Cyclic n,n'-diarylthioureas or n,n'-diarylureas - antagonists of androgen receptors, anti-cancer medication, method of obtaining and application

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel cyclic N,N'-diarylthioureas or N,N'-diarylureas of general formula (1), their optic (R)- and (S)-isomers and their pharmaceutically acceptable salts - antagonists of androgenic receptors. In formula (1), where: X represents oxygen or sulfur atom; m=0 or 1, mR1 represents C1-C3alkyl; R2 and R3 represent hydrogen atom; or R2 and R3 together with carbon atom, to which they are bound, form group C=O; or represents group NH; R4 and R5 represent hydrogen atom; or R4 represents hydrogen atom, and R5 represents methyl; or R4 represents hydrogen atom, methyl, and R5 represents group Zn-Y-R6, in which n=1 or 2, Z represents CH2 or C=0 and Y- oxygen atom or N-CH3, or Y represents C=O, and Z represents CH2; R6 represents hydrogen atom, methyl, benzyl, hydroxygroup or R5 and R4 together with atoms, to which they are bound, form five or sic-member heterocycle, including, at least, oxygen or nitrogen atom, which can be substituted by methyl. Invention also relates to method of obtaining compounds.

EFFECT: invention relates to anti-cancer substance, pharmaceutical composition, medication and method of treating prostate cancer with application of invention compounds.

12 cl, 6 dwg, 16 ex

 

The present invention relates to new cyclic N,N'-varietieseven or N,N'-deallocating, androgen receptor antagonists, anti-cancer agent, pharmaceutical compositions, medicinal product and method for the treatment of prostate cancer.

Known antagonists of androgen receptors, which represents a 1,3-diaryl-5,5-dimethyl-2-thioxo-imidazolidin-4-ones (I, 5,7-diaryl-6-thioxo-5,7-diaza-Spiro[3,4]octane-8-ons II and 1,3-diaryl-2-thioxo-1,3-diaza-Spiro[4,4]nonan-4-ones III, possessing anticancer activity [WO 2006124118, WO 2007127010]. In these series of compounds is the most advanced 4-[5,5-dimethyl-4-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-imidazolidin-1-yl]-N-methyl-2-perbenzoic MDV3100 (antagonist of androgen receptors with IC50=36 PM), which is currently in phase III clinical trials as a treatment for prostate cancer [Drug Data Rep., 2009, 31(6), 609].

Search for a highly effective anticancer drugs with high activity and low toxicity, is still one of the main directions of development of new pharmacological agents for the treatment of cancer, including prostate cancer. In this regard, it is urgent to develop new against the cancerous substances, pharmaceutical compositions and pharmaceutical preparations and methods for their preparation and use.

Below are definitions of terms used in the description.

"Azaheterocycle" means an aromatic or non-aromatic monocyclic or polycyclic system containing a loop, at least one nitrogen atom. Azaheterocycle can have one or more cyclic substituents" of the system.

"Active component" (drug substance, drug-substance) means a physiologically active substance is synthetic or other (biotechnology, plant, animal, microbial or other origin, possessing pharmacological activity and which is the active beginning of the pharmaceutical composition used for the production and manufacture of the medicinal product (tools).

"Alkyl" means an aliphatic hydrocarbon of linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. The alkyl may have one or more identical or different substituents ("alkyl substituents") including halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, ariloxiquinone is, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonates etc.

"Antagonists" refers to ligands that bind to receptors of a particular type and do not cause active cellular response. Antagonists inhibit the binding of agonists to receptors and thereby block the transmission of specific receptor signal.

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, preimushestvenno from 6 to 10 carbon atoms. Aryl can contain one or more "cyclic system substituents"which may be the same or different. Representatives of aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. The aryl may be annylirovan with non-aromatic cyclic system or heterocycle.

"Heterocyclyl" means an aromatic or non-aromatic saturated monocyclic or polycyclic system containing from 3 to 10 carbon atoms, mainly from 5 to 6 carbon atoms, in which one or more carbon atoms replaced by a heteroatom, such as nitrogen, oxygen, sulfur. The prefix "Aza", "oxa" or "thia" before heterocyclyl means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. Heterocyclyl can have one and the number of cyclic system substituents", which may be the same or different. Atoms of nitrogen and sulfur, in heterocyclyl, can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives heterocyclyl are piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, thiazolidine, 1,4-dioxane, tetrahydrofuran, tetrahydrothiophene, etc.

"Hydrate" means the MES, in which water is a molecule or molecules of solvent.

"Deputy" means a chemical moiety that is attached to scaffold (fragment), for example, "Deputy alkyl", "Deputy amino group", "Deputy carbamoyl", "Deputy cyclic system, the values of which are defined in this section.

"The drug (the drug), a substance (or mixture of substances in the form of pharmaceutical compositions in the form of tablets, capsules, injections, ointments and other ready-made forms, designed to restore, correct or modify physiological functions in humans and animals, as well as for treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others.

"Lower alkyl" means a linear or branched alkyl with 1-4 carbon atoms.

"Pharmaceutical composition" means a composition comprising a compound of formula 1 and at least one component selected from the group comprised the soup of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distributing and perceiving means, means of delivery, such as preservatives, stabilizers, fillers, shredders, moisturizers, emulsifiers, suspendresume agents, thickeners, sweeteners, flavors, fragrances, antibacterial agents, fungicides, lubricants, regulators prolonged delivery, the choice and the value of which depends on the nature and mode of appointment and dosage. Examples suspendida agents are ethoxylated isostearoyl alcohol, polyoxyethylene, sorbitol and sorbitol ester, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, as well as mixtures of these substances. Protection from the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and similar compounds. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged action of the composition can be achieved with agents that slow the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohol, and the x mixture vegetable oils (such as olive oil) and injectable organic esters (such as etiloleat). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of shredders and distributes funds are starch, aginova acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulphate, talc, and polyethylene with high molecular weight. Pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal injection of the active principle, one or in combination with other active beginning can be introduced animals and people in the standard form of administration, mixed with conventional pharmaceutical carriers. Usable standard form of introduction include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gum and oral solutions or suspensions, sublingual and transbukkalno forms of administration, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration. Pharmaceutical compositions typically obtained using the standard who procedures, providing a mixture of the active compound with a liquid or finely powdered solid carrier.

"Pharmaceutically acceptable salt" refers to the relatively non-toxic organic and inorganic salts of acids and bases, as claimed in the present invention. These salts can be obtained in situ during the synthesis, separation, or purification of compounds or prepared. In particular, salts of bases can be obtained specifically on the basis of the purified free base of the claimed compounds and a suitable organic or inorganic acid. Examples of the thus obtained salts are hydrochloride, hydrobromide, sulphates, bisulfate, phosphates, nitrates, acetates, oxalates, valeriote, oleates, palmitate, stearates, laurate, borate, benzoate, lactates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, mesylates, malonate, salicylates, propionate, econsultancy, bansilalpet, sulfamate and the like. (For a detailed description of the properties of such salts are described in Berge S.M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19.) Salts of the stated acids can also be specially obtained by the reaction of purified acid with a suitable base, can be synthesized metal salts and amines. The metal include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, the most chelation is Linyi of which are sodium and potassium salts. Suitable inorganic bases which can be obtained metal salts are the hydroxide, carbonate, bicarbonate and sodium hydride, hydroxide and bicarbonate of potassium, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases, of which can be obtained salts of the stated acids, selected amines and amino acids with sufficient basicity to form a stable salt, and suitable for use in medical purposes (in particular, they should have a low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, Tris(hydroxymethyl)aminomethane and the like. In addition, for the salt formation can be used tetraalkylammonium hydroxide, such as choline, Tetramethylammonium, tetraethylammonium and the like. As amino acids can be used basic amino acids such as lysine, ornithine and arginine.

The authors found new antagonists of androgen receptors, which represent previously unknown cyclic N,N'-directively or N,N'-dearylation General formula 1, their optical (R)- and (S)- isomers and their pharmaceutically acceptable salt,

where X represents an oxygen atom or sulfur; m=0 or 1;

R1 represents a C1-C3alkyl; R2 and R3 represent a hydrogen atom;

or R2 and R3 together with the carbon atom to which they are attached, form the group C=O;

orrepresents a group NH;

R4 and R5 represent a hydrogen atom;

or R4 represents a hydrogen atom, and R5 represents methyl;

or R4 represents a hydrogen atom, methyl, and R5 is a group of Zn-Y - R6, where n=1 or 2, Z represents CH2or C=O, Y represents an oxygen atom or N-CH3or Y represents C=O, and Z represents CH2;

R6 represents a hydrogen atom, methyl, benzyl, hydroxy group, or R4 and R5 together with the atoms to which they are linked, form a five - or six-membered heterocycle containing at least an oxygen atom or nitrogen, the latter may be replaced by stands.

Preferred are cyclic N,N'-directively or N,N'-dearylation General formula 1.2,1.3 or 1.4.

where X, R1, R2, R3, R4 and R5 have the above value.

More preferred are cyclic N,N'-directively formula 1.2(1), 1.2(2), 1.2.2 and 1.2.3, and their optical (R)-isomers, (R)1.2(2), (R)-1.2.2 and (R)-1.2.3 and (S)-isomers, (S)-1.2(2), (S)-1.2.2 and (S)-1.2.3.

where Y, Z and R6 have the above value.

More preferred are also the compounds of formula 1.2.2(1), 1.2.2(2), 1.2.2(3), 1.2.3(1), 1.2.3(2) and 1.2.3(3), optical (R)-isomers (R)-1.2.2(l), (R)-1.2.2(2), (R)-1.2.2(3), (R)-1.2.3(l), and (S)-isomers, (S)-1.2.2(l), (S)-1.2.2(2), (S)-1.2.2(3), (S)-1.2.3(l)

The subject of this invention are methods of obtaining cyclic N,N'-dearylation General formula 1, their optical (R)- and (S)- isomers and their pharmaceutically acceptable salts.

1,3-Diaryl-hydantoins of the General formula 1.2 is produced by interaction of the corresponding 4-(cyanomethyl)amino-benzamido 4.1 or (4-carbarnoyl-phenylamino)-acetic acid 4.2 with isothiocyanato 3.2 scheme 1.

Scheme 1

where R1, R4 and R5 have the above value.

Optically active isomers (R)-1.2 (S)-1.2 receive, or on the basis of the respective optical isomers of (R)-4, (S)-4, or separation of mixtures of 1.2.

where R1, R4 and R5 have the above value.

1,3-Diaryl-tetrahydro-pyrimidine-2-ones of General formula 1.3.1 get wsimages is of the appropriate N,N'-dearylation General formula 2 with 1,3-dibromopropane scheme 2.

Scheme 2

where R1 has the above value.

Compounds of General formula 1.3.2 is produced by interaction of the corresponding ethyl β-alaninate General formula 5 with isocyanate 3.1 or isothiocyanato 3.2 and cyclization of the resulting ureas of General formula 6 according to scheme 3.

Scheme 3

where X and R1 have the above value.

1,4-Diaryl-[1,2,4]thiazolidin-3,5-diones of General formula 1.4 is produced by interaction of the corresponding hydrazine 7 with isocyanate 3.1 and cyclization of the resulting semicarbazide 8 diphosgene scheme 4.

Scheme 4

where R1 has the above value.

New antagonists of androgen receptors is also suitable for studying the molecular mechanism of inhibition and activation of androgen receptors.

New cyclic N,N'-directively and N,N'-dearylation General formula 1 are antagonists of androgen receptors, and the activity they are superior to the known antagonists of androgen receptors, published in patent applications WO 2006124118, WO 2007127010, and Drug Data Rep., 2009, 31(6), 609.

In addition, the new antagonist 1.2.2(1) more than three times less toxic than the antagonist MDV3100, as its maximum tolerated dose (MTD)found in experiments with male mice of CD1 is MTD>100 is g/kg, while MDV3100 has MTD ~ 30 mg/kg

The subject of this invention is a new anti-cancer agent representing at least one cyclic N,N'-directively or N,N'- diarylphosphino General formula 1, or its optical (R)- and (S)-isomer, or its pharmaceutically acceptable salt.

The subject of this invention is also a pharmaceutical composition comprising as an active ingredient, at least one cyclic N,N'-directively or N,N'-diarylphosphino General formula 1, or its optical (R)- and (S)-isomers, or pharmaceutically acceptable salt, have anticancer activity, in an effective amount.

More preferred is a pharmaceutical composition having activity against prostate cancer, containing as an active ingredient, at least one cyclic N,N'-directively or N,N'-diarylphosphino General formula 1, or its optical (R)- and (S)-isomers, or pharmaceutically acceptable salt, have anticancer activity, in an effective amount.

Pharmaceutical compositions can include pharmaceutically acceptable excipients. Under the pharmaceutically acceptable experiencemy means used in the field of pharmaceutical diluents, auxiliary agents and/or carriers. The pharmaceutical is Skye composition, along with a new antitumor agent, according to the present invention may include other active ingredients, including possessing anticancer activity, provided that they do not cause unwanted effects.

If you want to use the pharmaceutical compositions of the present invention in clinical practice it can be mixed with conventional pharmaceutical carriers.

The media used in the pharmaceutical compositions of the present invention, are media that are used in the pharmaceutical industry to obtain common forms, including: oral forms are used binders, lubricating agents, disintegrators, solvents, diluents, stabilizers, suspendresume agents, colorless agents, korrigentami taste; in forms for injection are used antiseptic agents, solubilization, stabilizers; local forms are used bases, diluents, lubricating agents, antiseptic agents.

The aim of the present invention is also a method of obtaining pharmaceutical compositions.

This goal is achieved by the mixing of anticancer means with an inert filler and/or solvent, the distinctive feature of which is that as anticancer tools used in isout, at least one cyclic N,N'-directively or N,N'-diarylphosphino General formula 1 or its optical (R)- and (S)-isomer, or its pharmaceutically acceptable salt.

The subject of this invention is also a drug in the form of tablets, capsules, injections, incorporating new anti-cancer agent or a new pharmaceutical composition intended for the treatment of cancer.

Preferred drug incorporating a new anti-cancer agent or a new pharmaceutical composition is a tool designed for the treatment of prostate cancer.

The subject of this invention are also therapeutic cocktails for the treatment of cancer, including cancer of the prostate, comprising as one component of a new drug or a new pharmaceutical composition comprising as an active ingredient, at least one N,N'-diarylphosphino General formula 1 or its optical (R)- and (S)-isomer, or its pharmaceutically acceptable salt.

Therapeutic cocktail for and treatment of prostate cancer, along with the medicinal product according to this invention may include other known drugs intended for the treatment of cancer.

In accordance with this invention JV is a method for treatment of cancer in animals and humans, including prostate cancer, is the introduction of warm-blooded animals or humans of new drugs, new pharmaceutical compositions or new therapeutic cocktail.

Drugs can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally or topically). Clinical dosage means the General formula 1 in patients may be adjusted depending on therapeutic efficacy and bioavailability of the active ingredients in the body, the speed of their metabolism and excretion from the body, and depending on age, gender and stage of disease of the patient, the daily dose in adults is usually 10~500 mg, preferably -50~300 mg. Therefore, during the preparation of the pharmaceutical composition of the medicinal product according to the present invention in the form of dosage units it is necessary to consider the above-mentioned effective dosages, each unit dosage of the drug should contain 10~500 mg funds General formula 1, preferably -50~300 mg. In accordance with the instructions of the doctor or pharmacist these medications can be taken several times during a defined time period (preferably from one to six times).

The invention is illustrated by drawings.

Figure 1 - the change in weight of male mice in peroral the nom introduction connections 1.2.2(1).

Figure 2 - change in weight of male mice by oral administration of the compounds of MDV3100.

The following examples describe the synthesis of N,N'-directively and N,N'-dearylation and biological tests. The following examples illustrate but do not limit, the invention.

Example 1. Synthesis of N-methyl-4-{4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]-imidazolidin-1-yl}-2-fermentated 1.2(1). To a solution of 279 mg (1 mmol) 4-iodine-N-methyl-2-fermentated in 3 ml of DMF added 80 mg (1.07 mmol) of glycine and 207 mg (1.5 mmol) To a2CO3. The reaction mass is stirred in the microwave at 140°C for 18 minutes the Cooled mixture is diluted with 10 ml of AcOEt and 10 ml of water, neutralize the Hcl to pH 2-3, the organic layer separated and the aqueous extracted with AcOEt (5×20 ml). The combined extracts washed with brine, dried over Na2SO4and evaporated in vacuum. Target product highlight column chromatography on SiO2. Get N-(4-methylcarbamoyl-2-forfinal)glycine 4.2(1). A solution of 113 mg (0.5 mmol) of N-(4-methylcarbamoyl-2-forfinal)glycine 4.2(1) and 174 mg (1.0 mmol) 4-isothiocyanato-2-(trifluoromethyl)benzonitrile 3.2 in 2 ml of DMF was stirred at 90°C for 12 h, the Reaction mixture was evaporated in vacuum and release method HPLC N-methyl-4-{4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]-imidazolidin-1-yl}-2-perbenzoic 1.2(1). LCMS (M+H)+437.

Example 2. Overall the manual synthesis of N-methyl-4-{5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl}-2-fermentated 1.2(2), N-methyl-4-{(S)-5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl}-2-fermentated (S)-1.2(2) and N-methyl-4-{(R)-5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl}-2-fermentated (R)-1.2(2).

To a solution of 667 mg (3.9 mmol) of N-methyl-2,4-differentated in 3 ml of DMSO added 347 mg (7.8 mmol) of (D,L), (D)- or (L)-Lanina and 2.54 g (7.8 mmol) Cs2CO3. The reaction mass is stirred in a sealed tube at 90°C for 18 hours, the Cooled mixture is diluted with isopropanol, neutralize 1.36 ml (15.6 mmol) Hcl, filtered, evaporated in vacuum and release method HPLC N-(4-methylcarbamoyl-3-forfinal)alanine 4.2(2), (S)-N-(4-methylcarbamoyl-3-forfinal)alanine (S)-4.2(2) or (R)-N-(4-methylcarbamoyl-3-forfinal)alanine (R)-4.2(2). LC-MS (M+H)+241.1H NMR (DMSO-d6, 400 MHz): 12.66 (ush. s, 1H), 7.62 (m, 1H), 7.45 (t,J=8.8 Hz, 1H), 6.67 (ush. d, J=7.2 Hz, 1H), 6.42 (DD, J1=8.4 Hz, J2=2.0 Hz, 1 H), 6.29 (DD, J1=14.8 Hz, J2=2.0 Hz, 1H), 4.03 (m, 1H), 2.73 (d, J=4.4 Hz, 3H), 1.37 (d, J=7.2 Hz, 3H). A solution of 110 mg (0.46 mmol) of the amine 4.2(2), (S)-4.2(2) or (R)-4.2(2) and 144 mg (0.55 mmol) of 4-isothiocyanato-2-(trifluoromethyl)-benzonitrile 3.2 in 2 ml of DMF is stirred in a microwave oven at 90°C for 12 h, then add another 50 mg (0.19 mmol) 4-isothiocyanato-2-(trifluoromethyl)-benzonitrile 3.2 and conducting the reaction for 12 hours, the Reaction mixture was evaporated in vacuum and allocate method HPLC N-methyl-4-{5-methyl-4-oxo-2-thioxo-3-[3-(three is tormentil)-4-cyanophenyl]imidazolidin-1-yl}-2-perbenzoic 1.2(2), N-methyl-4-{(S)-5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl}-2-perbenzoic (S)-1.2(2) or N-methyl-4-{(R)-5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl}-2-perbenzoic (R)-1.2(2) high seeming constants of inhibition androgenetic receptors (Ki- high antagonistic activity: (Ki1.2(2)=140.2 PM, Ki(S)-1.2(2)=106.7 PM and Ki(R)-1.2(2)=73.6 PM. LC-MS (M+H)+451.1H NMR (CDCl3, 400 MHz): 8.28 (t, J=8.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.94 (d, J=1.2 Hz, 1H), 7.81 (DD, J1=8.0 Hz, J2=1.2 Hz, 1H), 7.48 (DD, J1=12.4 Hz, J2=1.6 Hz, 1H), 7.36 (DD, J1=8.4 Hz, J2=1.6 Hz, 1 H), 6.72 (ush. m, 1 H), 4.83 (K, J=7.2 Hz, 1 H), 3.08 (d, J=4.8 Hz, 3H), 1.60(d, J=7.2 Hz, 3H).

Example 3. Synthesis of N-methyl-4-{2-thio-3-[3-(trifluoromethyl)-4-cyanophenyl]-as-1-yl}-2-fermentation 1.2.2 and 1.2.3 (General method). A solution of 0.75 mmol of the corresponding N-methyl-2-fluoro-4-[(1-cyanomethyl)amino]benzamide 4.1 and 342 mg (1.5 mmol) 4-isothiocyanato-2-(trifluoromethyl)benzonitrile 3.2 in 3 ml of DMF is stirred in a microwave oven at 110°C for 12 h, the Reaction mixture was dissolved in 30 ml Meon, add 7.5 ml of 1N HCl and boiled for 1.5 hours the Solution is evaporated in vacuo, treated with water, the precipitate is filtered off, washed with water and dried in vacuum. Target product produce by the HPLC method.

Get the antagonist androgenetic receptors N-methyl-4-[5-m is Tyl-5-(methoxymethyl)-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]-imidazolidin-1-yl]-2-perbenzoic 1.2.2(1) with K i1.2.2(1)=115.9 PM, which is shared by using liquid chromatography high pressure on Chiralpak HD-H 25×1 cm (Chiral Technologies Inc., USA). As eluent used a mixture of 80% n-hexane, 20% 2-propanol and 0.02% of triethylamine. The flow rate of 4 ml/min Receive optically pure isomers (R)-l.2.2(1) and (S)-1.2.2(l), with high antagonistic activity Ki(S)-1.2.2(1)=721.5 PM and Ki(S)-1.2.2(1)- 53.3 nM. LC-MS (M+H)+495.1H NMR (CDCl3, 400 MHz): 8.28 (t, J=8.4 Hz, 1H), 7.99 (d,.7=8.0 Hz, 1H), 7.92 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.29 (DD, J1=8.8 Hz, J2=1.2 Hz, 1H), 7.21 (DD, J=11.6 Hz, J=1.2 Hz. 1H). 6.72 (K, J=4.4 Hz, 1H),3.71 (d, J=10.0 Hz, 1H),3.43(s, 3H),3.35(d, J=10.0 Hz, 1H), 3.09 (d, J=4.4 Hz, 3H),1.52(s, 3H).

N-Methyl-4-{5-[(benzyloxy)methyl]-5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl}-2-perbenzoic 1.2.2(2). LC-MS (M+H)+571.1H NMR (CDCl3, 400 MHz): 8.22 (t, J=8.4 Hz, 1H), 7.96 (a,J=8.0 Hz, 1H), 7.86 (s, 1H), 7.70 (DD, J=8.0 Hz, J2=1.2 Hz, 1 H), 7.39 (m, 3H), 7.29 (m, 2H), 7.25 (DD, J=8.4 Hz, J=1.6 Hz, 1H),7.18(DD, J1=8.4 Hz, J2=1.6 Hz, 1H),6.71 (K, J=4.8 Hz, 1H), 4.59 (m, 2H), 3.79 (d, J=10.2 Hz, 1H), 3.45 (d, J=10.2 Hz. 1 H). 3.08 (d, J=4.8 Hz. 31-1). is 1.51 (s, 3H).

Ethyl-{4-methyl-3-(4-methylcarbamoyl-3-forfinal)-5-oxo-2-thioxo-1-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-4-yl} acetate 1.2.2(4). LC-MS (M+N)+536.1H NMR (CDCl3, 400 MHz): 8.26 (t, J=8.4 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 8.00 (s, 1H), 7.90 (DD, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.18 (DD, J1=8.0 Hz, J2=1.6 Hz, 1 is), 7.10 (DD, J1=8.0 Hz, J2=1.6 Hz, 1H), 6.78 (K, J=4.8 Hz, 1H), 4.26(m, 1H), 3.13 (d, J=18.0 Hz, 1H),3.09 (d, J=4.8 Hz, 3H), 2.64(d, J=18.0 Hz, 1H), 1.67(s, 3H), 1.31 (t, J=7.0 Hz, 3H).

N-Methyl-4-{4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]-7-oxa-1,3-diazaspiro[4.4]non-1-yl}-2-perbenzoic 1.2.3(1) with Ki(S)-1.2.2(1)=33.9 nM. LC-MS (M+H)+493.1H NMR (CDCl3, 400 MHz): 8.30 (t, J=8.4 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.85 (DD, J=8.4 Hz, J=1.6 Hz, 1H), 7.34 (DD, J1=8.4 Hz, J2=1.6 Hz, 1H), 7.25 (DD, J1=11.8 Hz, J2=1.6 Hz, 1H), 6.78 (K, J=4.4 Hz, 1 H), 4.43 (d, J=10.0 Hz, 1H), 4.16 (d, 7=10.0 Hz, 1H),3.96(m, 1H), 3.75 (m, 1H), 3.09 (d, J=4.4 Hz, 3H), 2.74 (m, 1H), 2.48 (m,1H).

N-Methyl-4-{4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]-8-oxa-1,3-diazaspiro[4.5]Dec-1-yl}-2-perbenzoic 1.2.3(2). LC-MS (M+H)+507.1H NMR (CDCl3, 400 MHz): 8.32 (t, J=8.4 Hz, 1 H), 8.01 (d, J=8.0 Hz, 1 H), 7.95 (s, 1 H), 7.83 (d, J=8.0 Hz, 1 H), 7.20 (d, J=8.4 Hz, 1 H), 7.10 (d, J=8.0 Hz, 1 H), 6.73 (ush. m, 1 H), 4.18 (m, 2H), 3.94 (m, 2H), 3.09 (d, J=4.4 Hz, 3H), 2.07 (m, 4H).

N-Methyl-4-{8-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]-1,3,8-diazaspiro[4.5]Dec-1-yl}-2-perbenzoic 1.2.3(3). LC-MS (M+H)+520.1H NMR (DMSO-d6, 400 MHz): 10.09 (ush. s, 1H), 8.48 (K, J=4.4 Hz, 1H), 8.43 (d, J=8.4 Hz, 1H), 8.29 (s, 1 H), 8.11 (d, J=8.4 Hz, 1 H), 7.84 (t, J=8.0 Hz, 1 H), 7.42 (d, J=10.4 Hz, 1 H), 7.30 (d, J=8.0 Hz, 1H), 3.50 (m, 4H), 2.80 (d, J=4.4 Hz, 3H), 2.78 (s, 3H), 2.72(d, J=14.0 Hz, 1H), 2.16 (m, 2H).

Example 4. Synthesis of N-methyl-4-[5-(hydroxymethyl)-5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl]-2-CFT is benzamide 1.2.2(3). To a solution of 55 mg (0.11 mmol) N-methyl-4-[5-methyl-5-(methoxymethyl)-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl]-2-fermentated in 1.5 ml Snss under argon at -78°C is added dropwise 53 μl (0.55 mmol) VVG3. The reaction mass is stirred for 3 hours at -78°C and then another 3 hours at room temperature. Upon completion of the reaction, excess VVG3neutralized by adding 10 ml of 5% solution of sodium carbonate, the product is extracted with AcOEt, dried over Na2SO4, evaporated in vacuum and the HPLC method produce N-methyl-4-[5-(hydroxymethyl)-5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl]-2-perbenzoic 1.2.2(3) with Ki(S)-1.2.2(3)=46.3 nM,1H NMR (DMSO-d6, 400 MHz): 8.43 (ush. m, 1 H), 8.39 (d, J=8.4 Hz, 1 H), 8.13 (s, 1 H), 7.98 (d, J=8.4 Hz, 1 H), 7.78 (t, J=8.0 Hz, 1 H), 7.42 (d, J=10.8 Hz, 1 H), 7.37 (d, J=8.0 Hz, 1H), 5.93 (t, J=4.4 Hz, 1H), 3.81 (DD, J=11.6 Hz, J=4.4 Hz, 1H), 3.45 (DD, J1=11.6 Hz, J2=5.0 Hz, 1 H), 2.79 (d, J=4.0 Hz, 3H), 1.38 (s, 3H).

Example 5. Synthesis of {4-methyl-3-(4-methylcarbamoyl-3-forfinal)-5-oxo-2-thioxo-1-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-4-yl}acetic acid 1.2.2(5). To a solution of 46 mg (0.086 mmol) of the ester 1.2.2(4) 2 ml of alcohol, add a solution of 7 mg (0.172 mmol) of NaOH in 0. 5 ml of water and the reaction mass was stirred for 12 h (monitoring by LC-MS). The solution is evaporated, add 2 ml of isopropanol and 15 ml (0.172 mmol) model HC1, filtered and evaporated in vacuum. {4-Methyl-3-(4-methylcarbamoyl-3-CFT is henyl)-5-oxo-2-thioxo-1-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-4-yl}acetic acid 1.2.2(5) was isolated by HPLC method. LCMS (M+H)+469.1H NMR (DMSO-d6, 400 MHz): 13.31 (ush. s, 1 H), 8.44 (m, 2H), 8.10 (s, 1 H), 7.95 (d, J=7.6 Hz, 1 H), 7.81 (t, J=8.0 Hz, 1 H), 7.25 (a, J=10.8 Hz, 1H), 7.19 (d, J=8.0 Hz. 1H), 3.16 (d, J=17.6 Hz, 1H), 2.79 (d, J=3.6 Hz, 3H), 2.70 (d, J=17.6 Hz, 1 H), 1.59 (s, 3H).

Example 6. Synthesis of 4-[3-[3-(trifluoromethyl)-4-cyanophenyl]-2-oxo-tetrahydro-pyrimidine-1(2H)-yl]-N-methyl-2-perbenzoic 1.3(1). To a solution of 100 mg (0.26 mmol) of 4-[4-cyano-3-(trifluoromethyl)-phenylcarbonylamino]-N-methyl-2-fermentated 1.1(1) in 2 ml of DMF added 109 mg (0.79 mmol) To a2CO3and 32 μl (0.32 mmol) of 1,3-dibromopropane. The mixture was stirred at 90°Scares 18 h add another 109 mg2CO3and 32 μl of 1,3-dibromopropane and continue the reaction. Adding repeat 2 more times. The mixture is evaporated in vacuo, dissolved in chloroform, washed with water, dried over Na2SO4and evaporated. Target product produce by the method of column chromatography on SiO2(eluent - AcOEt). LC-MS (M+N)+421.1H NMR (DMSO-d6, 400 MHz): 8.17 (ush. m, 1 H), 8.13 (d, J=8.4 Hz, 1 H), 8.07 (d, J=2.0 Hz, 1 H), 7.83 (DD, J1=8.4 Hz, J2=2.0 Hz, 1 H), 7.62 (t, J=8.4 Hz, 1 H), 7.38 (DD, J1=12.4 Hz, J2=2.0 Hz, 1 H), 7.29 (DD, J1=8.4 Hz, J2=2.0 Hz, 1 H), 3.90 (t, J=5.8 Hz, 2H), 3.81 (t, J=5.8 Hz, 2H), 2.77 (d, J=4.8 Hz, 3H), 2.21 (m, 2H).

Example 7. Synthesis of N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-2,4-dioxotetrahydrofuran-1(2H)-yl}benzamide 1.3.1(1). To a solution of 9 g (53.6 mmol) of 4-amino-N-methyl-2-fermentated in 90 ml of DMSO PR is billaut 8 g (80 mmol) acrylate and 0.81 g (5.4 mmol) of DBU and stirred for 24 h at 70°C (control for LC-MS). The reaction mass is subjected to lyophilization and the residue is recrystallized from aqueous alcohol. Obtain ethyl N-[4-(methylcarbamoyl)-3-forfinal]-β-alaninate 5. LCMS (M+H)+269.1H NMR (DMSO-d6, 400 MHz) δ 7.57 (ush. SN). 7.48 (t, J=8.8 Hz, 1 H), 6.47 (ush. s, 1 H), 6.42 (d, J=8.8 Hz, 1 H). 6.33 (d, J=14.8 Hz, 1 H). 4.07 (K, J=7.2 Hz, 2H), 3.32 (ush. m, 2H), 2.73 (d, J=4.4 Hz, 3H), 2.55 (t, J=6.4 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H). A solution of 425 mg (1.87 mmol) of 4-isocyanato-2-(trifluoromethyl)benzonitrile 2.1 and 500 mg (1.87 mmol) of ethyl-N-[4-(methylcarbamoyl)-3-forfinal]-β-alaninate 5 in 10 ml of CH2CL2stirred for 15 hours, the Reaction mass is evaporated in vacuum and the target product produce by the method of column chromatography on SiO2(eluent - hexane: AcOEt: EtaN=1:1:0.03). Get ethyl-N-[4-(methylcarbamoyl)-3-forfinal]-N-{[3-(trifluoromethyl)-4-cyanophenyl]-carbarnoyl}-β-alaninate 6(1). LC-MS (M+H)+481. To a solution of 500 mg (1.04 mmol) of ethyl-N-[4-(methylcarbamoyl)-3-forfinal]-N-{[3-(trifluoromethyl)-4-cyanophenyl]-carbarnoyl}-β-alaninate 6(1) in 5 ml of Asón add 2.5 ml model HC1 and stirred for 15 h the Reaction was poured into water, the product extracted with EtOAc. The organic layer is dried over Na2SO4, evaporated in vacuum and allocate column chromatography on SiO2(eluent - hexane: AcOEt=1:1) N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-2,4-dioxo-tetrahydro-pyrimidine-1(2)-yl}benzamide 1.3.1(1). LC-MS (M+N)+435.1H NMR (DMSO-d6, 400 MHz) 5 8.29 (d, J=7.6 Hz, H), 8.23 (ush. m, 1H), 8.11 (s, 1H), 7.89 (d, J=2.0 Hz, 1 H), 7.67 (t, J=8.4 Hz, 1 H), 7.39 (d, J=12.4 Hz, 1 H), 7.33 (d, J=8.4 Hz, 1 H), 4.02 (t, J=6.4 Hz, 2H), 3.03 (t, J=6.4 Hz, 2H), 2.77 (d, J=4.4 Hz, 3H).

Example 8. Synthesis of N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-4-oxo-2-dioxotetrahydrofuran-1(2H)-yl}benzamide 1.3.1(2). A solution of 320 mg (1.51 mmol) of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile 3.2 and 404 mg (1.51 mmol) of ethyl-N-[4-(methylcarbamoyl)-3-forfinal]-β-alaninate 5 in 8 ml DMF nagrevom in a microwave oven at 60°C for 8 hours the Reaction mass is evaporated in vacuum and allocate column chromatography on SiO2(eluent - hexane: AcOEt=1:2) ethyl-N-[4-(methylcarbamoyl)-3-forfinal]-N-{[3-(trifluoromethyl)-4-cyanophenyl]thiocarbamoyl}-β-alaninate 6(2). LC-MS (M+N)+497. To a solution of 200 mg (0.4 mmol) of the obtained ester 6(2) 1 ml of alcohol, add a solution of 32 mg (0.8 mmol) of NaOH in 0.25 ml of water and the reaction mass stirred at 80°C for 2 h (monitoring by LC-MS). The reaction mass nejtralizovyvat 69 μl (0.8 mmol) Hcl, evaporated in vacuo, extracted the reaction product with hot isopropanol and evaporated in vacuum. Receive N-[4-(methylcarbamoyl)-3-forfinal]-N-{[3-(trifluoromethyl)-4-cyanophenyl]thiocarbamoyl}-β-alanine 6(3). LCMS (M+N)+469. To a solution of 114 mg (0.24 mmol) of the obtained acid 6.3 1.5 ml DMF added 86 mg (0.36 mmol) TBTU and 110 mg (0.84 mmol) of diisopropylethylamine. The reaction mass was stirred at 45°C for 15 hours At the end of the reaction (monitoring by LC-MS) RA the solution was poured into water and extracted with EtOAc. The organic layer is dried over Na2S04, evaporated in vacuum and release method HPLC M-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-4-oxo-2-dioxotetrahydrofuran-1(2H)-yl}-2-perbenzoic 1.3.2(2) with Ki(S)-1.3.2(2)=95.2 nM. LC-MS (M+H)+451.1H NMR (DMSO-d6400 MHz): 8.35 (K, J=4.4 Hz, 1H), 8.27 (doctor J=8.0 Hz, 1H),8.06(d, J=1.6 Hz, 1 H), 7.83 (DD, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.71 (t, J=8.2 Hz, 1H),7.42(DD, J1=11.0 Hz, J2=1.8 Hz, 1H), 7.33 (DD,.J1=8.2 Hz, J2=1.8 Hz, 1H), 4.13 (t, J=6.8 Hz, 2H), 3.17 (t, J=6.8 Hz, 2H), 2.78 (d, J=4.4 Hz, 3H).

Example 9. Synthesis of N-Methyl-2-fluoro-4-[4-[3-(trifluoromethyl)-4-cyanophenyl]for 3,5-dioxo-1,2,4-triazolin-1-yl]benzamide 1.4(1). To a solution of 1 g (5.95 mmol) of 4-amino-N-methyl-2-fermentated in 3.1 ml of 5N Hcl is added dropwise 2.38 ml of a 2.5M solution of NaNO2maintaining the temperature of the mixture <5°C. the Mixture is stirred for another 30 min at a given temperature, after which the resulting solution was pinned to the suspension 4.03 g (17.9 mmol) SnCl2*2H2O in 4.2 ml of hydrochloric acid at 0°C. After 2 h stirring at a predetermined temperature the precipitate is filtered off, dissolved in 40 ml of water and add NaOH until strongly alkaline reaction. The mixture is extracted with ether (3*100 ml), dried over MgSO4and evaporated in vacuum. Get 4 hydrazino-N-methyl-2-perbenzoic 7. LC-MS (M+H)+184.1H NMR (CDCl3, 400 MHz): 7.96 (t, J=8.4 Hz, 1H), 6.64 (ush. m, 1 H), 6.60 (t, J=1.6 Hz, 1 H), 6.57 (DD, J1=7.2 Hz, J2=2.0 Hz, 1 H), 5.60 (ush. s,1H), 3.66 (ush. c, 2H),3.00(DD, J1=4.8 Hz, J2=1.2 Hz, 1H). To a solution of 54 mg (0.29 mmol) of 4-hydrazino-N-methyl-2-fermentated 7 in 3 ml of dioxane was added a solution of 59 mg (0.27 mmol) 4-isocyanato-2-(trifluoromethyl)benzonitrile in 2 ml of dioxane. After 2 h stirring, the dioxane is distilled off in vacuo, the residue triturated in ether, filtered and dried in vacuum. Get 2-[(4-methylcarbamoyl)-3-forfinal]-N-[3-(trifluoromethyl)-4-cyanophenyl]-hydrazinecarboxamide 8(1). LC-MS (M+N)+405. 'H NMR (DMSO-d6, 400 MHz): 9.65 (ush. s, 1 H), 8.72 (ush. s, 1 H), 8.37 (s, 1 H), 8.25 (ush. s, 1 H), 8.03 (ush. m, 1 H), 7.88 (d, J=8.8 Hz, 1 H), 7.58 (m, 2H), 6.63 (d, J=8.4 Hz. 1 H), 6.48 (d, J=14.0 Hz, 1H), 2.77 (d, J=4.4 Hz, 3H). To 80 mg (0.2 mmol) 2-[(4-methylcarbamoyl)-3-forfinal]-N-[3-(trifluoromethyl)-4-cyanophenyl]-hydrazinecarboxamide 8.1 in 2 ml of dichloroethane add 56 μl (0.4 mmol) of triethylamine and then added 27 μl (0.22 mmol) of diphosgene. The reaction mass is stirred in a sealed tube at 80°C for 15 hours, the Solvent is distilled off in vacuum and the residue chromatographic on SiO2(eluent CH2CL2: Meon, gradient from 100:1 to 20:1). Get N-methyl-2-fluoro-4-[4-[3-(trifluoromethyl)-4-cyanophenyl]for 3,5-dioxo-1,2,4-triazolin-1-yl]benzamide 1.4(1). LC-MS (M+H)+422.1H NMR(DMSO-d6, 400 MHz): 11.53 (s, 1H), 8.22 (ush. m, 1H), 8.16 (d, J=8.8 Hz, 1 H), 7.99 (DD, J1=8.8 Hz, J2=1.6 Hz, 1 H). 7.95 (d, J=1.6 Hz, 1 H), 7.81 (t, J=8.4 Hz, 1H), 7.69 (DD, J1=8.8 Hz. J2=2.0 Hz, 1H), 7.62 (DD, J1=12.0 Hz, J 2=2.0 Hz, 1H), 2.79 (d,7=4.4 Hz, 3H).

Example 10. Determination of antagonistic activity of cyclic N,N'-dearylation General formula 1 and the well-known analogue of MDV3100 in relation to androgen receptors. The ability of the new cyclic N,N'-dearylation General formula 1 and a known drug MDV3100 to block androgen receptors was determined by their efficiency inspirowane stimulated dehydrotestosterone expression specific for prostate specific antigen (PSA) in concernig cells of the human prostate LNCap was obtained from the American Bank tissue cultures (ATSS, USA). These cells sensitive to 5-a-dihydrotestosterone (DHT) and produce Chancery marker (PSA) in his presence. Cells were grown in RPMI 1640 medium (Invitrogen, USA)containing 10% calf serum (Hyclone, USA), 1% antibiotic/antifungal mixture (Sigma, USA) and 4.5% glucose. Before experiments, cells were washed and suspended in the same medium, but where calf serum was replaced with serum-treated to remove traces of hormones activated carbon. The cells were poured into 100 µl (10000 cells) cell 96-well plates and left for 4 days in an incubator at 37°C (100% humidity) in an atmosphere of 95% air/5% CO2. After 4-day incubation, the cells were added cyclic N,N'-dearylation General formula 1 at various concentrations and then add what took place 20 nm DHT (concentration, corresponding to 80-90% of the maximum stimulation). Cells were left for 5 days for an additional incubation in the same conditions. After incubation the samples supra-cellular environment were selected for analysis on the PSA. The analysis was carried out according to the Protocol recommended by the manufacturer of the kit for determination of PSA (Alpha Diagnostic International, USA). After moistening hole, with the bottom attached antibodies against PSA, thereto was added 25 μl of samples and then 100 μl of antibodies against PSA, to which is conjugated to horseradish peroxidase. After 30-minute incubation at room temperature, the contents of the wells were removed, the wells washed several times and the wells were filled with 100 μl of a chromogenic peroxidase substrate. The die was maintained for 15 min at room temperature, the wells were added to 50 ál of stop solution and the developed color was measured by absorption at 450 nm. The number of the resulting colour is proportional to the concentration of PSA in the sample. On the basis of the results obtained according to the reduction caused by dihydrotestosterone (DHT) practices of PSA in the presence of different concentrations of the substances were constructed curves dose-response, which determined the IC50 values, which were used to determine the values of the apparent inhibition constants (Kifor these subjects the compounds of General formula I according the equation Cheng-Prusova [Cheng, Y., Prusoff, W.H. "Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (150) of an enzymatic reaction". Biochem Pharmacol. (1973) 22, 3099-3108]:

Ki=IC50/(1+L/KD),

where L is the concentration of agonist (DHT) and KDis a constant activation of the receptor, is numerically equal to the value of the EU50determined in parallel in each experiment based on the stimulation of the synthesis of PSA concentration of DHT.

The results presented in the respective examples, suggests that the new antagonists androgenetic receptors according to this invention in some cases more active than MDV3100, tested in the same conditions, as a witness, for whichiMDV3100=79.5 nM.

Example 11. Determination of the maximum tolerated dose of a new antagonist 1.2.2(1) and its known analogue of MDV3100. The maximum tolerated dose (MTD) of a new antagonist 1.2.2(1) and its analogue MDV3100 was determined in experiments on male CD1 mice when administered orally 1 time a day for 5 days at doses of 10, 30 and 100 mg/kg of the Substance was dissolved in sterile water with tween-80. The control animals (Placebo group) were injected with sterile water with tween-80. Take into account the body weight and mortality of animals. Statistical comparison of groups was performed by nonparametric criterion ANOVA using Statistica.

In the introduction the Institute of compounds 1.2.2(1) in doses up to 100 mg/kg mortality of mice was not observed. On the 3rd-4th days in the group of mice treated with the studied substance in the dose of 100 mg/kg body weight was compared with the control animals, however, statistical significance was not observed (figure 1). These data indicate that the connection 1.2.2(1) has a MTD>100 mg/kg

With the introduction of connection MDV3100 in doses of 10 and 30 mg/kg of death of mice was not observed. In the group of mice to which the target substance was administered at a dose of 100 mg/kg on day 3 body weight began to decline. On the 5th day body weight in animals of this group were statistically significantly different from body mass of the animals in the Placebo group (p=0.002, figure 2). Killed animal. These data indicate that the connection MDV3100 has MTD ~ 30 mg/kg

Example 12. Obtaining medicines in tablet form. Mix 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg N-methyl-4-[5-methyl-5-methoxymethyl-3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-imidazolidin-1-yl]-2-fluoro-benzamide 1.2.2(1). The obtained pharmaceutical composition pressed into the bar. The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 560 mg each.

Example 13. Obtaining medicines in capsule form. Thoroughly mixed with N-methyl-4-[5-methyl-5-methoxymethyl-3-(3-thrift metil-4-cyanophenyl)-4-oxo-2-thioxo-imidazolidin-1-yl]- 2-fluoro-benzamide 1.2.2(1) with lactose powder in a 2:1 ratio. The obtained pharmaceutical composition is Packed 300 mg in gelatin capsules of suitable size.

Example 16. Obtaining medicines in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection. Mix 500 mg N-methyl-4-[5-methyl-5-methoxymethyl-3-(3-trifluoromethyl-4-cyanophenyl)-4-oxo-2-thioxo-imidazolidin-1-yl]-2-fluoro-benzamide 1.2.2(1) with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed in 1 ml ampoules which are sealed.

1. Antagonists of androgen receptors, representing a cyclic N,N'-directively or N,N'-dearylation General formula 1, their optical (R)-and (S)-isomers and their pharmaceutically acceptable salts,

where X represents an oxygen atom or sulfur;
m=0 or 1;
R1 represents a C1-C3alkyl;
R2 and R3 represent a hydrogen atom;
or R2 and R3 together with the carbon atom to which they are attached, form the group C=O;
orrepresents a group NH;
R4 and R5 represent a hydrogen atom;
or R4 represents a hydrogen atom, and R5 represents methyl;
or R4 represents a hydrogen atom, methyl, and R5 is a group of Zn-Y-R6, where n=1 or 2, Z represents CH2; or= and Y is an oxygen atom or N-CH 3or Y represents C=O, and Z represents CH2;
R6 represents a hydrogen atom, methyl, benzyl, or hydroxy-group
R5 and R4 together with the atoms to which they are linked, form a five or six-membered heterocycle containing at least an oxygen atom or nitrogen, which may be substituted by the stands.

2. Connection represents a cyclic N,N'-directively or N,N'-dearylation General formula 1.2, 1.3 or 1.4, optical (R)- and (S)-isomers and their pharmaceutically acceptable salts


where X, R1, R2, R3, R4 and R5 have the above in claim 1 value.

3. Compounds according to claim 2, representing a cyclic N,N'-directively formula 1.2(1), 1.2(2), 1.2.2 and 1.2.3, and their optical (R)-isomers (R)-1.2(2), (R)-1.2.2 and (R)-1.2.3 and (S)-isomers, (S)-1.2(2), (S)-1.2.2 and (S)-1.2.3




where Y, Z and R6 have the above in claim 1 value.

4. Compounds according to claim 2, which are compounds of formula 1.2.2(1), 1.2.2(2), 1.2.2(3), 1.2.3(1), 1.2.3(2) and 1.2.3(3), and optical (R)-isomer: (R)-1.2.2(1), (R)-1.2.2(2), (R-1.2.2(3), (R)-1.2.3(l) and (S)-isomers: (S)-1.2.2(l), (S)-1.2.2(2), (S)-1.2.2(3), (S)-1.2.3(1)




5. The method of obtaining compounds of General formula 1.2, and their optical (R) or (S)-isomers according to any one of claim 2 to 4 by the interaction of the corresponding 4-(cyanomethyl)amino-benzamido General formula 4.1, or (4-carbarnoyl-phenylamino)-acetic acids of the General formula 4.2, or optical (R) or (S)-isomers, with isothiocyanato formula 3.2

6. An anti-cancer agent representing at least one cyclic N,N'-directively or N,N'-diarylphosphino General formula 1 according to any one of claims 1 to 4, having the properties of an androgen receptor antagonist.

7. Pharmaceutical composition having the property of androgen receptor antagonist for the treatment of cancer comprising as active ingredient an anti-cancer agent according to claim 6.

8. A method of obtaining a pharmaceutical composition according to claim 7 mix anticancer tool according to claim 6 with an inert filler and/or diluent.

9. The drug is in the form of tablets, capsules or injections, suitable for the treatment of cancer, including St. the first part of an anti-cancer agent according to claim 6 or a pharmaceutical composition according to claim 7.

10. The drug according to claim 9, intended for the treatment of prostate cancer.

11. The method of treatment of cancer, including prostate cancer, by administration of a medicinal product on PP and 10, or a pharmaceutical composition according to claim 7, or anti-cancer tool according to claim 6.

12. Antagonists according to claim 1 for studying the molecular mechanism of inhibition of androgen receptor according to any one of claims 1 to 4.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) given below or pharmaceutically acceptable salts thereof:

[where: each of X, Y, Z and W independently denotes a methane group which optionally contains substitutes selected from a group of substitutes α, or a nitrogen atom (except when all elements X, Y, Z and W denote a methane group which optionally contain substitutes selected from the group of substitutes α); A denotes -(C(R3)(R4))m1-; B denotes -O-; D denotes -C(O)-; m1 equals 0; Q denotes a methane group or a nitrogen atom; R denotes a group of formula (II)

, where R6 denotes a lower alkyl group; R7 and R8, together with the nitrogen atom with which they are bonded, form a 5-6-member nitrogen-containing aliphatic heterocyclic group; and where the group of substitutes α includes the following substitutes. Group of substitutes α: halogen atom, hydroxyl group, lower alkyl group, alkoxyl group (said group can be substituted with a cycloalkyl group), amino group, mono- or disubstituted lower alkylamino group, aryl group (said group can be substituted with a halogen atom, a -SO2CH3 group), aryloxy group (said group can be substituted with a halogen atom), heteroaryl group, where 'heteroaryl group' denotes a 5- or 6-member monocyclic saturated or unsaturated group containing 1-2 heteroatoms selected from an oxygen atom or a nitrogen atom (said group can be substituted with an alkoxyl group, alkyl group). The invention also relates to a histamine 3 receptor antagonist, histamine 3 receptor inverse agonist, a prophylactic or medicinal agent, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having histamine H3 receptor antagonist or inverse agonist action.

15 cl, 57 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I) or to its salt or ester in which radicals and symbols have the values presented in claim 1. These compounds are ACC inhibitors.

EFFECT: production of compounds to be applied as a therapeutic agent for various ACC-related disorders such as bacony liver, hyperlipidemia, obesity and diabetes.

13 cl, 48 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds -(Z)-1'-R-6',6'-dimethyl-3-(phenyl(arylamino)methylene)-6',7'-dihydro-3H-spiro[furane-2,3'-indol]-2',4,4',5(1'H,5'H)-tetraons of formula: , where Ar=phenyl, n-methoxyphenyl, n-tollyl; R=allyl, benzyl, phenyl, n-tollyl, n-methoxyphenyl, α-naphtyl, as well as to method of their obtaining, which consists in the following: isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates are subjected to interaction with N-substituted 3-amino-5,5-dimethylcyclohex-2-enons in medium of inert aprotonic solvent with further separation of target products. Process is carried out at temperature 20-22°C. As solvent, absolute chloroform is used.

EFFECT: obtaining compounds possessing analgesic activity.

4 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds, and more specifically to 5-formyl-substituted indoline spirobenzopyrans with general formula 1 where R1, R2 - Alk or c-Alk; R3 -CHO or NO2 group (electron-acceptor substitute), with photochromic properties. The invention also relates to the method of producing 5-formyl substituted derivatives of indoline spirobenzopyrans with formula 1. Spirobenzopyrans, which have electron-acceptor substitutes in the pyran part of the molecule, are subjected to direct selective formylation in position 5 in a trifluoroacetic acid medium with urotropine (hexamethylenetetramine) at boiling point of the mixture in an inert atmosphere for 1-1.5 hours. The obtained 5-formyl-substituted spirobenzopyrans are photochromic compounds are photochromic and can be used for making new photochromic materials (recording devices or information storage; photo-switching activity of biological objects and polymer matrices, complex formation; information security media, maps, special document protection equipment) or as advanced initial compounds for further synthesis of a large number of new photochromic objects.

EFFECT: wider field of application of the compounds.

2 cl, 1 tbl, 3 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinospiropyrane of the formula (1): wherein R1 means (C1-C18)-alkyl; each among R2 and R3 mean independently (C1-C4)-alkyl; R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl formyl, (C1-C)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2. Method comprises the following steps: (i) synthesis of indoline on polymeric carrier of the formula (III): wherein R1 means (C1-C18)-alkyl; each among R2 and R means independently (C1-C4)-alkyl; (ii) treatment of indoline-carrying polymeric carrier wherein this carrier represents hydroxy-resin at temperature from 50°C to 120°C in inert atmosphere for time from 14 h to 11 days with a derivative of salicylic aldehyde of the formula (VI): wherein R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl, formyl, (C1-C4)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2 to yield indolinospiropyrane compound of the formula (I), and (iii) release of indolinospiropyrane compound of the formula (I). Invention proves synthesis of novel derivatives of indolinospiropyrane possessing photochromic properties.

EFFECT: improved method of synthesis.

8 cl, 28 ex

FIELD: organic chemistry.

SUBSTANCE: invention describes C2-phenyl-substituted cyclic ketoenols of the general formula: wherein W means hydrogen atom, alkyl with 1-6 carbon atoms; X means alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms; Y means hydrogen atom, methyl, ethyl, isopropyl, alkenyl with 2-6 carbon atoms, ethynyl; Z means hydrogen atom, alkyl with 1-6 carbon atoms under condition that at least one of residues W, X, Y or Z means a chain with at least 2 carbon atoms but only one of residues X and Y can mean alkenyl with 2-6 carbon atoms; CKE means one of the following groups: , , and wherein A means hydrogen atom, alkyl with 1-6 carbon atoms; B means hydrogen atom, alkyl with 1-6 carbon atoms; A and B in common with carbon atom to which they are bound mean cycloalkyl with 5-6 carbon atoms wherein the ring carbon atom can be substituted with oxygen atom and can be substituted with alkyl with 1-6 carbon atoms or alkoxyl with 1-6 carbon atoms; A and B in common mean group of the formula: D means hydrogen atom or phenyl substituted with fluorine atom if CKE means group of the formula (4); G means hydrogen atom (a) or one of groups of the formula: or wherein R1 means alkyl with 1-6 carbon atoms, alkoxymethyl with 1-2 carbon atoms; R2 means alkyl with 1-4 carbon atoms; A and Q1 in common mean alkanediyl with 3-4 carbon atoms; Q2 means hydrogen atom. Invention provides preparing compound of the formula (I) possessing with insecticide, acaricide and herbicide activity.

EFFECT: valuable properties of compounds.

2 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

FIELD: pharmaceutical chemistry, in particular pharmaceutical compositions.

SUBSTANCE: new spyro(2H-1-benzopyrane-2,4'-piperidine) derivatives of general formula I

and pharmaceutically acceptable salts thereof are disclosed. In formula dotted line is optional bond; Y is 1-4 substituents independently selected from hydrogen, halogen, C1-C4-alkyl, optionally substituted with one or more halogen, C1-C6-alkyloxy, optionally substituted with halogen or C3-C6-cycloalkyl, C2-C6-alkenyloxy, C2-C6-alkinyloxy, C3-C6-cycloalkyloxy, C6-C12-aryloxy, arylalkyloxy, pyridilmethoxy, SR3, NR3R4, OSO2R5, and NR3SO2R4; or two Y together may form O-(CH2)n-O or O-(CF2)n-O, wherein n is 1 or 2: or Y is condensed C5-C6-aryl group; X is 1-3 substituents independently selected from hydrogen, halogen, hydroxyl, C1-C6-alkoxy, and C1-C4-alkyl; R1 is hydrogen, C1-C4-alkyl, or C6-C12-aryl; R2, R3, and R4 are independently hydrogen or C1-C4-alkyl; R5 is C6-C12-aryl. Also disclosed are pharmaceutical compositions including said derivatives and having activity in relation to CNS.

EFFECT: new compounds with valuable pharmacological action.

9 cl, 1 tbl, 83 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to novel derivatives of quinolone or one pharmaceutically acceptable salts thereof, solvates thereof or solvates of salts thereof, having general formula I , in which R1 denotes fluorine, R3 denotes halogen, a hydroxy group or a C1-C4-alkoxy group, R4 denotes C1-C6-alkyl or C3-C8-cycloalkyl, where the alkyl can contain 1-3 substitutes, and the substitutes are independently selected from a group comprising halogen or trifluoromethyl, and where the cycloalkyl can contain 1-3 halogen atoms as substitutes, or R3 and R4 together with atoms to which they are bonded form a ring with a group of formula , in which * indicates a site for bonding with a carbon atom, and # indicates a site for bonding with a nitrogen atom, R7 and R8 independently denote halogen, trifluoromethyl, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, C1-C3-alkyl or C1-C3-alkoxy group, and R9 denotes hydrogen, halogen or C1-C3-alkyl, or R8 denotes a trifluoromethoxy group, and R7 and R9 denote hydrogen, R10 denotes a group of formula or , in which * indicates a site for bonding with a carbon atom, R2 is bonded in position 3 or 4 and denotes a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxycarbonyl, C3-C6-cycloalkylcarbonyl or optionally hydroxy-substituted C1-C6-alkylaminocarbonyl, where the alkyl is substituted with one substitute and the substitute is selected from a group comprising a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkoxycarbonyl and 2-oxopyrrolidin-1-yl, R5 and R6 are independently bonded in positions 3, 4 or 5 and independently denote hydrogen, hydroxy group, methyl or ethyl, and Y denotes a methylene group or an oxygen atom. The invention also relates to methods of producing a compound of formula I, a medicinal agent based on the compound of formula I, use of the compound of formula I and a method of fighting viral infections.

EFFECT: novel substituted quinolone derivatives which are useful in treating viral diseases are obtained.

11 cl, 1 tbl, 69 ex

FIELD: medicine.

SUBSTANCE: invention refers to indole-3-yl-carbonyl-spiro-piperidine derivatives which have an effect of Vla-receptor antagonists and are presented by Formula I: where a tail spiropiperidine group A and residual R1, R2 and R3 are such as specified in the patent claim.

EFFECT: higher efficiency of applying the compounds in drugs effective in dysmenorrhea, hypertension, chronic heart failure, inadequate vasopressin secretion, hepatic cirrhosis, nephrotic syndrome, obsessive-compulsive disorder, anxious and depressive disorders.

22 cl, 42 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel indol-3-yl-carbonyl-asaspiro-derivatives of formula I: where R1 represents H,-(CH2)m-Ra, where Ra represents NRiRii, phenyl, possibly substituted by one or more than one B, -(CH2)n-(CO)-Rb , where Rb represents NRiRii; there exists one or more than one R2 , where each R2 is the same or different and represents one or more than one H, in halogen way; R3 represents H, C1-6-alkyl; B represents in halogen way; Ri and Rii each independently represents H, C1-6-alkyl, C1-6alkyl-NRiiiRiv; Riii and Riv each independently represents C1-6alkyl; m equals 1-6; n equals 1-4; A represents group : where R4 represents H or C1-6alkyl; R5 represents phenyl, possibly substituted in halogen way; or its pharmaceutically acceptable salt; on condition that 1-(1H-indol-3-yl-carbonyl)-4-(1,3-dioxolan-2-yl)pyperidine is excluded.

EFFECT: compounds demonstrate antagonistic activity with respect to Via vasopressin receptor, which makes it possible to apply them for obtaining pharmaceutical composition.

22 cl, 4 dwg, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to indol-3-yl-carbonyl-spiro-piperadine derivatives used as V1a receptor antagonists and which have formula I: , where the spiro-piperadine A head group and residues R1, R2 and R3 are as defined in claim 1 of the invention. The invention also pertains to pharmaceutical compositions which contain such compounds and use thereof in preparing medicines with V1a receptor antagonist activity.

EFFECT: high activity of derivatives.

37 cl, 1 tbl, 285 ex

FIELD: chemistry.

SUBSTANCE: described are spirocyclic derivatives of cyclohexane of general formula . Values of radicals are given in the formula of invention. The compounds have affinity to the ORL1 receptor and can be used for treating abstinence syndrome (withdrawal syndrome) and pain. Also described is a medicinal agent and use of formula (I) compounds for preparing respective medicinal agents.

EFFECT: increased effectiveness of using the compounds.

13 cl, 17 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel derivatives of diazaspiropiperidine of the formula I: , where A-B is -CH2-CH2-, -CH2-O- or -O-CH2-; X is hydrogen or hydroxy; R1 is aryl optionally substituted by one or more substitutes selected out of group including haloid, (lower) alkyl, cyano, CF3, -OCF3, (lower) alkoxy, -SO2-(lower)alkyl, or heteroaryl with two nitrogen atoms; R2 is phenyl optionally substituted by one or more substitutes selected out of group including haloid, (lower) alkyl, CF3 or (lower) alkoxy; R3 is hydrogen or (lower)alkyl; n is 0, 1 or 2; and their pharmaceutically acceptable salts.

EFFECT: medicine based on compounds of the formula 1 and their application in obtaining medicine for neuropathological and neuropsychiatric disease treatment.

12 cl, 1 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (1) where: R1 represents hydrogen atom, halogen, CP3, (1-3C)alkoxy group, m is an integer within 1 to 4, provided when m is equal to 2, 3 or 4, R1 substitutes can be either identical or different, R2 represents hydrogen atom, alkyl (1-6C) group optionally substituted with alkoxy group, cycloalkyl (3-6C) group, -CH2OH, -CH2OCH3, acetyl group, benzyl group optionally substituted with amino group, or group Q of the following composition (2): were: [ ]n symbolically represents -(CH2)n-, where n is an integer within 0 to 7, R3 represents hydrogen atom or alkyl (1-3C) group, R4 represents hydrogen atom, alkyl (1-6C) group optionally substituted with one or more groups, chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkoxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, amido group dialkyl, carboxyl group, saturated, unsaturated or partially saturated mono- or dicyclic 5-10-meroud ring optionally substituted with one or more groups, chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl group, or alkyl (1-3C) group substituted with saturated, unsaturated or partially saturated five- or hexamerous ring optionally containing one or more heteroatoms, such as nitrogen atom, oxygen atom or sulphur atom, optionally substituted with one or more groups chosen from alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl group, or (R3+R4) together with nitrogen atom, they are attached to, represent saturated, unsaturated or partially saturated mono- or dicyclic five- or hexamerous ring optionally containing one or more heteroatoms, such as nitrogen atom, oxygen atom or sulphur atom, optionally substituted with one or more groups chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl groups, as well as to all stereoisomers, to pharmaceutically acceptable salts. Additionally, the invention concerns pharmaceutical compositions and application of compounds.

EFFECT: production of new biologically active compounds with agonist activity to ORL1 receptors.

9 cl, 488 ex, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to novel derivatives of imidazolidine of the formula (I): , wherein symbols B, E, W, Y, R, R2, R3, R30, e and h have values given in claim 1 of the invention. Compounds of the formula (I) represent pharmaceutically active substances. Compounds of the formula (I) relates to inhibitors of adhesion and migration of leukocytes and/or antagonists of adhesion receptor VLA-4 that relates to group of integrins. Proposed compounds can be used in treatment of diseases that are induced or associated with undesirable degree of leukocyte adhesion and/or migration of leukocytes, or wherein interaction between cells or between cells and matrix are very significant and important and these interactions are based on interaction of VLA-4 receptors and ligands. Except for, invention relates to methods for synthesis of compounds of the formula (I) and pharmaceutical compositions containing compounds of the formula (I).

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

12 cl, 19 ex

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