O; each of R3, R4 and R5 independently represents H or low alkyl; each of R6, R7, R8, R9, R10, R11 and R12 are independently chosen from H, NH2, F, CI, Br, O-alkyl and CH2NMe2; R13 is chosen from H, F, CI, Br, NO2, NH2, OH, Me, Et, OMe and NMe2; R14 is chosen from H, methyl and ethyl; W is chosen from CH and N; X is chosen from CH2, O and NH; Y1 is chosen from CO-low alkyl, CO(CH2)bY3, CO(CH2)bCOY3 and CO(CH2)bNHCOY3; Y2 is chosen from OR15, NRI6R17 and NH(CH2)cCOY3; Y3 is chosen from alkyl, OR15 and NR16R17; R15 represents H; each of R16 and R17 is independently chosen from H, low alkyl and (CH2)aR18, or together represent -(CH2)2-Z-(CH2)2-; R18 is chosen from OH, pyridyl, pyrizinyl and oxadiazolyl; Z represents NH; a represents 0-4; and b and c represent 1-3. The invention also relates to use of formula 1 a compound as a therapeutic agent and pharmaceutical composition, with antagonistic effect to GnRH receptor. Description is also given of the method of obtaining compounds with the given formula.

EFFECT: obtaining new compounds, with useful biological properties.

27 cl, 70 ex

 

The present invention relates to a group of compounds that act as antagonists of the GnRH receptor. These compounds are useful in the treatment of endometriosis and hormone-dependent cancers and in the regulation of ovulation in the protocols of in vitro fertilization.

Prior art

Gonadotropin-releasing hormone (GnRH, also known as hormone-releasing factor, luteinizing hormone, LHRH) is Decapeptide hormone-containing substances that occur in the hypothalamus. After release he is transported to the pituitary gland, where it causes the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These two hormones then act on the ovaries (in women) or testicles (in men). They regulate follicle Genesis and ovulation in women and the release of steroid hormones in both men and women.

It is widely known that excessive secretion of steroid hormones can be harmful to health. For example, some tumors (such as breast cancer or prostate cancer and endometriosis caused by high levels of steroids. Therefore, agents that modulate the system of the hypothalamic-pituitary-sex glands, are of therapeutic interest. The first clinically used compounds represented super-agonists GnRH. They are analogues of GnRH, which retain all biological d is istia native hormone, but they are administered in such a way as to cause chronic activation of GnRH receptors. For several days this chronic activation negative negative regulation of receptor-mediated signal transduction and falling levels of FSH and LH. The disadvantage of these agents is that for the first few days they cause overproduction FSH and LH, which may cause allergic reactions ("flare" reaction). Therefore, attention was focused on the development of GnRH antagonists. Modification of the peptide sequence led to the discovery of a number of peptide antagonists, which are currently undergoing clinical trials. However, since these compounds are peptides, they should be administered parenterally (usually by subcutaneous or intramuscular injection). These compounds are also relatively expensive to manufacture and cleaning. Thus, there is a need in therapeutically effective ones the GnRH antagonists and, especially, the compounds that can be administered orally and which are inexpensive.

Brief description of the invention

Here are described a number of arylsulfonamides that are potent and selective antagonists of the GnRH receptor. Accordingly, in the first aspect of the present invention proposed connections, which represent the th derivative of General formula 1, and their pharmaceutically acceptable salts.

In this General structure, each And1-And3can be selected from And5and6where And5can be either =CR13-or =N-, and6can be a-NR14-, -O - or-S-. And4can be either a covalent bond or A5. If a4is a covalent bond, so that the ring, which includes And1-And4represents a five-membered ring, one of the A1-And3must be a6and the other two must represent And5. If a4represents A5so that this ring is a six-membered ring, And all1-And3must be a5. The group R1can be selected from H (hydrogen atom), NHY1and COY2. In any of these cases, R2represents N. Alternative and R1and R2can be a methyl group, or together may represent a =O to form a carbonyl group. Each of the groups R3, R4and R5independently selected from H, groups representing lower alkyl and lower alkenyl. Each of the groups R6, R7, R8, R9, R10, R11and R12Nezavisimaya from N, groups representing lower alkyl, lower alkenyl, NH2, halogen (F, Cl and Br), O-alkyl, O-lower alkyl, O-lower alkenyl, CH2NMe2and CF3. The group R13selected from H, F, Cl, Br, NO2, NH2HE, Me, Et, OMe, NMe2and CF3. The group R14selected from H, methyl and ethyl. W is selected from =CH - and =N-. X is selected from CH2, O, S, SO2, NH, groups representing N - lower alkyl and N - lower alkenyl. Group Y1selected from - lower alkyl, CO - lower alkenyl, (CH2)bY3, CO(CH2)bCOY3and CO(CH2)bNHCOY3where b means 1-3. Group Y2selected from OR15, NR16R17and NH(CH2)cCOY3where means 1-3. Group Y3selected from alkyl, lower alkenyl, OR15and NR16R17. The group R15selected from H, lower alkyl, lower alkenyl and (CH2)aR18where a represents 0-4. Each of the groups R16and R17independently selected from H, lower alkyl and (CH2)aR18or together they represent -(CH2)2-Z-(CH2)2-. The group R18HE is a, phenyl group or an aromatic heterocycle selected from pyridyl, pyrimidinyl, pyrazinyl, furil, teinila, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, triazolyl, Arcadia olila and thiadiazolyl, each of them may possibly have a Deputy representing a group of lower alkyl or alkenyl. Z is selected from O, CH2, S, SO2, NH, N - lower alkyl and N - lower alkenyl.

In other aspects of the present invention proposed a pharmaceutical composition in which one of the active agents is a compound of General formula 1, the use of compounds of General formula 1 for preparing such pharmaceutical compositions and methods of treatment of certain medical conditions.

Detailed description of the invention

In the first aspect of the present invention proposed compounds that are derivatives of General formula 1

The ring includes A1-And4represents a five - or six-membered carbocyclic or heterocyclic group. The circumference of the points within this group is intended to show that the ring contains appropriate to the aromatic ring of a certain size, the number of single and double bonds, namely two double bonds and three single bond for five-membered ring and three double bonds and three single bond for six-membered rings. Under certain conditions, depending on the nature And4each And1-And3can be selected from And5and6where And5m which can be either =CR 13-or =N-, and6can be a-NR14-, -O - or-S-. And4can be either a covalent bond or A5. If a4is a covalent bond, so that the ring, which includes And1-And4represents a five-membered ring, one of the A1-And3must be a6and the other two must represent And5. If a4represents A5so that this ring is a six-membered ring, And all1-And3must be a5. These limits take into account that the ring has one of the following four partial structures:

For partial structures 2-4 two groups, presents And5are independent from each other, so that both can be a =N - or =CR13or one can be a =N-, and the other =CR13-. Similarly, in the partial structure 5 four groups, presents And5are independent, so that all groups can be a =N, all groups can be a =CR13-or from one to three groups can be a =N, a remaining =CR13-. In addition, if =CR13- appears in the connection more than once, the value of R13whenever does not depend on the other is H. In all cases 1,3-bond between the carbonyl and aminomethyl substituents is stored.

The group R1can be selected from H (hydrogen atom), NHY1and COY2. In any of these cases, R2represents N. Alternative and R1and R2can represent methyl or together may represent a =O to form a carbonyl group.

Each of the groups R3, R4and R5independently selected from H, groups representing lower alkyl and lower alkenyl.

Each of the groups R6, R7, R8, R9, R10, R11and R12independently selected from H, groups representing lower alkyl and lower alkenyl, NH2, halogen (F, Cl and Br), O-alkyl, CH2NMe2and CF3.

The group R13selected from H, F, Cl, Br, NO2, NH2HE, Me, Et, OMe, NMe2and CF3.

The group R14selected from H, methyl and ethyl.

W is selected from =CH - and =N-.

X is selected from CH2, O, S, SO2, NH, N - lower alkyl and N - lower alkenyl.

Group Y1selected from - lower alkyl, CO - lower alkenyl, CO(CH2)bY3, CO(CH2)bCOY3and CO(CH2)bNHCOY3where b means 1-3.

Group Y2selected from OR15, NR16R17and NH(CH2)cCOY3where means 1-3.

Group Y3selected from lower al the sludge, lowest alkenyl, OR15and NR16R17.

The group R15selected from H, lower alkyl, lower alkenyl and (CH2)aR18where a represents 0-4.

Each of the groups R16and R17independently selected from H, lower alkyl, lower alkenyl and (CH2)aR18or together they represent -(CH2)2-Z-(CH2)2-.

The group R18HE is a, phenyl group or an aromatic heterocycle selected from pyridyl, pyrimidinyl, pyrazinyl, furil, teinila, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, triazolyl, oxadiazolyl and thiadiazolyl, each of which may possibly have a Deputy representing a group of lower alkyl or lower alkenyl.

Z is selected from O, CH2, S, SO2, NH, groups representing N - lower alkyl and N - lower alkenyl.

In the context of the present description of the group, which represents a lower alkyl includes linear, branched and cyclic alkyl groups containing up to six carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, tert-amyl, neopentyl, cyclopropyl, cyclohexyl, cyclopropylmethyl and the like, but is not limited to this. Groups representing lower alkenyl include monón asimenia linear, branched and cyclic alkeneamine group containing up to six carbon atoms, including allyl, but-2-enyl, cyclopent-3-enyl and the like, but is not limited to this. Alkeneamine group, where the double bond is at the point of connection, such as vinyl and 1-propenyl not be considered as groups representing the lowest alkenyl, in the context of the present description.

Some compounds of General formula 1 are capable of forming salts with acids or bases. For example, compounds of General formula 1, which have an acid functional group can form a sodium, potassium, calcium, magnesium or tetraalkylammonium salt after processing the corresponding hydroxide, carbonate or bicarbonate, or dialkylammonium salt after interaction with the appropriate amine. Alternative compounds of General formula 1, which have a core group that can form a salt accession with inorganic and organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, triperoxonane acid, benzoic acid, pamula acid, citric acid, fumaric acid, methanesulfonate acid and the like. To the extent that these salts are pharmaceutically acceptable, they are included in the scope of the present invention.

With the organisations of General formula 1 can contain one or more than one stereogenic ("asymmetric"). Such compounds exhibit optical isomerism, and can therefore exist as enantiomers or diastereomers. Such isomers, in pure form or as mixtures, including racemic mixtures, but not limited to, are also included in the scope of the present invention.

In the preferred embodiment of the present invention proposed a compound of General formula 1, where R3and R4represent N.

In another preferred embodiment of the present invention proposed a compound of General formula 1, where R5is a group that represents lower alkyl or lower alkenyl and more preferably methyl group.

In another preferred embodiment of the present invention proposed a compound of General formula 1, where all And1And2And3and4represent And5. More preferably they all are =CR13or three of them are =CR13and one is a =N-. Even more preferably1And3and4are =CH - and2is a =CR13-. It is most preferable And1And3and4are =CH - and2is a =CF -, or =CCl-. In an alternative, more preferred embodiment one of the A1And2And3and4is =N-, while others are =CH-. It is most preferable And1is a =N and2And3and4are =CH-.

In another preferred embodiment of the present invention proposed a compound of General formula 1, where a4is a covalent bond. More preferably And1and one of the A2and3represent And5and the other is a6. It is most preferable And1represents A5one of the A2and3represents =CH-and the other represents-S-.

In another preferred embodiment of the present invention proposed a compound of General formula 1, where at least three of R6-R10represent N. More preferably four of R6-R10are H and one is a halogen or trifluoromethyl. Most preferably, R6, R7, R9and R10represent N and R8represents halogen or trifluoromethyl.

In another preferred embodiment of the present invention proposed a compound of General formula 1, where R1is a COY2and R2represents N. More preferably Y2represents NR16R17or NHCH2COY3. Most preferred is entrusted Y 2represents NH-CH2-R18or NHCH2CONHCH3where R18represents pyridyl or 3-methyl-1,2,4-oxadiazol-5-yl.

Compounds of General formula 1 can be obtained in two ways, as described in the following schema.

Requires three starting compound corresponding to the General formulas 6, 7 and 8. 6 and 7 combine to obtain the intermediate compounds of General formula 9, or 7 and 8 combine to obtain the intermediate compounds of General formula 10. Then or 8 and 9 or 6 and 10 combined with the product of General formula 1. At certain stages of the synthesis is usually necessary to use suitable protective groups, in order to avoid adverse reactions. The use of such protective groups are well known in the art. For example, see Greene, TW; "Protective Groups in Organic Synthesis", Wiley, New York, 1999. In particular, the amino group of the parent substance 7 will probably be incompatible with the conditions necessary for the implementation of the interaction of 6 to 7, and therefore must be protected. Suitable protective groups are, for example, tert-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Z) group. For the carboxylic acid group of compound 7 may also need protection. If so, it may be protected in the form of ester, such as methyl, who milovy, tert-butyl or benzyl ether.

The scheme shows that the two strategies of synthesis require the same chemical transformations and differ only in the order in which they are performed. These two transformations are

1) the amide formation from carboxylic acids and cyclic amine (6+7→9; 6+10→1) and

2) education sulfonamida from sulphonylchloride and amine (7+8→10; 8+9→1).

The amide formation is a well known reaction. Carboxylic acid and amine are mixed in a suitable solvent, which is typically an aprotic solvent, such as dichloromethane or dimethylformamide, and add a condensing agent. Currently, the majority of these agents are available. Suitable agents include carbodiimide, such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and N-(dimethylaminopropyl)-N'-(ethyl)carbodiimide (water-soluble carbodiimide, WSC·HCl), derivatives of phosphorus, such as sexafter-phosphate (benzotriazol-1 yloxy)Tris(dimethylamino)phosphonium (THIEF), hexaflurophosphate (benzotriazol-1 yloxy)triprolidine (trademark Rumor) and bis-(2-oxo-3-oxazolidinyl)fatfingered (BOP-CI)and derivatives of urea, such as hexaphosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (HBTU). The tertiary amine may also be included in the reaction mixture. PR is measures such tertiary amines include triethylamine, diisopropylethylamine and 4-dimethylaminopyridine. Communication is usually carried out at room temperature or at lower temperatures, such as 0°or -20°C. In cases where the reaction proceeds slowly, the mixture can be heated to a temperature not exceeding the boiling point of the solvent.

Education sulfonamida is also a well known reaction. Usually sulphonylchloride and amine are mixed in an aprotic solvent such as dichloromethane or dimethylformamide, in the presence of tertiary amine (e.g. triethylamine, diisopropylethylamine and 4-dimethylaminopyridine). Add the condensing agent is not necessary. The reaction is usually carried out at approximately room temperature.

The source connection (6, 7 and 8) are obtained according to published methods or by modifications of these methods. In some cases it may be necessary or desirable to perform the final modification of the molecule after these three components will be combined. Such additions and modifications will be apparent to a person skilled in this technical field.

Compounds of General formula 1 are potent and specific antagonists of the GnRH receptor. Therefore, they are useful in the treatment of conditions where GnRH involved in the pathophysiology. For example, these compounds can be used to treat some is, some hormone-dependent cancers, such as breast cancer or prostate cancer. They can also be used to treat non-cancerous conditions such as benign prostatic hyperplasia and endometriosis. Because of their ability to block the release of LH and FSH, these compounds can be used to regulate fertility. They can be used as contraceptive agents either for men or for women. They can also be used in the implementation of programs of in vitro fertilization, where it is necessary to regulate the levels of circulating hormones to optimize the possibilities of getting a Mature oocyte. They can also be used to control criminal anti-social behaviour.

Therefore, in the second aspect of the present invention proposed the use of compounds of General formula 1 as a therapeutic agent in medicine or veterinary medicine. When used for this purpose, the connection will be prepared and administered just as is already known in the art and as will be described in more detail below.

In the preferred embodiment, this connection is used to treat hormone-dependent cancer, benign prostatic hyperplasia, or endometriosis, as a contraceptive agent as a support for the tool in the implementation of the programme of artificial insemination or as agent, modifying behavior. In another preferred embodiment, this connection is used in medicine.

In the third aspect of the present invention proposed pharmaceutical composition, characterized in that as the active agent it includes at least one compound of General formula 1. The composition may be solid, such as a tablet, capsule, powder, suppository, or the like, or a liquid such as solution, suspension, emulsion or cream. The composition may include excipients, which are generally known in the art, including fillers, binding agents, diluents, dispersing agents, lubricating agents, solvents, preservatives and corrigentov.

In a preferred embodiment the composition is a tablet or capsule suitable for oral administration.

In another preferred embodiment the composition is intended for the treatment of hormone-dependent cancer, benign prostatic hyperplasia, or endometriosis, as a contraceptive agent, as an aid in the implementation of the programme of artificial insemination or as agent for modifying behavior.

In the fourth aspect of the present invention proposed the use of compounds of General formula 1 in kachestvennostju pharmaceutical compositions.

In the fifth aspect of the present invention proposes a new method of treatment in medicine or veterinary medicine, wherein the subject is administered a therapeutically effective amount of the compounds of General formula 1, in order to achieve the desired result.

The connection is made in the form of suitable pharmaceutical compositions may be introduced by any suitable means, including oral, transbukkalno, nasal, pulmonary, rectal, vaginal, transdermal, intramuscular, subcutaneous and intravenous administration. Enter the amount and the frequency with which repeat the introduction, will be determined by the attending physician (or veterinarian) in accordance with the condition and medical history of the subject and the desired therapeutic result. The usual dose for humans will be in the range from 0.1 to 500 mg Dose can be administered once a day or up to four times per day. Treatment may include a single introduction or re-introduction during the period of a few days or weeks to several years, if the condition to be treated is chronic.

In the preferred embodiment the subject is a man or a woman.

In another preferred embodiment, the condition to be treated, is a hormone-dependent cancer. More preferably it represents the AK prostate or breast cancer.

In another preferred embodiment, the condition to be treated, is an endometriosis.

In another preferred embodiment, the condition to be treated, is a benign hyperplasia of the prostate.

In another preferred embodiment, the condition to be treated, infertility is. In particular, the treatment is part of a programme of artificial insemination.

In another preferred embodiment the goal of treatment is the provision of contraception.

In another preferred embodiment the subject is a person, a sex offender", i.e. the subject who committed a sexual assault on other people.

The present invention described above, further described using the following examples, which are intended to illustrate the invention and not to limit in any way the scope of the invention.

Examples

Chromatography means flash chromatography on silica gel, unless otherwise noted.

A. Synthesis of intermediate compounds.

Benzomorphan

2H-1,4-Benzoxazin-3(4H)-he (4.5 g, 30 mmol) was added in portions to a stirred suspension of lithium aluminum hydride (4.7 g, 120 mmol) in tetrahydrofuran (THF) (100 ml) and boiled under reflux for 3 hours the Mixture is cooled in a bath of ice/water and with stirring solution was added ammonia (8 ml) and water (40 ml). The mixture was filtered through celite and concentrated. Chromatography (50% EtOAc/50% 60-80 petroleum ether) gave benzomorphan (3.7 g, 91%) as a light brown oil.

Pyrido[3,2-b]morpholine

2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-he (1.9 g, 12.6 mmol) was added to a suspension of lithium aluminum hydride (2.0 g, 53 mmol) in dry THF (100 ml) under cooling in a bath of ice/water. The mixture was heated to 60°and was stirred for 4 h the Mixture was again cooled in a bath of ice/water and slowly added water (20 ml), then ethyl acetate (200 ml). The mixture was filtered and separated. The organic phase is washed with water and brine, dried and concentrated to obtain pyrido[3,2-b]the research (1.5 g, 89%) as a white solid.

Ethylbenzonitrile-2-carboxylate

Ethyl-2,3-dibromopropionate (24 g, 92 mmol) was added dropwise to boiling at the temperature of reflux distilled solution of o-aminophenol (10 g, 92 mmol) and potassium carbonate (15 g, 110 mmol) in acetone (100 ml). After 18 h the mixture was cooled and concentrated. Added ethyl acetate and water and the mixture was separated. The organic phase was washed with brine, filtered and concentrated. Chromatography (30% EtOAc/70% 60-80 petroleum ether) gave ethylbenzonitrile-2-carboxylate (4.5 g, 24%) as a red oil.

Benzomorphan-2-carboxylic acid

R is the target of lithium hydroxide (290 ml, 7,0 mmol) in water (10 ml) was added to a solution of ethylbenzonitrile-2-carboxylate (750 mg, 3.6 mmol) in dioxane (15 ml). The mixture was stirred for 18 h and then concentrated to obtain benzomorphan-2-carboxylic acid in the form of a lithium salt, which was used without further purification.

1,2,3,4-Tetrahydroquinoxalin-2-he

a) Hydrochloride of the methyl ester of glycine (2.2 g, 18 mmol), diisopropylethylamine (2.9 g, 29 mmol), 18-crown-6 (370 mg, 1.4 mmol) and potassium fluoride (1.6 g, 28 mmol) was added to a solution of 1-fluoro-2-nitrobenzene (2 g, 14 mmol) in acetonitrile (150 ml). The mixture was heated at 80°C for 48 h and cooled. Added to 0.3 N. the potassium hydrosulfate and ethyl acetate and the mixture was separated. The organic phase is washed with water and brine, filtered through paper to separate the phases and concentrated. Chromatography (15% EtOAc/85% 60-80 petroleum ether) gave the methyl ester of N-(2-nitrophenyl)glycine in the form of a yellow solid (2.5 g, 85%).

b) a Solution of methyl ester of N-(2-nitrophenyl)glycine (740 mg, 3.6 mmol) in ethyl acetate (50 ml) and methanol (25 ml) was first made at atmospheric pressure over a catalytic amount of 10%palladium on carbon. After 1 h the mixture was filtered and concentrated to obtain 1,2,3,4-tetrahydroquinoxalin-2-it is in the form of a yellow solid (530 mg, 99%).

3-Acetamido-1,2,3,4-tetrahydroquinolin

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a) acetylchloride (410 mg, 5.2 mmol) and triethylamine (620 mg, 6.2 mmol) was added to a solution of 3-aminoquinoline (710 mg, 4.9 mmol) in dichloromethane (50 ml) and the mixture was stirred at room temperature for 18 hours was Added chloroform (100 ml), the mixture was acidified using 1 N. hydrochloric acid (50 ml) and the phases were separated. The aqueous phase was podslushivaet 1 N. a solution of sodium hydroxide and was extracted with a mixture of chloroform/isopropanol (IPA) (85:15, 175 ml). The organic extract was washed with water, brine, dried and concentrated to obtain 3-acetamidophenol (780 mg, 84%) as a yellow solid.

b) borane-pyridine complex (320 mg, 3.5 mmol) was added to a solution of 3-acetamidophenol (320 mg, 1.7 mmol) in acetic acid (20 ml) and the mixture was stirred at room temperature for 18 hours was Added chloroform (150 ml) and the mixture was washed 2 N. a sodium hydroxide solution, water and brine. The organic phase was dried and concentrated.

Chromatography (80% EtOAc/20% 60-80 petroleum ether) gave 3-acetamido-1,2,3,4-tetrahydroquinolin (180 mg, 55%) as a pale yellow solid.

N-(2-Hydroxyethyl)benzomorphan-2-carboxamide

NOWT (1-hydroxybenzotriazole) (3.1 g, 20 mmol) was added to a solution of benzomorphan-2-carboxylate lithium (2.6 g, 15 mmol) in dichloromethane (75 ml) and dimethylformamide (DMF) (7,0 is l) and cooled in a bath of ice/water. Added WSC·HCl (3.2 g, 17 mmol), the mixture was left to warm to room temperature and was stirred for 1 h, the Mixture was again cooled in a bath of ice/water and was added ethanolamine (1.0 g, 17 mmol) and triethylamine (2.8 ml, 2.0 g, 20 mmol).

Stirring was continued at room temperature for 3 days. The mixture was concentrated and dissolved in ethyl acetate and 0.3 N. the solution of potassium hydrosulfate. The phases were separated. The organic phase was washed with a saturated solution of sodium bicarbonate and the aqueous phase was again extracted with ethyl acetate and chloroform. The combined organic phase was dried and concentrated. Chromatography (6% methanol/94% chloroform) gave N-(2-hydroxyethyl)benzomorphan-2-carboxamide (1.1 g, 33%) as a brown resin.

N-(3-Methyl-1,2,4-oxadiazol-5-ylmethyl)benzomorphan-2-carboxamide

NOWT (1.0 g, 6.5 mmol) and WSC·HCl (1.1 g, 5.8 mmol) was added to a solution of benzomorphan-2-carboxylate lithium (900 mg, 5.0 mmol) in dichloromethane (25 ml) and DMF (4.0 ml) under cooling in a bath of ice/water. The mixture was left to warm to room temperature and was stirred for 45 minutes was Added triethylamine (0,73 ml, 530 mg, 5.2 mmol) and a solution of 3-methyl-1,2,4-oxadiazol-5-ylmethylamino (590 mg, 5.2 mmol, obtained according Nvee et al., Liebigs Ann. Chem. 1749 (1986)) in dichloromethane (5.0 ml) and the mixture was stirred for 18 hours the Mixture is the end of what was tarawali, was dissolved in ethyl acetate and washed with 0.3 N. the potassium hydrosulfate, saturated sodium bicarbonate and brine. The organic phase was dried and concentrated. Chromatography (80% ethyl acetate/20% 60-80 petroleum ether) gave N-(3-methyl-1,2,4-oxadiazol-5-ylmethyl)benzomorphan-2-carboxamide (900 mg, 65%) as a brown resin.

tert-Butyl N-(3-chloro-2-(methoxycarbonyl)thiophene-4-methyl)-N-methylcarbamate

a) a Solution of methyl 3-chloro-4-methylthiocarbamate (10 g, 53 mmol), N-bromosuccinimide (9.4 g, 53 mmol) and azo-bis-(isobutyronitrile) (860 mg, 5.3 mmol) in carbon tetrachloride (300 ml) was boiled under reflux for 18 hours the Mixture was filtered and concentrated. Chromatography (10% EtOAc/90% hexanol) gave methyl 4-methyl bromide-3-chlorothiophene-2-carboxylate (5.5 g, 39%) as a white solid.

b) a Solution of methyl-4-methyl bromide-3-chlorothiophene-2-carboxylate (7.6 g, 28 mmol) in a mixture of saturated ammonia/ethanol (200 ml) was stirred at room temperature for 18 hours the Mixture was concentrated in vacuo, triturated in diethyl ether and dissolved in dioxane (200 ml). Was added sodium hydroxide (3.4 g, 85 mmol), di-tert-BUTYLCARBAMATE (9,2 g, 42 mmol) and water (200 ml) and the mixture was stirred for 18 hours was Added an excess of sodium hydroxide and the mixture was heated at 70°C for 3 hours the Mixture was washed with diethyl ether and padcal is whether solid potassium hydrosulfate. The mixture was extracted with ethyl acetate and dichloromethane, dried and concentrated to obtain tert-butyl-N-(3-chloro-2-carboxylate-4-methyl)carbamate (6.0 g, 73%) as a brown oil.

b) sodium Hydride (60%dispersion, 820 mg, 21 mmol) was added to a solution of tert-butyl N-(3-chloro-2-carboxylate-4-methyl)carbamate (2.0 g, 6.8 mmol) in DMF (30 ml) under cooling in a bath of ice/water. The mixture was left to warm to room temperature over 1 h was Added logmean (4,0 ml) and the mixture was stirred for 18 hours was Added water and the mixture was acidified using dilute solution of potassium hydrosulfate and was extracted with EtOAc. The organic phase is washed with water and brine, dried and concentrated. Chromatography (20% EtOAc/80% hexanol) gave tert-butyl N-(3-chloro-2-(methoxycarbonyl)thiophene-4-methyl)-N-methylcarbamate (1.52 g, 70%) as a brown oil.

Ethyl-2-(methylaminomethyl)thiazole-4-carboxylate

a) a Solution of ethyl-2-methylthiazole-4-carboxylate (5.0 g, 29 mmol), N-bromosuccinimide (6.2 g, 35 mmol) and azo-bis-(isobutyronitrile) (480 mg, 2.9 mmol) in carbon tetrachloride (150 ml) was boiled under reflux for 18 hours the Mixture was filtered and concentrated. Chromatography (20% EtOAc/80% hexanol and 30% EtOAc/70% hexanol) gave ethyl-2-brometalia-4-carboxylate (3.25 g, 44%).

b) a Solution of ethyl-2-brometalia-4-carboxylate (4,25 g, 17 mmol) in T is f (50 ml) was added dropwise to a solution of methylamine in THF (2 M, 30 ml, 60 mmol) under cooling to -10°C. the Mixture was left to warm to room temperature and stirred for another 30 minutes the Mixture was diluted with EtOAc and washed with 0.3 N. a solution of potassium hydrosulfate and brine. The organic phase was dried and concentrated to obtain ethyl-2-(methylaminomethyl)thiazole-4-carboxylate (a 3.06 g, 70%) as an orange oil which was used without further purification.

tert-Butyl-N-methyl-N-(3-(methoxycarbonyl)benzyl)carbamate

a) a Mixture of 3-cyanobenzoic acid (5.0 g, 34 mmol), 10%palladium on carbon (1 g) and concentrated hydrochloric acid (3 ml) in methanol (150 ml) was stirred in a stream of gaseous hydrogen at atmospheric pressure for 6 hours the Mixture was filtered through Celite®, concentrated and subjected to azeotropic distillation with toluene. The residue was dissolved in 1 M solution of potassium bicarbonate (105 ml) and dioxane (50 ml) and cooled in a bath of ice/water. Solution was added di-tert-BUTYLCARBAMATE (7.9 g, 36 mmol) in dioxane (25 ml) and the mixture was left to warm to room temperature. After stirring for 3 days the dioxane was removed in vacuum. The aqueous residue was washed 60-80 petroleum ether, acidified 1 N. hydrochloric acid and was extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated to obtain tertbutyl-N-(3-carboxybenzoyl)carbamate (8,2 g, 86%) as a white solid.

b) sodium Hydride (60%dispersion, 700 mg, 18 mmol) was added to a solution of tert-butyl N-(3-carboxybenzoyl)carbamate (2.0 g, 8.0 mmol) in DMF (40 ml) under cooling in a bath of ice/water. After 15 min the mixture was left to warm to room temperature for 15 minutes the Mixture was again cooled in a bath of ice/water and was added logmean (3,7 ml of 8.4 g, 60 mmol). The mixture was stirred at room temperature for 18 hours was Added water and the mixture was concentrated in vacuum. Added ethyl acetate and 0.3 called potassium hydrosulfate, the mixture was separated. The organic phase was washed with brine, dried and concentrated. Chromatography (20% EtOAc, 80% 60-80 petroleum ether) gave tert-butyl N-methyl-N-(3-(methoxycarbonyl)benzyl)carbamate (1.6 g, 69%) as a colourless oil.

tert-Butyl N-(3-carboxybenzoyl)-N-methylcarbamate

The monohydrate of lithium hydroxide (420 mg, 10 mmol) and water (15 ml) was added to a solution of tert-butyl-N-methyl-N-(3-(methoxycarbonyl)benzyl)carbamate (1.6 g, 5.6 mmol) in dioxane (20 ml) and the mixture was stirred for 2 hours, the Dioxane was removed in vacuo and the residue was dissolved in 0.3 N. the potassium hydrosulfate. The mixture was extracted with ethyl acetate, the organic phase is washed with water and brine, dried and concentrated to obtain tert-butyl-N-(3-carboxybenzoyl)-N-methylcarbamate (1.4 g, 95%).

tert-Butyl(1-(4-CT is exitiosa-2-yl)ethyl)carbamate

a) potassium Bicarbonate (1,58 g, 15.7 mmol) and ethylbromide (2,1 ml and 16.9 mmol) was added to a solution of (R,S)-2-(tert-butyloxycarbonyl)thiopropionate (800 mg, 3.9 mmol) in 1,2-dimethoxyethane (10 ml) at -10°C. the Mixture was stirred and left to warm to 0°C for 2 h and at room temperature for 1.5 hours the Mixture was filtered and the solid is washed with diethyl ether. The filtrate was concentrated, dissolved in 1,2-dimethoxyethane (10 ml) and cooled to -30°C. To this solution was added triperoxonane anhydride (1.8 ml, 12.8 mmol) and 2,6-lutidine (3.2 ml, to 27.2 mmol). After 50 min the solution was concentrated and distributed between chloroform and water. The organic layer was dried and concentrated to obtain tert-butyl(1-(4-(ethoxycarbonyl)thiazol-2-yl)ethyl)carbamate (1.4 g) as a crude material, which was used directly in the next stage.

b) the Monohydrate of lithium hydroxide (165 mg, 3.9 mmol) was added to a solution of tert-butyl(1-(4-(ethoxycarbonyl)thiazol-2-yl)ethyl)carbamate (1.4 g crude material) in THF (25 ml) and water (20 ml) and stirred at room temperature for 18 hours was Added an additional amount of the monohydrate of lithium hydroxide (165 mg) and stirring was continued for 4 h THF was removed in vacuo, the aqueous residue was acidified using 1 N. hydrochloric acid and twice extragear the Wali chloroform. The combined organic layers were washed with brine, dried and concentrated. Chromatography (chloroform, methanol, acetic acid, 50:2:1) and recrystallization (EtOAc/hexane) gave tert-butyl(1-(4-carboxymethy-2-yl)ethyl)carbamate (686 mg, 64% over two stages).

B. Synthesis of compounds according to the invention.

EXAMPLE 1

4-Bromo-N-methyl-N-(3-(1,2,3,4-tetrahydroquinolin-1-carbonyl)benzyl)benzosulfimide

a) 1,2,3,4-Tetrahydroquinolin (4,2 g, 31 mmol) was added dropwise to a solution of 3-cyanobenzaldehyde (5.2 g, 31 mmol) and triethylamine (3.1 g, 31 mmol) in dichloromethane (125 ml) under cooling in a bath of ice/water. The mixture was left to warm to room temperature and was stirred for 18 hours the mixture was washed with 0.3 M solution of potassium hydrosulfate, a saturated solution of sodium bicarbonate and brine. The organic phase was filtered through paper to separate the phases and concentrated to obtain 1-(3-cyanobenzoyl)-1,2,3,4-tetrahydroquinoline (7,1 g, 86%).

b) a Solution of 1-(3-cyanobenzoyl)-1,2,3,4-tetrahydroquinoline (7,1 g, 27 mmol) and hydrochloric acid (2.2 ml) in methanol (100 ml) was first made at atmospheric pressure for 8 hours over a catalytic amount of 10%palladium on carbon. The mixture was filtered through Celite® and concentrated to obtain hydrochloride of 1-(3-aminomethylbenzoic)-1,2,3,4-tetrahydroquinoline (8,1 g, 99%) as logo solids.

C) Di-tert-BUTYLCARBAMATE (7,1 g, 32 mmol) was added to a solution of hydrochloride of 1-(3-aminomethylbenzoic)-1,2,3,4-tetrahydroquinoline (8,1 g, 27 mmol) and triethylamine (7.5 ml, 54 mmol) in dichloromethane (200 ml) and was stirred for 18 hours the Mixture was washed with 0.3 M solution of potassium hydrosulfate, water, sodium hydrogen carbonate solution and brine. The organic phase was dried over sodium sulfate, filtered through paper to separate the phases and concentrated. Chromatography (silica gel, 30% EtOAc, 70% 40-60 petroleum ether) gave tert-butyl N-(3-(1,2,3,4-tetrahydroquinolin-1-carbonyl)benzyl)carbamate (8.0 g, 84%) as a white solid.

g) sodium Hydride (0,91 g, 60%dispersion in oil, 23 mmol) was added to a solution of tert-butyl N-(3-(1,2,3,4-tetrahydroquinolin-1-carbonyl)benzyl)carbamate (8.0 g, 22 mmol) in DMF in a stream of nitrogen while cooling in a bath of ice/water. Left to warm to room temperature over 45 minutes and the Mixture was cooled in a bath of ice/water and was added dropwise logmean (9,8 g, 68 mmol). Left to warm to room temperature and was stirred for 5 hours was Added to 0.3 N. the potassium hydrosulfate and the mixture was extracted with EtOAc. The organic phase is washed with water, dried over sodium sulfate and evaporated. Chromatography (30% EtOAc, 70% 60-80 petroleum ether) gave tert-butyl N-methyl-N-(3-(1,2,3,4-tetrahydroquinolin-1-carbonyl)benzyl)carbamate (7.7 g, 93%) as a yellow the resin.

d) a Solution of tert-butyl-N-methyl-N-(3-(1,2,3,4-tetrahydroquinolin-1-carbonyl)benzyl)carbamate (7.7 g, 20 mmol) in a solution of 4 n hydrogen chloride in dioxane (20 ml) was stirred for 30 minutes the Mixture was concentrated and subjected to azeotropic distillation with toluene and dichloromethane to obtain hydrochloride of 1-(3-methylaminoethanol)-1,2,3,4-tetrahydroquinoline in the form of a glassy substance (6.3 g, 99%).

e) 1-(3-Methylaminoethanol)-1,2,3,4-tetrahydroquinolin in the form of the free base was isolated by aqueous processing of the HCl-salt of a saturated solution of sodium bicarbonate, extraction with dichloromethane and concentration in vacuum. 4-Bromobenzonitrile (41 mg, 0.16 mmol) was added to a solution of free base (42 mg, 0.15 mmol) and triethylamine (30 μl, 0.20 mmol) in dichloromethane (10 ml) and was stirred for 3 hours the Mixture was evaporated and subjected to chromatography (35% EtOAc/65% 60-80 petroleum ether) to give 4-bromo-N-methyl-N-(3-(1,2,3,4-tetrahydroquinolin-1-carbonyl)benzyl)benzosulfimide in the form of a white solid (40 mg, 53%).

1H-NMR (CDCl3): 1.88-2.08 (2H, m), 2.35 (3H, s), 2.65-2.75 (2H, m), 3.70-3.90 (2H, m), 3.95 (2H, s), 6.55-6.62 (1H, m), 6.75 (1H, t, J=8 Hz), 6.90 (1H, t, J=8 Hz), 7.05-7.15 (2H, m), 7.20-7.35 (3H, m), 7.50-7.65 (4H, m).

Mass spectrometry with ionization by elektrorazpredelenie (MCEER), m/z=499.4, 501.4 (50:50, MH+).

The microanalysis. Found: at 57.79%; N, 4.69%; N, 5.76%. Calculated for C24H23BrN 2O3S: 57.72%; N, 4.64%; N 5.61%.

EXAMPLE 2

4-(3-Chloro-4-(N-(4-chlorobenzenesulfonyl)-N-methylaminomethyl)thiophene-2-carbonyl)-N-(3-methyl-1,2,4-oxadiazol-5-ylmethyl)benzomorphan-2-carboxamide

a) 4-Chlorobenzenesulfonamide (10 g, 47 mmol) was added to a solution of methylamine hydrochloride (3.5 g, 52 mmol) and triethylamine (16.5 ml, 12.0 g, 119 mmol) in dichloromethane (100 ml) under cooling in a bath of ice/water. The mixture was left to warm to room temperature and was stirred for 18 hours the Mixture was concentrated and chromatography (30% EtOAc/70% hexanol) gave 4-chloro-N-methylbenzenesulfonamide (7.9 g, 81%) as a colourless oil.

b) sodium Hydride (60%dispersion, 150 mg, 3.8 mmol) was added to a solution of 4-chloro-N-methylbenzenesulfonamide (640 mg, 3.1 mmol) in DMF (12 ml) under cooling in a bath of ice/water. After stirring for 15 min the mixture was left to warm to room temperature and was stirred for 30 minutes was Added methyl-4-methyl bromide-3-chlorothiophene-2-carboxylate (1.08 g, 4.0 mmol) and the mixture was stirred for 18 hours was Added to 0.3 n solution of potassium hydrosulfate and the mixture was evaporated. The mixture was extracted with ethyl acetate and the organic extract was washed with brine, dried and concentrated. Chromatography (25% EtOAc/75% 60-80 petroleum ether) gave methyl 3-chloro-4-(N-(4-chlorobenzenesulfonyl)-N-methylaminomethyl)thiophene-2-carboxyla is (1.25 g, 79%) as a white solid.

C) lithium Hydroxide (210 mg, 5.0 mmol) and water (10 ml) was added to a solution of methyl 3-chloro-4-(N-(4-chlorobenzenesulfonyl)-N-methylaminomethyl)thiophene-2-carboxylate (990 mg, 2.5 mmol) in dioxane (20 ml) and the mixture was stirred for 18 hours the Mixture was evaporated and added to 0.3 N. the potassium hydrosulfate. The mixture was extracted with ethyl acetate, the organic extracts were washed with water and brine, dried and concentrated to obtain 3-chloro-4-(N-(4-chlorobenzenesulfonyl)-N-methylaminomethyl)thiophene-2-carboxylic acid (800 mg, 84%) as a white solid.

g) a Solution of 3-chloro-4-(N-(4-chlorobenzenesulfonyl)-N-methylaminomethyl)thiophene-2-carboxylic acid (57 mg, 0.15 mmol) in thionyl chloride (2 ml) and dichloromethane (5 ml) was boiled under reflux for 1 h the Mixture was cooled and concentrated in vacuum. The residue was added to a solution of N-{3-methyl-1,2,4-oxadiazol-5-ylmethyl)benzomorphan-2-carboxamide (40 mg, 0.15 mmol) and triethylamine (42 μl, 0.30 mmol) in dichloromethane (10 ml) and stirred at room temperature for 3 days. The mixture was concentrated and chromatography (30% EtOAc/70% hexanol and 100% EtOAc) gave 4-(3-chloro-4-(N-(4-chlorobenzenesulfonyl)-N-methylaminomethyl)thiophene-2-carbonyl)-N-(3-methyl-1,2,4-oxadiazol-5-ylmethyl)benzomorphan-2-carboxamide as a colourless oil (31 mg, 33%).

1H-NMR (CDCl3): 2.37 (3H, s), 2.65 (3H, s), 4.01 (1H, dd, J=6.9 Hz, 13.3 Hz, 4.09 (2H, s), 4.38 (1H, dd, J=3.0 Hz, 13.3 Hz), 4.72 (1H, dd, J=5.4 Hz Hz), 4.82 (1H, dd, J=6.2 Hz, 17.3 Hz), 4.91 (1H, dd, J=3.0 Hz, 6.9 Hz), 6.81-6.92 (1H, m), 7.03-7.14 (3H, m), 7.28 (1H, s), 7.51 (1H, s), 7.52 (2H, d, J=8.4 Hz), 7.74 (2H, d, J=8.4 Hz).

Mass spectrometry with chemical ionization at atmospheric pressure (head MS), m/z=635.9 (MN+).

EXAMPLE 3

4-(3-Chloro-4-(N-(4-chlorobenzenesulfonyl)-N-methylaminomethyl)-thiophene-2-carbonyl)-N-(2-hydroxyethyl)benzomorphan-2-carboxamide

a) tert-Butyldimethylsilyloxy (135 mg, 0.9 mmol) was added to a solution of N-(2-hydroxyethyl)benzomorphan-2-carboxamide (185 mg, 0.83 mmol) and imidazole (61 mg, 0.90 mmol) in DMF (3 ml) under cooling in a bath of ice/water. The mixture was left to warm to room temperature and was stirred for 18 hours the Mixture was concentrated, dissolved in ethyl acetate, washed with 0.3 N. the potassium hydrosulfate and brine, filtered through paper to separate the phases and concentrated. Chromatography (70% EtOAc/30% 60-80 petroleum ether) gave N-(2-(tert-butyldimethylsilyloxy)benzomorphan-2-carboxamide (230 mg, 82%) as a brown resin.

b) 3-Chloro-4-(N-(4-chlorobenzenesulfonyl)-N-methylaminomethyl)thiophene-2-carboxylic acid (69 mg, 0.18 mmol) was dissolved in thionyl chloride (5 ml) and was heated to the temperature of reflux distilled within 90 minutes the Mixture was cooled, concentrated and dissolved in dichloromethane (5 ml). This solution was added to a solution of the N-(2-(tert-butyldimethylsilyloxy)benzomorphan-2-carboxamide (61 mg, 0.18 mmol) and triethylamine (84 μl, 0.6 mmol) in dichloromethane (5 ml). The mixture was stirred for 1 h and concentrated. Chromatography (40% EtOAc/60% 60-80 petroleum ether) gave N-(2-tert-butyldimethylsilyloxy)-4-(3-chloro-4-(N-(4-chlorobenzenesulfonyl)-N-methylaminomethyl)thiophene-2-carbonyl)benzomorphan-2-carboxamide (65 mg, 52%) as a white solid.

C) a Solution of tetrabutylammonium fluoride in THF (1.0 M, 1.0 ml, 1.0 mmol) was added to a solution of N-(2-tert-butyldimethylsilyloxy)-4-(3-chloro-4-(N-(4-chlorobenzenesulfonyl)-N-methylaminomethyl)thiophene-2-carbonyl)benzomorphan-2-carboxamide (65 mg, 0,093 mmol) in THF (4.0 ml) and was stirred for 1 h the Mixture was concentrated, dissolved in ethyl acetate, washed with 1 N. hydrochloric acid and brine, filtered and concentrated. Chromatography (95% 60-80 petroleum ether/5% EtOAc) gave 4-(3-chloro-4-(N-(4-chlorobenzenesulfonyl)-N-methylaminomethyl)thiophene-2-carbonyl)-N-(2-hydroxyethyl)benzomorphan-2-carboxamide in the form of a white solid (25 mg, 46%).

1H-NMR (CDCl3): 2.67 (3H, s), 3.36-3.46 (2H, m), 3.64-3.70 (2H, m), 4.09-4.16 (4H, m), 4.85 (1H, t, J=4.2 Hz), 6.85-6.90 (2H, m), 7.01-7.10 (2H, m), 7.25-7.29 (1H, m), 7.51 (1H, s), 7.53 (2H, d, J=8.4 Hz), 7.74 (2H, d, J=8.4 Hz).

Head MS m/z=584 (MH+).

EXAMPLE 4

4-(3-Chloro-4-(N-(4-chloro-3-nitrobenzenesulfonyl)-N-methylaminomethyl)thiophene-2-carbonyl)benzomorphan

a) 1 n lithium hydroxide (aq.) of 7.0 ml, 7.0 mmol) was added to a solution of tert-butyl N-(3-chloro-2-(methoxycarbonyl)thiophene-4-methyl)-N-methylcarbamate (1.52 g, of 4.75 mmol) in dioxane (20 ml) and the mixture was stirred at room temperature for 18 hours the Mixture was diluted with ethyl acetate, acidified to 1 N. the potassium hydrosulfate (aq.) and shared. The organic phase is washed with water and brine, dried and concentrated to obtain tert-butyl-N-(2-carboxy-3-chlorothiophene-4-methyl)-N-methylcarbamate in the form of a colorless oil (1,38 g, 95%).

b) Benzomorphan (405 mg, 3.0 mmol) and triethylamine (0,49 ml, 356 mg, 3.5 mmol) was added to a solution of tert-butyl N-(3-chloro-2-carboxylate-4-methyl)-N-methylcarbamate (0.73 g, 2.5 mmol) in dichloromethane (10 ml) and the mixture was cooled in a bath of ice/water. Added Pybrop® (1.4 g, 3.0 mmol) and the mixture was stirred for 10 minutes and the Mixture was left to warm to room temperature and was stirred for 3 days. The mixture was washed with water, dried over sodium sulfate and concentrated. Chromatography (25% EtOAc/75% 60-80 petroleum ether) gave the mixture of product and unreacted benzomorphan. This mixture was dissolved in ethyl acetate, twice washed with 1 N. hydrochloric acid, once with brine, dried over sodium sulfate and concentrated to obtain tert-butyl-N-(2-(benzomorphan-4-carbonyl)-3-chlorothiophene-4-methyl)-N-methylcarbamate (0,70 g, 66%) as a light brown resin.

C) a Solution of 4 n hydrogen chloride in dioxane (5 ml) was added to a solution of tert-butyl N-(2-(benzomorphan-4-carbonyl)-3-chlorothiophene-4-methyl)-N-is ethylcarbamate (0,70 g, 1.7 mmol) in dioxane (10 ml) and cooled to 12°C. the Mixture was left to warm to room temperature and was stirred for 18 hours the Mixture was concentrated in vacuo and subjected to azeotropic distillation with toluene and 60-80 petroleum ether to obtain the hydrochloride of 4-(3-chloro-4-(methylaminomethyl)thiophene-2-carbonyl)benzomorphan (0,58 g, 95%) as a white solid.

g) 4-Chloro-3-nitrobenzenesulfonamide ones (0.46 g, 1.8 mmol) was added to a solution of the hydrochloride of 4-(3-chloro-4-(methylaminomethyl)thiophene-2-carbonyl)benzomorphan (0.54 g, 1,49 mmol) and triethylamine (0,50 ml, 0.36 g, 3.6 mmol) in dichloromethane (20 ml) under cooling in a bath of ice/water. The mixture was left to warm to room temperature and was stirred for 3 days. The mixture was concentrated and subjected to chromatography to obtain 4-(3-chloro-4-(N-(4-chloro-3-nitrobenzenesulfonyl)-N-methylaminomethyl)thiophene-2-carbonyl)benzomorphan (0,61 g, 76%) as a white crystalline solid.

1H-NMR (d6DMSO): 2.61 (3H, s), 3.86-3.98 (2H, m), 4.17 (2H, s), 4.30-4.40 (2H, m), 6.75 (1H, dt, J=1.5, 8.4 Hz), 6.91 (1H, dd, J=1.5, 8.4 Hz), 7.05 (1H, dt, J=1.5, 8.4 Hz), 7.20 (1H, d, J=8.4 Hz), 7.85 (1H, s), 8.04 (1H, d, J=8.4 Hz), 8.10 (1H, dt, J=2.0, 8.4 Hz), 8.50 (1H, d, J=2.0 Hz).

MSER m/z=541.6 (MH+).

EXAMPLE 5

4-(4-(N-(3-Amino-4-chlorobenzenesulfonyl)-N-methylaminomethyl)-3-chlorothiophene-2-carbonyl)benzomorphan

A mixture of 4-(3-chloro-4-(N-(4-the ENT-3-nitrobenzenesulfonyl)-N-methylaminomethyl)thiophene-2-carbonyl)benzomorphan (200 mg, of 0.37 mmol) and zinc dust (400 mg) in glacial acetic acid (10 ml) was heated at 100°C for 5 hours the Mixture was cooled in a bath of ice/water and was diluted with water. Was slowly added pellets of sodium hydroxide (5 g) to obtain a pH of 14. The mixture was extracted with dichloromethane, dried over sodium sulfate and concentrated. Flash chromatography (35% EtOAc/65% 60-80 petroleum ether) gave the mixture of product and unreacted educt. Preparative high-performance liquid chromatography (HPLC) of this mixture gave 4-(4-(N-(3-amino-4-chlorobenzenesulfonyl)-N-methylaminomethyl)-3-chlorothiophene-2-carbonyl)benzomorphan (102 mg, 54%) as a white solid.

1H-NMR (d6DMSO): 2.51 (3H, s), 3.92 (2H, t, J=4.3 Hz), 4.03 (2H, s), 4.34 (2H, J=4.3 Hz), 6.76 (1H, t, J=6.9 Hz), 6.88-6.96 (2H, m), 7.05 (1H, t, J=6.9 Hz), 7.18-7.30 (2H, m), 7.45 (1H, d, J=8.4 Hz), 7.86 (1H, s).

Head MC m/z=512 (MH+).

EXAMPLE 6

1-(2-(N-(4-Brabanthallen)-N-methylaminomethyl)thiazole-4-carbonyl)-1,2,3,4-tetrahydroquinolin

a) 4-Bromobenzonitrile (2.1 g, 8.2 mmol) was added to a solution of ethyl-2-(methylaminomethyl)thiazole-4-carboxylate (1.5 g, 7.5 mmol) and triethylamine (2.1 ml, 1.5 g, 15 mmol) in dichloromethane (30 ml) and the mixture was stirred for 18 hours the Mixture was diluted with ethyl acetate and washed with 1 N. the potassium hydrosulfate, water and brine, dried and concentrated. Chromatography (35% EtOAc/65% Huck is ANOVA) gave ethyl-2-(N-(4-brabanthallen)-N-methylaminomethyl)thiazole-4-carboxylate (2.1 g, 67%) as a white solid.

b) Ethyl-2-(N-(4-brabanthallen)-N-methylaminomethyl)thiazole-4-carboxylate (2.1 g, 5.2 mmol) was added to a mixture of 1 n solution of lithium hydroxide (10 ml, 10 mmol) and dioxane (20 ml) and heated to 50°until then, until he had the solution. The mixture was stirred at room temperature for 3 days. The mixture was evaporated, dissolved in EtOAc and acidified 1 N. solution of potassium hydrosulfate. The phases were separated and the organic phase is washed with water and brine, dried and concentrated to obtain 2-(N-(4-brabanthallen)-N-methylaminomethyl)thiazole-4-carboxylic acid (1.86 g, 95%) as a white solid.

C) thionyl chloride (2.0 ml) was added to a solution of 2-(N-(4-brabanthallen)-N-methylaminomethyl)thiazole-4-carboxylic acid (460 mg, 1.2 mmol) in dichloromethane (20 ml) and the solution boiled under reflux for 2 hours the Mixture was cooled to room temperature, concentrated in vacuo and subjected to azeotropic distillation with toluene to obtain a white solid. This substance was dissolved in dichloromethane (20 ml) was added thereto triethylamine (0,34 ml, 250 mg, 2.4 mmol) and 1,2,3,4-tetrahydroquinolin (of 0.18 ml, 190 mg, 1.4 mmol). After stirring for 1 h the mixture was concentrated in vacuum. Chromatography (50% EtOAc/50% hexanol) gave 1-(2-(N-(4-brabanthallen)-N-methylaminomethyl)thiazole-4-carbonyl)-1,2,3,4-tetrahydroquinolin (580 mg, 97%) as a white solid.

1H-NMR (CDCl3): 1.98 (2H, quintet, J=6.6 Hz), 2.60 (3H, s), 2.75 (2H, t, J=6.6 Hz), 3.87 (2H, t, J=6.6 Hz), 4.36 (2H, s), 6.62-6.78 (1H, m), 6.85-6.90 (1H, m), 6.95 (1H, dt, J=1.3, 7.3 Hz), 7.08 (1 H, d, J=7.3 Hz), 7.59-7.64 (4H, m), 7.65 (1H, s).

MSER m/z=506.1, 508.1 (50:50, MH+).

EXAMPLE 7

4-Bromo-N-methyl-N-(3-(pyrido[3,2-b]morpholine-1-carbonyl)benzyl)benzosulfimide

a) WSC·HCl (470 mg, 2.5 mmol) and 4-(dimethylamino)pyridine (290 mg, 2.4 mmol) was added to a solution of tert-butyl N-(3-carboxybenzoyl)-N-methylcarbamate (520 mg, 2.0 mmol) and pyrido[3,2-b]the research (290 mg, 2.1 mmol) in dichloromethane (25 ml). The mixture was boiled under reflux for 18 hours the Mixture was concentrated in vacuo, dissolved in ethyl acetate, washed with water and brine, dried and concentrated. Chromatography (40% EtOAc/60% 60-80 petroleum ether) gave tert-butyl N-methyl-N-(3-(pyrido[3,2-b]morpholine-1-carbonyl)benzyl)carbamate (700 mg, 94%) as a colourless oil.

b) a Solution of tert-butyl-N-methyl-N-(3-(pyrido[3,2-b]morpholine-1-carbonyl)benzyl)carbamate (610 mg, 1.6 mmol) in a mixture of 4 n hydrogen chloride/dioxane (30 ml) was stirred for 1 h the Mixture was concentrated in vacuo to obtain the dihydrochloride of 1-(3-(methylaminomethyl)benzoyl)pyrido[3,2-b]the research (512 mg, 100%) as a white solid.

C) 4-Bromobenzonitrile (31 mg, 0.12 mmol) was added to a solution of dihydrochloride of 1-(3-(methyl shall Enomatic)benzoyl)pyrido[3,2-b]the research (35 mg, 0.11 mmol) in dichloromethane (20 ml). the pH was brought to 9 with triethylamine, and the mixture was stirred for 18 hours the Mixture was concentrated in vacuo, dissolved in ethyl acetate, washed with water and brine, dried and concentrated. Chromatography (80% chloroform/20% cyclohexane) gave 4-bromo-N-methyl-N-(3-(pyrido[3,2-b]morpholine-1-carbonyl)benzyl)benzosulfimide (42 mg, 77%) as a solid white color with a yellowish tinge.

1H-NMR (CDCl3): 2.49 (3H, s), 4.09 (2H, s), 4.13 (2H, t, J=4.6 Hz), 4.46 (2H, t, J=4.8 Hz), 6.87-6.91 (1H, m), 7.19-7.51 (5H, m), 7.52 (1H, d, J=1.6 Hz), 7.63-7.71 (4H, m).

MSER m/z=502, 504 (50:50, MH+).

EXAMPLE 8

4-Bromo-N-methyl-N-(3-(1,2,3,4-tetrahydroquinoxalin-3-one-1-carbonyl)benzyl)benzosulfimide

a) WSC·HCl (640 mg, 3.4 mmol) and 4-(dimethylamino)pyridine (330 mg, 2.7 mmol) was added to a solution of tert-butyl N-(3-carboxybenzoyl)-N-methylcarbamate (700 mg, 2.6 mmol) and 1,2,3,4-tetrahydroquinoxalin-2-she (440 mg, 2.9 mmol) in dichloromethane (20 ml). The mixture was stirred for 18 h, concentrated in vacuo and dissolved in ethyl acetate. This solution was washed with a solution of 0.3 N. potassium hydrosulfate and a saturated solution of sodium bicarbonate, dried and concentrated. Chromatography (50% EtOAc/50% 60-80 petroleum ether) gave tert-butyl N-(3-(1,2,3,4-tetrahydroquinoxalin-3-one-1-carbonyl)benzyl)-N-methylcarbamate (280 mg, 27%) as an orange oil.

b) Rest the p-tert-butyl-N-(3-(1,2,3,4-tetrahydroquinoxalin-3-one-1-carbonyl)benzyl)-N-methylcarbamate (280 mg, 0.71 mmol) in a mixture of 4 n hydrogen chloride/dioxane (30 ml) was stirred at room temperature for 1 h the Mixture was concentrated in vacuo, dissolved in chloroform, washed with a saturated solution of sodium bicarbonate and brine, dried and concentrated. Chromatography (10% methanol/90% chloroform) gave 1-(3-(methylaminomethyl)benzoyl-1,2,3,4-tetrahydroquinoxalin-3-one (98 mg, 49%) as an orange solid.

C) 4-Bromobenzonitrile (29 mg, 0.11 mmol) was added to a solution of 1-(3-(methylaminomethyl)benzoyl-1,2,3,4-tetrahydroquinoxalin-3-one (30 mg, 0.10 mmol) in dichloromethane (10 ml). the pH was brought to 9 with triethylamine, and the mixture was stirred for 18 hours the Mixture was concentrated in vacuo, dissolved in ethyl acetate, washed with water and brine, dried and concentrated. Chromatography (50% EtOAc/50% 60-80 petroleum ether) gave 4-bromo-N-methyl-N-(3-(1,2,3,4-tetrahydroquinoxalin-3-one-1-carbonyl)benzyl)benzosulfimide (34 mg, 60%) as a white solid.

1H-NMR (CDCl3): 2.46 (3H, s), 4.06 (2H, s), 4.59 (2H, s), 6.66 (1H, s), 6.76 (1H, t, J=7.6 Hz), 6.97 (1H, d, J=6.6 Hz), 7.06-7.12 (1H, m), 7.21 (1H, s), 7.31-7.43 (3H, m), 7.63-7.71 (4H, m), 8.97 (1H, s).

MSER m/z=514, 516 (50:50, MH+).

EXAMPLE 9

3-Acetamido-1-(2-(N-(4-brabanthallen)-N-methylaminomethyl)thiazole-4-carbonyl)-1,2,3,4-tetrahydroquinolin

Thionyl chloride (5.0 ml) was added to a solution of 2-(N-(4-Brabanthal sulfonyl)-N-methylaminomethyl)thiazole-4-carboxylic acid (250 mg, 0.64 mmol) in dichloromethane (20 ml) and the solution boiled under reflux for 2 hours the Mixture was cooled and concentrated in vacuo to obtain the acid chloride as a white solid. This acid chloride (130 mg, 0.32 mmol) was dissolved in dichloromethane (10 ml) and to it was added 3-acetamido-1,2,3,4-tetrahydroquinolin (61 mg, 0.32 mmol) and triethylamine (0,089 ml, 65 mg, 0.64 mmol). The mixture was stirred at room temperature for 18 h and concentrated in vacuum. Chromatography (EtOAc) gave 3-acetamido-1-(2-(N-(4-brabanthallen)-N-methylaminomethyl)thiazole-4-carbonyl)-1,2,3,4-tetrahydroquinolin (96 mg, 53%) as a white solid.

1H-NMR (CDCl3): 1.85 (3H, s), 2.61 (3H, s), 2.78 (1H, dd, J=3.6 Hz, 16.8 Hz), 3.21 (1H, dd, J=5.9 Hz, 16.8 HZ), 3.69 (1H, dd, J=3.0 Hz, 12.9 Hz), 4.30-4.35 (3H, m), 4.55-4.60 (1H, m), 6.02 (1H, d, J=7.6 Hz), 6.97-7.15 (3H, m), 7.15-7.20 (1H, m), 7.66 and 7.69 (each 2H, each d, J=3.6 Hz), 7.88 (1H, s).

MSER m/z=563.0, 565.0 (50:50. MN+).

EXAMPLE 10

1-(2-(1-(4-Bromobenzonitrile)ethyl)thiazole-4-carbonyl)-1,2,3,4-tetrahydroquinolin

and HBTU (306 mg, 0.81 mmol) was added to a solution of tert-butyl(1-(4-carboxymethy-2-yl)ethyl)carbamate (200 mg, 0.73 mmol) in DMF (5 ml) at room temperature. Added diisopropylethylamine (of 0.26 ml, 190 mg, 1.5 mmol) and 1,2,3,4-tetrahydroquinolin (of 0.11 ml, 117 mg, 0.88 mmol) and the mixture was stirred for 18 hours the Mixture was distributed between etelaat the Ohm 1 and N. hydrochloric acid and separated. The organic layer was washed with water and brine, dried and concentrated. Chromatography (45% EtOAc/55% hexanol) gave tert-butyl(1-(4-(1,2,3,4-tetrahydroquinolin-1-carbonyl)thiazol-2-yl)ethyl)carbamate (180 mg, 63%).

b) a Solution of tert-butyl(1-(4-(1,2,3,4-tetrahydroquinolin-1-carbonyl)thiazol-2-yl)ethyl)carbamate (180 mg, 0.47 mmol) in a mixture of 4 n hydrogen chloride/dioxane (10 ml) was stirred in a bath of ice/water and left to warm to room temperature. The mixture was concentrated and was twice subjected to azeotropic distillation with toluene, twice with carbon tetrachloride and once with dichloromethane to obtain hydrochloride of 1-(2-(1-amino-ethyl)thiazole-4-carbonyl)-1,2,3,4-tetrahydroquinoline. It was assumed that the yield is quantitative, and this substance is used directly by dissolving it in dichloromethane (5 ml) and triethylamine (0.16 ml, 118 mg, 1.2 mmol). The resulting solution was cooled in a bath of ice/water and was added 4-bromobenzonitrile (119 mg, 0.47 mmol). The mixture was left to warm to room temperature and was stirred for 18 hours Evaporation and chromatography (50% EtOAc/50% hexanol) gave 1-(2-(1-(4-bromobenzonitrile)ethyl)thiazole-4-carbonyl)-1,2,3,4-tetrahydroquinolin in the form of a white solid (144 mg, 61%).

1H-NMR (CDCl3): 1.38 (3H, d, J=6.9 Hz), 2.05 (2H, dt, J=3.3 Hz, 6.6 Hz), 2.79-2.84 (2H, m), 3.80-4.01 (2H, m), 4.56 (1H, quintet, J=6.9 Hz), 5.29 (1H,d, J=7.6 Hz), 6.63-6.79 (1H, br m), 6.94 (1H, t, J=7.6 Hz), 7.07 (1H, dt, J=1.3 Hz, 7.6 Hz), 7.18 (1H, d, J=7.6 Hz), 7.58 (2H, d, J=8.9 Hz), 7.59 (1H, s), 7.64 (2H, d, J=8.9 Hz).

MSER m/z=506.0, 507.9 (50:50, MH+).

EXAMPLES 11-70

The compounds listed in the table were obtained using the same methods.

Etc.R1R2R3R11R12WX[M+H]+
12NNBrHHCHCH2539.0
13NNBrHHNO541.9
14NNClCH2NMe2HCHAbout553.9
15NNClHFCHAbout514.9
16MeMeClHHCHNH524.0
17 =OBrHHCHNH554.1

Etc.Y2R8R11R12[M+H]+
18HEBrHH584.9
19NHMeBrHH598.0
20NHCH2CH2OHBrHH627.9
21NHCH2CH2OHClOMeH630.9
22NHCH2CH2OHClHF601.9
23NHCH2CO2MeBrHH655.9
24NHCH2CONHMeClHH611.0
25NHCH2CONHMeClOMeH641.0
26 BrHH674.9
27ClHH631.0
28ClOMeH661.0
29ClOMeH662.0
30ClOMeH666.0
31BrHH653.0

Etc.Y1R8R11X[M+H]+
32C(=O)IUBrHCH2596.1
33C(=O)CH2NHMeBrHCH2625.0
34C(=O)(CH2)2NH2Br HCH2625.0
35C(=O)(CH2)2NH2BrHAbout627.0
36C(=O)(CH2)2NH2ClOMeAbout613.0
37C(=O)(CH2)3NH2BrHCH2639.0
38C(=O)(CH2)3NH2BrHAbout641.0
39C(=O)(CH2)3NHMeBrHCH2653.0
40C(=O)(CH2)2NHC(=O)MeBrHCH2668.9
41C(=O)(CH2)3NHC(=O)IUBrHCH2682.9
42C(=O)(CH2)3NHC(=O)NHEtBrHCH2711.9
Etc.And1 And2And3[M+H]+
43SNSSN504.9
44SNN(CH2CH3)N517.1
45C(NMe2)SSN548.1

Etc.And1And2And3[M+H]+
46SSNSN505.1
47OSNSN489
48SSNN505.9
Etc.R5A1A2 A3[M+H]+
49NNCHS492.0
50MeNCHO490.1
51MeNCHNH489.0
52MeNCHNMe502.9
53MeNC(Et)S534.2
54MeCHNO490.1
55MeCHNNMe503.0

SN
Etc.And1And2And3And4[M+H]+
56SNSNC(OMe)529.1
57SNSNNSN500
58SNSNSNN500
59SNSN(IU)N514
60C(NO2)SNSNSN544.2
61C(NH2)SNSNSN514.3
62NSNSNSN499.9
63SN(Cl)SNSN533.1
64C(Cl)SNSNSN533
65SNWith(NH2)SNSN514
66SNS(HE)SNSN515.0
67SNC(F)SNSN517
68SNC(NO2)SNSN 544
69SNC(Br)SNSN577
70SNSNSN(Cl)533.1

The connection described above, displace the ligand from the radioactive label of GnRH receptortargeted membrane preparations at concentrations below 5 microns.

1. Compound which is a derivative of General formula 1, or its pharmaceutically acceptable salt

where each And1And2and3independently selected from And5and6and

And4represents either a covalent bond or A5provided that

if a4is a covalent bond, then one of the A1-And3represents A6and the other two represent And5and that

if a4represents A5all And1-And3represent And5;

And5selected from C-R13and N;

And6selected from N-R14, S and O;

R1selected from N, NHY1and COY2and R2represents H; or R1and R2represent methyl or together represent =O;

each R3, R4and R5illegal is ASIMO represents H or lower alkyl;

each R6, R7, R8, R9, R10, R11and R12independently selected from N, NH2, F, Cl, Br, O-alkyl, and CH2NMe2;

R13selected from H, F, Cl, Br, NO2, NH2HE, Me, Et, OMe and NMe2;

R14selected from H, methyl and ethyl;

W is selected from CH and N;

X is selected from CH2, O and NH;

Y' is selected from-lower alkyl, (CH2)bY3, CO(CH2)bCOY3and CO(CH2)bNHCOY3;

Y2selected from OR15, NR16R17and NH(CH2)cCOY3;

Y3selected from alkyl, OR15and NR16R17;

R15represents N;

each R16and R17independently selected from H, lower alkyl and (CH2)andR18or together they represent -(CH2)2-Z-(CH2)2-;

R18selected from HE, pyridyl, pyrazinyl and oxadiazolyl;

Z represents NH;

and means 0-4 and

b and C mean 1-3.

2. The compound according to claim 1, where R3and R4represent N.

3. The compound according to claim 1, where R5represents lower alkyl.

4. The compound according to claim 3, where R5represents methyl.

5. The compound according to any one of claims 1 to 4, where all And1And2And3and4represent And5

6. The compound according to claim 5, where at least three of the A1And2And3and4represent =CR13-.

7. The connection according to claim 6, where a1And3and4are =CH - and2is a =CR13-.

8. The connection according to claim 7, where a2is a =CF -, or =CCl-.

9. The connection according to claim 6, where one of the A1And2And3and4represents =N-, while others are =CH-.

10. The connection according to claim 9, where a1is a =N and2And3and4are =CH-.

11. The compound according to any one of claims 1 to 4, where a4is a covalent bond.

12. Connection to item 11, where a1represents A5.

13. The connection section 12, where one of the A2and3represents =CH-and the other represents-S-.

14. The compound according to claim 1, where at least three of R6-R10represent N.

15. The connection 14, where four of R6-R10are N and the other represents F, Cl or Br.

16. The connection indicated in paragraph 15, where R6, R7, R9and R10represent N and R8represents F, Cl or Br3.

17. The compound according to claim 1, where R1is a COY2and R2represents N.

18. The connection 17, where Y2is the way the nd NR 16R17or NHCH2COY3.

19. Connection p, where Y2represents NHCH2R18or NHCH2CONHCH3and R18represents pyridyl or 3-methyl-1,2,4-oxadiazol-5-yl.

20. The compound according to claim 1, chosen from:

(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-amide 4-(3-chloro-4-{[(4-chloro-benzazolyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-carboxylic acid,

(2-hydroxy-ethyl)-amide 4-(3-chloro-4-{[(4-chloro-benzazolyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-carboxylic acid,

4-chloro-N-[4-chloro-5-(2,3-dihydro-benzo[1,4]oxazin-4-carbonyl)-thiophene-3-ylmethyl]-N-methyl-3-nitro-benzosulfimide,

3-amino-4-chloro-N-[4-chloro-5-(2,3-dihydro-benzo[1,4]oxazin-4-carbonyl)-thiophene-3-ylmethyl]-N-methyl-benzosulfimide,

4-bromo-N-[4-(3,4-dihydro-2H-quinoline-1-carbonyl)-thiazole-2-ylmethyl]-N-methyl-benzosulfimide,

N-[1-(2-{[(4-bromo-benzazolyl)-methyl-amino]-methyl}-thiazole-4-carbonyl)-1,2,3,4-tetrahydro-quinoline-3-yl]-acetamide", she

4-bromo-N-[4-chloro-5-(3,4-dihydro-2H-quinoline-1-carbonyl)-thiophene-3-ylmethyl]-N-methyl-benzosulfimide,

4-bromo-N-[4-chloro-5-(2,3-dihydro-pyrido[3,2-b][1,4]oxazin-4-carbonyl)-thiophene-3-ylmethyl]-N-methyl-benzosulfimide,

4-chloro-N-[4-chloro-5-(7-fluoro-2,3-dihydro-benzo[1,4]oxazin-4-carbonyl)-thiophene-3-ylmethyl]-N-ethyl-benzosulfimide,

4-chloro-N-[4-chloro-5-(3,3-dimethyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)-thiophene-3-ylmethyl]-N-methyl-benzosulfimide,

4-bromo-N-[4-chloro-5-(3-oxo-3,4-dihydro-2H-cinoxacin-1-carbonyl)-thiophene-3-ylmethyl]-N-methyl-benzosulfimide,

methylamide 4-(4-{[(4-bromo-benzazolyl)-methyl-amino]-methyl}-3-chloro-thiophene-2-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-carboxylic acid,

(2-hydroxy-ethyl)-amide 4-(5-{[(4-bromo-benzazolyl)-methyl-amino]-methyl}-4-chloro-thiophene-3-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-carboxylic acid,

(2-hydroxy-ethyl)-amide 4-(3-chloro-4-{[(4-chloro-benzazolyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-carboxylic acid,

(2-hydroxy-ethyl)-amide 4-(3-chloro-4-{[(4-chloro-benzazolyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-7-fluoro-3,4-dihydro-2H-benzo[1,4]oxazin-2-carboxylic acid,

methyl ester {[4-(5-{[(4-bromo-benzazolyl)-methyl-amino]-methyl}-4-chloro-thiophene-3-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-carbonyl]-amino}-acetic acid,

methylcarbamoylmethyl-amide 4-(3-chloro-4-{[(4-chloro-benzazolyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-carboxylic acid,

methylcarbamoylmethyl-amide 4-(3-chloro-4-{[(4-chloro-benzazolyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-carboxylic acid,

(pyridine-4-ylmethyl)-amide 4-(5-{[(4-bromo-benzazolyl)-methyl-amino]-methyl}-4-chloro-thiophene-3-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-carboxylic acid,

(pyridine-3-ylmethyl)-amide 4-(3-chloro-4-{[(4-chloro-benzazolyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-carboxylic acid,

(pyridine-3-ylmethyl)-amide 4-(3-chloro-4-{[(4-chloro-benzazolyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-carboxylic acid,

(pyrazin-2-ylmethyl)-amide 4-(3-chloro-4-{[(4-chloro-benzazolyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-carboxylic acid,

(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-amide 4-(3-chloro-4-{[(4-chloro-benzazolyl)-methyl-amino]-methyl}-thiophene-2-carbonyl)-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-carboxylic acid,

N-[1-(4-{[(4-bromo-benzazolyl)-methyl-amino]-methyl}-3-chloro-thiophene-2-carbonyl)-1,2,3,4-tetrahydro-quinoline-3-yl]-acetamide", she

3-amino-N-[1-(4-{[(4-bromo-benzazolyl)-methyl-amino]-methyl}-3-chloro-thiophene-2-carbonyl)-1,2,3,4-tetrahydro-quinoline-3-yl]-propionamide,

(2-amino-ethyl)-amide 4-(4-{[(4-bromo-benzazolyl)-methyl-amino]-methyl}-3-chloro-thiophene-2-carbonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-carboxylic acid,

(2-amino-ethyl)-amide 4-(3-chloro-4-{[(4-chloro-benzazolyl)-methyl-amino]-methyl}-type the-2-carbonyl)-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-carboxylic acid,

3-acetylamino-N-[1-(4-{[(4-bromo-benzazolyl)-methyl-amino]-methyl}-3-chloro-thiophene-2-carbonyl)-1,2,3,4-tetrahydro-quinoline-3-yl]-propionamide,

4-acetylamino-N-[1-(4-{[(4-bromo-benzazolyl)-methyl-amino]-methyl}-3-chloro-thiophene-2-carbonyl)-1,2,3,4-tetrahydro-quinoline-3-yl]-butyramide,

N-[1-(4-{[(4-bromo-benzazolyl)-methyl-amino]-methyl}-3-chloro-thiophene-2-carbonyl)-1,2,3,4-tetrahydro-quinoline-3-yl]-4-(3-ethyl-ureido)-butyramide,

4-bromo-N-[5-(3,4-dihydro-2H-quinoline-1-carbonyl)-thiophene-3-ylmethyl]-N-methyl-benzosulfimide,

4-bromo-N-[5-(3,4-dihydro-2H-quinoline-1-carbonyl)-furan-2-yl]-N-methyl-benzosulfimide,

4-bromo-N-[6-(3,4-dihydro-2H-quinoline-1-carbonyl)-pyridine-2-ylmethyl]-N-methyl-benzosulfimide,

4-bromo-N-[4-chloro-3-(3,4-dihydro-2H-quinoline-1-carbonyl)-benzyl]-N-methyl-benzosulfimide,

4-bromo-N-[3-(3,4-dihydro-2H-quinoline-1-carbonyl)-4-fluoro-benzyl]-N-methyl-benzosulfimide,

4-bromo-N-[3-(3,4-dihydro-2H-quinoline-1-carbonyl)-4-nitro-benzyl]-N-methyl-benzosulfimide,

4-bromo-N-[4-bromo-3-(3,4-dihydro-2H-quinoline-1-carbonyl)-benzyl]-N-methyl-benzosulfimide

or their pharmaceutically acceptable salts.

21. The use of compounds according to any one of claims 1 to 20 as a therapeutic agent for the treatment of gormonzawisimogo cancer, endometriosis or benign prostatic hyperplasia, image quality is as a contraceptive agent, as an aid in the implementation of the programme of artificial insemination or as agent for modifying behavior in medicine or veterinary medicine.

22. Use item 21 in medicine.

23. The pharmaceutical composition exhibiting the activity of the GnRH receptor antagonist containing a compound according to any one of claims 1 to 20.

24. The composition according to item 23, which is a tablet or capsule for oral administration.

25. The composition according to item 23 or 24, which is used for the treatment gormonzawisimogo cancer, endometriosis or benign prostatic hyperplasia, as a contraceptive agent, as an aid in the implementation of the programme of artificial insemination or as agent for modifying behavior.

26. A method of obtaining a compound which is a derivative of General formula 1, or its pharmaceutically acceptable salt

where

each And1And2and3independently selected from And5and6and

And4represents either a covalent bond or A5provided that

if a4is a covalent bond, then one of the A1-And3represents A6and the other two represent And5 and that

if a4represents A5all And1-And3represent And5;

And5selected from C-R13and N;

And6selected from N-R14, S and O;

R1selected from N, NHY1and COY2and R2represents N or R1and R2represent methyl or together represent =O;

each R3, R4and R5independently represents H or lower alkyl;

each R6, R7, R8, R9, R10, R11and R12independently selected from N, NH2, F, Cl, Br, O-alkyl, and CH2NMe2;

R13selected from H, F, Cl, Br, NO2, NH2HE, Me, Et, OMe and NMe2;

R14selected from H, methyl and ethyl;

W is selected from CH and N;

X is selected from CH2, O and NH;

Y1selected from-lower alkyl, (CH2)bY3, CO(CH2)bCOY3and CO(CH2)bNHCOY3;

Y2selected from OR15, NR16R17and NH(CH2)cCOY3;

Y3selected from alkyl, OR15and NR16R17;

R15represents N;

each R16and R17independently selected from H, lower alkyl and (CH2)andR18or together they represent -(CH2)2-Z-(CH2)2 -;

R18selected from HE, pyridyl, pyrazinyl and oxadiazolyl;

Z represents NH;

and means 0-4 and

b and C mean 1-3,

which includes stages:

a) interaction of the compounds of formula 7

where a1-And4and R3-R5such as defined above,

with the compound of the formula 6

where R1, R2, R11and R12W and X are such as defined above,

obtaining the compounds of formula 9

where A1-A4, R1-R5, R11, R12W and X are such as defined above; and

b) interaction of the obtained compound of formula 9 with a compound of formula 8

where R6-R10such as defined above.

27. A method of obtaining a compound which is a derivative of General formula 1, or its pharmaceutically acceptable salt,

where each And1And2and3independently selected from And5and6and

And4represents either a covalent bond or A5provided that

if a4represents covalently the link, one And1-And3represents A6and the other two represent And5and that

if a4represents A5all And1-And3represent And5;

And5selected from C-R13and N;

And6selected from N-R14, S and O;

To1selected from N, NHY1and COY2and R2represents H or R', and R2represent methyl or together represent =O;

each R3, R4and R5independently represents H or lower alkyl;

each R6, R7, R8, R9, R10, R11and R12independently selected from N, NH2, F, Cl, Br, O-alkyl, and CH2NMe2;

R13selected from H, F, Cl, Br, NO2, NH2HE, Me, Et, OMe and NMe2;

R14selected from H, methyl and ethyl;

W is selected from CH and N;

X is selected from CH2, O and NH;

Y1selected from-lower alkyl, (CH2)bY3WITH(CH2)bCOY3and CO(CH2)bNHCOY3;

Y2selected from OR15, NR16R17and NH(CH2)cCOY3;

Y3selected from alkyl, OR15and NR16R17;

R15represents N;

each R16and R17independently selected from H, lower alkyl and (CH 2)aR18or together they represent -(CH2)2-Z-(CH2)2-;

R18selected from HE, pyridyl, pyrazinyl and oxadiazolyl;

Z represents NH;

and means 0-4 and

b and C mean 1-3,

which includes stages:

a) interaction of the compounds of formula 7

where a1-And4and R3-R5such as defined above,

with the compound of the formula 8

where R6-R10such as defined above,

obtaining the compounds of formula 10

where a1-And4and R3-R10such as defined above; and

b) interaction of the compounds of formula 10 with a compound of formula 6

where R1, R2, R11and R12W and X are such as defined above.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of the formula (1a) or its pharmaceutically acceptable salt, esters or imides where A is a thiophenyl group containing, probably, substitution, the thiophenyl group A containing, probably, substitution with one or several groups as follows: alkyl, halo or arylalkyl, Y is O, S or NR2 where R2 is hydrogen or alkyl group containing 1 to 6 carbon atoms, and R1 is an non-ramified alkyl group containing 6 to 25 carbon atoms, ramified alkyl group containing 6 to 25 carbon atoms, aryl alkyl group where the alkyl group contains 2 to 25 carbon atoms or phenyl group containing substitution with one or several groups as follows: phenyloxy, phenylthio, SO2-phenyl, alkylphenyl, CO-phenyl, CONR16- phenyl, NR16CO-phenyl or NR16 -phenyl containing, probably, substitution where R16 is hydrogen or alkyl group containing 1 to 4 carbon atoms, the groups phenyloxy, phenylthio, SO2-phenyl, alkylphenyl, CO-phenyl, CONR-phenyl or NR-phenyl containing, probably, substitution with one or several groups as follows: halo, alkyl, alkylhalo or phenyl group containing substitution with one or several groups or alkyl groups provided the above compound is not 5-methyl-2-(4-metoxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazine-4-on, 6-amyl-2-(4-chlorophenyl)amino-4H-thieno[2,3-d][1,3]oxazine-4-on or 6-amyl-2-(4-metoxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazine-4-on Invention also relates to method of obtaining compounds of the formula (Ia) or (IIa), to pharmaceutical compound and application, as well as cosmetic technique.

EFFECT: obtaining of new biologically active compounds and pharmaceutical compounds based on them.

27 cl, 4 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): , wherein X represents heteroatom, such as oxygen (O) or sulfur (S) atoms; X and Z mean independently of one another one or some identical or different substitutes bound any available carbon atom and they can represent hydrogen atom or halogen atom; R1 represents a substitute of the formula (II): , wherein R2 and R3 can represent simultaneously or independently of one another hydrogen atom or (C1-C4)-alkyl, or R1 can represent hydrogen, halogen atom, (C1-C7)-alkyl, -CHO, -(CH2)2COOH, -(CH2)2CO2Et, (CH2)mL wherein L means -OH or bromine atom (Br); m represents a whole number from 1 to 3; n represents a whole number from 0 to 3; Q1 and Q2 represent independently of one another oxygen atom or group of the formula: wherein substitutes y1 and y2 represent hydrogen atom, and to their pharmacologically acceptable salts. Also, invention relates to use of these compounds as intermediate substances used in synthesis of novel compounds of dibenzoazulene class, and to their using for preparing drugs.

EFFECT: valuable medicinal properties of compounds.

9 cl, 4 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy, chemical technology.

SUBSTANCE: invention relates to novel substituted esters of 1,2,3,7-tetrahydropyrrolo[3,2-f][1,3]benzoxazin-5-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and/or hydrates possessing the antiviral effect. In compounds of the general formula (1) each R1 and R4 represents independently of one another a substitutes of amino group chosen from hydrogen atom, optionally substituted linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms or their oxides; R2 represents alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl or cycloalkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, optionally substituted linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and optionally an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms or their oxides; R6 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and optionally annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms or their oxides. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention. Proposed compounds can be used as active components of drugs used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods of synthesis.

22 cl, 3 tbl, 6 dwg, 7 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of general formula 1 (G1 is group of general formulae 2 G1 is group of general formulae ; meanings of the rest substituents are as described in specification) or pharmaceutically acceptable salts thereof and use thereof in srug production. Said compounds are useful in treatment of male and female sexual disorders.

EFFECT: new oxytocin antagonists.

30 cl, 177 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of general formula I and pharmaceutically acceptable salt thereof, wherein R1, R3, R4, R5, and R10 are independently H, halogen, C1-C4-alkyl, etc.; R2 is H, halogen, NO2, etc.; R6 is H, C1-C6-alkyl, C1-C6-alkoxy-substituted C1-C4-alkyl, etc.; R7 is H, C1-C4-alkyl or C2-C4-alkenyl, optionally substituted with halogen; R8 and R9 are H, R11 and R12; meanings of the rest substituents are as define in specification.

EFFECT: new compounds with value biological properties and useful as drug having activity in relates to progesterone receptor.

15 cl, 3 tbl, 80 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new method for production of E-2-aroylmethylene-1-phenyl-1,2,3,4-tetrahydroquinazolin-4-ones of general formula I wherein R represents H, methyl, Cl. Claimed method includes interaction of 5-aryl-2,3-dihydro-2,3-furandiones with N-phenylanthranyl acid amide in medium of inert aprotic solvent (preferably benzene) followed by isolation of target products. Process is carried out preferably at 79-80°C. Claimed compounds have fluorescent properties and are useful in labeling and copying agents, intermediates for synthesis of new heterocyclic compounds, etc.

EFFECT: new fluorescent compounds.

3 cl, 1 dwg, 3 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to an agent used against acid-resistant microorganisms containing derivative of pyridone carboxylic acid as an active component, its pharmaceutically acceptable salt or its hydrate that elicits high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms. Invention describes agent used against acid-resistant microorganisms containing compound represented by the following formula (I) its salt or its hydrate as an active component wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise substitute(s) chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; A1 represents incomplete structure represented by the formula (2): wherein X2 represents halogen atom, alkyl group comprising 1-6 carbon atoms or alkoxy-group comprising 1-6 carbon atoms; A1, A2 and A3 form incomplete structure of the formula: in common with carbon atoms combined with them; X1 represents halogen atom; Y represents hydrogen atom; Z represents phenylpiperazine substitute. Invention provides synthesis of pyridone carboxylic acid eliciting high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms in combination with good pharmacokinetics indices and safety.

EFFECT: valuable biological property of agent.

10 cl, 9 tbl, 10 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a synthetic quinolone agent that is effective as medicinal agents, veterinary preparations, drugs used in fishing industry or as antibacterial preserving agents. Invention describes compound represented by the following general formula (I): as its separate isomers or their mixture, its salt and their hydrates wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise a substitute chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; R4 represents hydrogen atom, amino-group, hydroxyl group; A represents nitrogen atom or part of structure as given in the invention claim; each R5 and R6 represents independently alkyl group comprising 1-6 carbon atoms or hydrogen atom; n means a whole number 1 or 2. Also, invention describes antibacterial agent and therapeutic agent based on compounds of the formula (I) used in treatment of infectious disease, a method for preparing antibacterial agent, a method for preparing a medicinal agent used in treatment of infectious disease and using compound of the formula (I) for preparing an antibacterial agent and using compound of the formula (I) for preparing a medicinal agent used in treatment of infectious disease. Invention provides novel compounds possessing useful biological properties.

EFFECT: improved preparing method of agents, valuable medicinal properties of compounds and agents.

35 cl, 2 tbl, 15 ex

FIELD: chemistry of heterocyclic compounds, antibacterial agents.

SUBSTANCE: invention relates to agent used against acid-resistant microorganisms. Invention describes agent against acid-resistant microorganisms containing as an active component the compound represented by the general formula (1) or its hydrate wherein R2 represents hydrogen atom; R3 represents hydrogen atom; A1, A2 and A3 form incomplete structure of the formula: wherein A1 represent incomplete structure of the formula: wherein X2 and above described R1 can be combined to form six-membered cyclic structure comprising part of the parent nucleus wherein formed ring can comprise oxygen atom and, except for, can comprise alkyl group having 1-6 carbon atoms as a substitute; X1 represents halogen atom, hydrogen atom or amino-group; Y represents hydrogen atom; Z represents incomplete structure of the formula: . Agent elicits high antibacterial activity of broad spectrum and possesses good pharmacokinetics and safety also.

EFFECT: improved and valuable properties of agent.

3 cl, 9 tbl, 10 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns applications of compositions formulated as follows or its salt, solvate or prodrug of medical agent for treatment or prevention of disease state mediated by glucokinase (GLK). Besides, given invention concerns new group of composition formulated as (I) and to method of specified compositions production. The invention enables to widen range of agents used for treatment or prevention of disease conditions mediated by glucokinase (GLK) where each of R1, R2, R3, n and m has values specified in the description.

EFFECT: increased efficiency.

19 cl, 51 ex

FIELD: chemistry; obtaining of medicinal preparations.

SUBSTANCE: description is given of a compound with general formula where R1 represents a halogen, C1-C6alkyl, CF3, CF2H or cyano, R2 represents C1-C6alkyl, R3 represents 5- or 6 - member hetero-aryl, optionally substituted with one, two or three substitutes, chosen from a group, consisting of a halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylhalogen, C1-C6alkoxy, NR'R", or substituted with a 1-morpholinyl group or substituted with thiomorpholinyl groups, 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl; R', R" independently represent hydrogen, C1-C6alkyl, (CH2)0,1-(C3-C6)cycloalkyl, R represents hydrogen as well as its pharmaceutical salts and the method of obtaining them. The invention also relates to use of the given amidazole derivatives for obtaining medicinal preparations and to medicinal preparations containing them, meant for prevention or treatment of damages, through the mGluR5 receptor, such as acute and/or chronic neurologic damages, primarily shock pain, or for treatment of chronic and sharp pain.

EFFECT: obtaining of new compounds, with useful biological properties.

40 ex

FIELD: chemistry; oxa-and thiazole derivatives.

SUBSTANCE: oxa- and thiazole derivatives have general formula . Their stereoisomers and pharmaceutical salts have PPARα and PPARγ activity. The compounds can be used for treating diseases, eg. diabetes and anomaly of lipoproteins through PPARα and PPARγ activity. In the general formula, x has value of 1, 2, 3 or 4; m has value of 1 or 2; n has value of 1 or 2; Q represents C or N; A represents O or S; Z represents O or a bond; R1 represents H or C1-8alkyl; X represents CH; R2 represents H; R2a, R2b and R2c can be the same or different and they are chosen from H, alkoxy, halogen; R3 represents aryloxycarbonyl, alkyloxycarbonyl, alkyl(halogen)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylcarbonylamino, alkylsulphonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, halogenalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenylsulphonyl, heteroarylsulphonyl, arylsulphonyl, arylalkenylarylalkyl, arylalkoxycarbonyl-heteroarylalkyl, heteroaryloxyarylalkyl, where alkyl is in form of C1-8alkyl; Y represents CO2R4, where R4 represents H or C1-8alkyl; including all their stereoisomers and pharmaceutical salts, under the condition that, if A is O, then R3 is not aryloxycarbonyl or alkoxyaryloxycarbonyl.

EFFECT: the compounds can be used in curing such diseases as diabetes and lipoprotein anomalies.

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: chemistry.

SUBSTANCE: description is given of the substituted pyridine with formula in which the substituting groups have values given in paragraph 1 of the formula of invention. Description is also given of the herbicide compound on its base and the derived pyridine of formula , in which the substituting groups have values given in paragraph 4 of the formula of invention, which is an intermediate product.

EFFECT: compounds have an herbicide action.

5 cl, 24 tbl, ex

FIELD: chemistry.

SUBSTANCE: invention pertains to compounds with formula I or to its pharmaceutically accepted salts: where R1 is chosen from phenyl, thienyl, furanyl and thyazolyl; and R2, R3, R4 and R5 are independently chosen from hydrogen and C1-6alkyl. The invention also relates to the use and methods of obtaining compounds of formula I, as well as to compounds of formula III.

EFFECT: obtaining new biologically active compounds.

12 cl, 5 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzimidazol of the general formula I R1 designates phenyl group which unessentially contains up to three substitutors independently chosen of the group including F, Cl, Br, J, R4; R2 designates monocyclic or bicyclic 5-10-terms heteroaryl group which contains 1-2 heteroatoms, chosen of N, S and O; R3 designates H; R4 designatesC1-6alkyl; A designates C2-6 alkylene group; B designates group COOH, CONH2, CONHR5 or CONR5R5, in each case attached to atom of carbon of group A; R5 and R5 ' independently designate the residue chosen from group includingC1-6 alkyl where one C-atom can be replaced by O, and(C0-3 alkandiil-C3-7 cycloalkyl); and to their pharmaceutically acceptable salts, except for following compounds: 6 [[1-phenyl-2 (pyridine-4-il)-1H-benzimidazol-6-il] oxi] hexanic acid and 6 [[1-phenyl-2 (benzothien-2-il)-1H-benzimidazol-6-il] oxi] hexanic acid. The invention relates also to pharmaceuticals and to application of compounds of general formula I.

EFFECT: new biologically active compounds possess inhibiting effect on activation of microglia.

10 cl, 34 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention is related to the compounds of general formula (I) and their pharmaceutically acceptable salts with properties β2-adrenoreceptor agonists, to the method of their production and based on them pharmaceutical composition. The compounds can be used for treatment of conditions when the symptomatic severity can be reduced by β2- adrenoreceptor activation, e.g., obstructive or inflammatory respiratory diseases. In the general formula (I) , X means -R1-Ar-R2 or -Ra-Y; Ar means phenylen, optionally substituted by group of the row: halogen, hydroxy, C1-C10alkyl, C1-C10alcoxy, phenyl, C1-C10 alcoxy, substituted by phenyl group or phenyl, substituted by C1-C10 alcoxy group; R1 and R2 are bound to the adjacent carbon atoms within Ar group, and either R1 means C1-C10alkylen, and R2 means hydrogen, C1-C10alkyl or halogen, Ra means the bond or C1-C10 alkylen optionally substituted by group of the row: hydroxy, C1-C10 alcoxy, C6-C10aryl or C7-C14aralkyl; Y means C1-C10alkyl, or C2-C10alkynil, optionally substituted by hydroxyl group, C3-C10cycloalkyl, optionally condensed with one or more benzene rings and optionally substituted by group of the row: C1-C10alkyl, C1-C10alcoxy, C3-C10cycloalkyl, C7-C14aralkyl, C7-C14aralkyloxy or C6-C10aryl, where groups C7-C14aralkyl, C7-C14aralkyloxy or C6-C10 aryl are optionally substituted by group of the row: halogen, C1-C10alkyl, C1-C10alcoxy; C6-C10aryl, optionally substituted by group of the row: halogen, hydroxy, C1-C10alkyl, C1-C10alcoxy, C1-C10halogenalkyl, phenoxy, C1-C10alkylthio, C6-C10aryl, 5-6-term saturated heterocyclic ring, containing one nitrogen atom in cycle; phenoxy, optionally substituted by C1-C10alcoxy group; 5-6-term heterocyclic ring, containing one or two nitrogen or oxygen atoms in cycle, and the described heterocyclic ring is optionally substituted by group of the row: C1-C10alkyl, C6-C10aryl, C7-C14aralkyl, C1-C10alcoxycarbonil or 5-7-term heterocyclil (C1-C10)alkyl, containing one nitrogen atom in cycle; -NRdRe, where Rd means hydrogen or C1-C10alkyl, and Re means C1-C10alkyl, or Re means C6-C10aryl, or Re means 5-6-term heterocyclic ring, containing one nitrogen or sulfur atom in cycle, and the ring is optionally substituted by halogen-substituted phenyl group or Re means C6-C10arylsypfonil, optionally substituted by groups C1-C10alkylamino or di(C1-C10alkyl)amino; -SRf, where Rf means C6-C10aryl or C7-C14aralkyl, optionally substituted by group of row: halogen or C1-C10halogenalkyl; or -CONHRg, where Rg means C6-C10aryl, provided, if Ra means the bond, then Y doesn't mean C1-C5alkyl.

EFFECT: compound can prevent or reduce symptom's intensity.

15 cl, 4 tbl, 157 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the novel compounds with formula (I) and their pharmaceutically acceptable salts. The compounds of this invention has the properties of the NPY receptor antagonists and can be used fortreatment of such diseases as arthritis, diabetes, malnutrition, obesity. In general formula (I) , R1 means phenyl or 6-term nitrogen-containing heteroaryl, where in at least one of two meta-positions each phenyl group or 6-term nitrogen-containing heteroaryl group is substituted by group R5; R2 means hydrogen; R3 means C3-C6cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, where in at least one of two ortho-positions each group of C3-C6 cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, substituted by group R6; R4 means hydrogen, C1-C6alkyl; R5 means hydrogen, cyano, trifluoromethyl, C1-C6alkyl-SO2-, amino-SO2-, halogen, C1-C6alcoxy, C1-C6alkylcarbonil or aminocarbonil; R6 means hydrogen, halogen, cyano, nitro, trifluoromethyl, C1-C6 alkyl, C1-C6 alcoxy or hydroxy, provided, one R5 group, and R6 doesn't mean hydrogen.

EFFECT: described compounds and based on them pharmaceutical agents are efficient in treatment and prevention of above listed diseases.

19 cl, 2 tbl, 2 dwg, 130 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the novel compounds with formula (I) and their pharmaceutically acceptable salts. The compounds of this invention has the properties of the NPY receptor antagonists and can be used fortreatment of such diseases as arthritis, diabetes, malnutrition, obesity. In general formula (I) , R1 means phenyl or 6-term nitrogen-containing heteroaryl, where in at least one of two meta-positions each phenyl group or 6-term nitrogen-containing heteroaryl group is substituted by group R5; R2 means hydrogen; R3 means C3-C6cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, where in at least one of two ortho-positions each group of C3-C6 cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, substituted by group R6; R4 means hydrogen, C1-C6alkyl; R5 means hydrogen, cyano, trifluoromethyl, C1-C6alkyl-SO2-, amino-SO2-, halogen, C1-C6alcoxy, C1-C6alkylcarbonil or aminocarbonil; R6 means hydrogen, halogen, cyano, nitro, trifluoromethyl, C1-C6 alkyl, C1-C6 alcoxy or hydroxy, provided, one R5 group, and R6 doesn't mean hydrogen.

EFFECT: described compounds and based on them pharmaceutical agents are efficient in treatment and prevention of above listed diseases.

19 cl, 2 tbl, 2 dwg, 130 ex

FIELD: chemistry.

SUBSTANCE: invention covers new compounds of formula I or its salts suitable for pharmacology: , where R1 is selected from phenyl, pyridyl, thienyl, difurylglyoxal, imidazolyl, pyrrolyl and thiazolyl; R2, R3 and R4 independently are d-zalkyl or halogenated C1-zalkyl; and R5 is hydrogen. And also new intermediate compounds formula III: , where R2, R3 and R4 independently are C1-3alkyl or halogenated C1-6alkyl; and R5 is hydrogen. Invention also covers method of production of compound formula I and their applications.

EFFECT: production of new biologically active compounds.

12 cl, 9 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzimidazol of the general formula I R1 designates phenyl group which unessentially contains up to three substitutors independently chosen of the group including F, Cl, Br, J, R4; R2 designates monocyclic or bicyclic 5-10-terms heteroaryl group which contains 1-2 heteroatoms, chosen of N, S and O; R3 designates H; R4 designatesC1-6alkyl; A designates C2-6 alkylene group; B designates group COOH, CONH2, CONHR5 or CONR5R5, in each case attached to atom of carbon of group A; R5 and R5 ' independently designate the residue chosen from group includingC1-6 alkyl where one C-atom can be replaced by O, and(C0-3 alkandiil-C3-7 cycloalkyl); and to their pharmaceutically acceptable salts, except for following compounds: 6 [[1-phenyl-2 (pyridine-4-il)-1H-benzimidazol-6-il] oxi] hexanic acid and 6 [[1-phenyl-2 (benzothien-2-il)-1H-benzimidazol-6-il] oxi] hexanic acid. The invention relates also to pharmaceuticals and to application of compounds of general formula I.

EFFECT: new biologically active compounds possess inhibiting effect on activation of microglia.

10 cl, 34 ex

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