Substituted 2-aryl-3-(heteroaryl)imidazo[1,2-a]-pyrimidines, pharmaceutical compositions comprising thereof and associated methods

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted 2-aryl-3-(heteroaryl)imidazo[1,2-a]-pyrimidines of the formula (I):

or to their pharmaceutically acceptable salts wherein: (a) R1 is taken among the group consisting of -NH2, C1-5-alkylamino-, di-C1-5-alkylamino-, phenylmethylamino-group; (b) Y is taken among the group consisting of hydrogen atom (H), halogen atom, piperidine, OR4, SR4, -SO2CH3, NHR4 and NR4R5 wherein R4 and R5 are taken independently among hydrogen atom (H), α-alkylphenyl-C1-5-alkyl, linear or branched alkyl substituted optionally with C3-5-carbocycle, phenyl or substituted phenyl wherein indicated phenyl can be substituted with one or some substituted taken among C1-5-alkoxy-group; (c) R2 represents from one to five members taken independently among the group including hydrogen atom (H), halogen atom, trifluoromethyl; (d) R3 represents hydrogen atom (H), or radicals R3 taken in common form aromatic ring; (e) X represents nitrogen atom (N) or -CH. Also, invention relates to methods for preparing indicated compounds and to a method for treatment based on these compounds. Invention provides preparing novel compounds that can be used in relief states by reducing the level of inflammatory cytokines, for example, the indicated state represents proliferative (rheumatic) arthritis.

EFFECT: valuable medicinal properties of compounds and compositions.

40 cl, 1 tbl, 4 ex

 

The technical field to which the invention relates.

This invention relates to a series of substituted imidazopyrimidines containing pharmaceutical compositions. Compounds of the invention inhibit the production of several cytokines of inflammation, in particular TNF-α and IL-1β. The compounds of this invention are useful in the treatment of diseases mediated R, such as rheumatoid arthritis, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, neurodegenerative diseases and diseases associated with AIDS.

Background of invention

Cytokines inflammation TNF-α and IL-1β play an important role in several inflammatory diseases such as rheumatoid arthritis (Dinarello et al., Curr. Opin. Immunol., 1991, 3: 941-8). Arthritis is an inflammatory disease that is affecting millions of people, and can destroy any joint of the person. Its symptoms range from mild pain and weak inflammation in parsunnyh joints to severe and debilitating pain and severe inflammation. Although the disease is associated mainly with the elderly, it affects people of another age.

The most common arthritis treatment includes the use of nonsteroidal anti-inflammatory drugs ("NSAID") to relieve symptoms. However, despite widespread use of NSAID, many individuals are not allowed to transfer the dose needed to treat for a long time. In addition, NSAID treats only the symptoms of the disease without affecting the reasons underlying it. When the patient reacts badly to NSAID often use other drugs, such as methotrexate, D-penicillamine, gold salts and Freddie. These drugs also have significant toxicity, and mechanism of their action is still unknown.

In clinical trials on a small scale shown that antagonists of the receptors for IL-1β and monoclonal antibodies to TNF-α weaken the symptoms of rheumatoid arthritis. In addition to therapy, based on the use of proteins, there are tools with small molecules that inhibit the production of these cytokines and their activity shown in animal models of arthritis (Boehm et al., J. Med. Chem., 1996, 39: 3929-37). It is proved that the product of such funds with small molecules, SB 203580, effectively reduces the production of TNF-α and IL-1β in LPS-stimulated cell lines of human monocytes with values IC5050-100 nm (Adams et A1., WO 93/14081, July 23, 1993). In addition to this test it was shown in vitro that SB 203580 inhibits the production of cytokines inflammation in rats and mice when the values of the IC5015-25 mg/kg (Badger et al., J. Pharm. Exp.Therap., 1996, 279: 1453-61). Although to date information about the effect of SB 203580 on the human is organism yet, it is proved that monoclonal antibodies to TNF-α effective in the treatment of rheumatoid arthritis (Elliot et al., Arthritis Rheum., 1993, 36: 1681-90). On the basis of the oral activity of SB 203580 and its effectiveness in animal models, the researchers suggest that the connection with such a profile has practical potential for the treatment of rheumatoid arthritis (Badger et al., J. Pharm. Exp.Therap., 1996, 279: 1453-61).

SB 203580 and other tools with small molecules reduce the production of cytokines inflammation by inhibiting the activity of serine/trionychinae R, sometimes known as CSBP, with IC50200 nm (Griswold et al., Pharm. Commun., 1996, 7: 323-9). Although the exact role of this kinase is unknown, it is involved in the production of TNF-αand in signalling pathways associated with the receptor to TNF-α.

In WO 91/00092 describes a method of inhibiting the production of interleukin-1 by monocytes and/or macrophages in humans by introducing diarylamino imidazole, condensed with other heterocyclic ring containing the nitrogen atom at the bridge, where specified other ring may contain a sulfur atom, oxygen or an additional nitrogen atom, and may contain additional unsaturation.

In WO 90/15534 and EP 0403251 describes the treatment of people affected by T-cell-virus (TIV) infection, comprising introducing an effective amount for reducing AK is Yunosti of monokines.

In WO 91/19497 describes diarylethylenes imidazol useful for dual inhibition - of diseases mediated by the metabolism of 5-lipoxygenase, and diseases mediated by cyclooxygenase metabolism. This compound is condensed with another unsaturated 5 - or 6-membered heterocyclic ring containing nitrogen atom in a bridge connection, where the specified other 5-membered ring contains a sulfur atom or an oxygen atom, and specified other 6-membered ring may contain an additional nitrogen atom.

Despite the existence of these known compounds, and methods in this field, there remains a need for improved methods of reducing the production of cytokines inflammation by inhibiting the activity of serine/trionychinae R, and corresponding methods of treatment and prevention of arthritis and other inflammatory disorders.

Summary of the invention

This invention relates to new compounds which inhibit the in vitro activity R in the range of nanomolar concentrations, as well as to methods for their preparation. In addition, the compounds of the present invention inhibit in vitro the secretion of TNF-α and IL-1β in the range of nanomolar concentrations.

Animal models demonstrate the inhibition of production of TNF-α, induserve the aqueous LPS. Compounds biological activity which demonstrates in vitro and in vivo using the steps described here tests are the compounds of the present invention represented by formula I

This invention also relates to pharmaceutical compositions that contain the compound and pharmaceutically acceptable carrier, and to corresponding methods of synthesis.

This invention also relates to a method of treatment of a subject suffering from the condition, the relief which is achieved by reducing cytokines inflammation, which contributes to the specified state, and the method includes introducing to the subject a therapeutically effective dose of the pharmaceutical composition of the present invention.

This invention also relates to a method of inhibiting the occurrence of the subject's condition, the relief which is achieved by reducing cytokines inflammation, which contributes to the specified state, and this method includes the introduction to the subject prophylactically effective dose of the pharmaceutical composition of the present invention.

Detailed description of the invention

This invention relates to the compound of formula I

or its pharmaceutically acceptable salt, where/p>

(a) R1selected from the group consisting of NH2C1-5alkylamino, di-C1-5alkylamino, hydroxy, C1-5alkoxy, phenylethylamine, heterocyclyl,1-5alkylcarboxylic and replaced phenylcarbonylamino, where

these phenylethylamine and heterocyclyl can be substituted at its phenyl group by one or more substituents selected from the group consisting of halogen, C1-5of alkyl, C1-5alkoxy, aryl-C1-3alkylamino, R R NCH=N - OR"', and R', R' and R' chosen, independently, from H, C1-5of alkyl, phenylmethyl, substituted phenylmethyl, α-alkyltrimethyl, substituted α-alkyltrimethyl, heterocyclyl and substituted heterocyclyl;

(b) Y is chosen from the group consisting of H, halogen, heterocycle, OR4, SR4, Other4and NR4R5where

R4and R5chosen, independently, from H, heterocyclyl,3-5carbocycle, phenyl, α-ALKYLPHENOLS1-5of alkyl, straight or branched alkyl, optionally substituted by R, other, N(R)2With3-5carbocycle, phenyl or substituted phenyl, where (i) R is H, halogen, C1-5alkyl, phenylmethyl, substituted phenylmethyl, SO2Ph, pyridyl or pyridylmethyl, and (ii) the phenyl, heterocyclyl and α-ALKYLPHENOLS1-5the alkyl can be substituted one or more is their deputies, selected from the group consisting of halogen, C1-5of alkyl, C1-5alkoxy, aryl-C1-3alkylamino, phenylmethyl, substituted phenylmethyl, R R NCH=N - OR ' is', as indicated in (a);

(c) R2represents from one to five members independently selected from the group comprising halogen, trifluoromethyl, -NHCH2PH1-5the alkyl and C1-5alkoxy;

(d) R3represents H, or R3taken together, form an aromatic ring; and

(e) X is N or CH.

In one embodiment, compounds of the present invention R1represents NH2. In another embodiment, R2is a member selected from the group consisting of halogen, trifloromethyl, -NHCH2PH and C1-5alkoxy. In one embodiment, Y is other4and R4represents phenylmethyl. In another embodiment, X is CH.

Unless otherwise specified, the term "alkyl" refers to straight, branched or cyclic Deputy consisting only of carbon and N in the absence of unsaturation. The term "alkoxy" refers to O-alkyl, where alkyl has the meaning specified above. The term "aromatic ring" refers to a 5-6-membered ring containing a system of delocalized conjugated PI-bonds of 6 electrons, such as phenyl, furanyl and pyrrolyl. The term "aryl" includes mono - and condensed aromaticheskimi, such as phenyl, naphthyl, diphenyl, forfinal, differenl, benzyl, benzyloxyphenyl, carbamaxepine, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, triptoreline, methoxyethanol, acetamidophenyl, tolyl, xylyl, dimethylcarbamoyl, etc. the Term "halogen" denotes fluorine, chlorine, bromine and iodine. The symbol "Ph" refers to phenyl. The term "heterocyclyl", "heterocycle" or "heterocyclic residue" represents a single ring or condensed ring having as ring atom of at least one atom other than carbon atom, for example, pyridine, pyrimidine, oxazoline, pyrrole, imidazole, morpholine, furan, indole, benzofuran, pyrazole, pyrrolidine, piperidine and benzimidazole.

Substituted heterocyclyl and substituted phenylmethyl contain substituents such as halogen, C1-5alkyl, C1-5alkoxy, aryl-C1-3alkylamino, R R NCH=N - and OR OR', where R', R" and R' chosen, independently, from H, C1-5of alkyl, phenylmethyl, substituted phenylmethyl, α-alkyltrimethyl and substituted α-alkyltrimethyl, heterocyclyl and substituted heterocyclyl.

The term "FCS" is fetal calf serum, "TPA" means triperoxonane acid, and "RPMI" refers to the environment from Roswell Park Memorial Inst. (Sigma, cat. No. R0833).

"Independently" means that when several deputies, they can be the ut to be different. "DME" refers to etilenglikolevye. The term "NaHMDS" refers to hexamethyldisilazide sodium.

The expression "pharmaceutically acceptable salt" refers to salts of the free base with the desired pharmacological activity of the free base which is not undesirable from a biological or a different point of view. Such salts can be formed of inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, Hydrobromic acid, itestosterone acid, Perlina acid, nitric acid, sulfuric acid and phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, grape acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, oxalic acid, pamula acid, sugar acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, methylsulfonate acid, salicylic acid, hydrometerology acid, benzolsulfonat acid, 2-naphthalenesulfonate acid, p-toluensulfonate acid, cyclohexanesulfamic acid, etc.

When in the compounds of this from the retene there is one or several centers of stereoisomerism, it should be borne in mind that all possible optical isomers, antipodes, enantiomers and diastereoisomers, appearing as a result of the presence of such centers stereoisomer that may exist in the optical isomers, the antipodes, racemates and racemic mixtures are also part of this invention. Antipodes can be separated by methods known to experts in the art, such as, for example, fractional recrystallization of the diastereomeric salts enantiomer pure acids. On the other hand, the antipodes can be separated by chromatography on a column of type Pirkle.

Examples of compounds of the present invention are the following compounds:

compound 1: 2-(4-forfinal)-3-(4-pyridinyl)imidazo[1,2-a] pyrimidine-7-amine;

compound 2: 2-(3-forfinal)-3-(4-pyridinyl)imidazo[1,2-a]pyrimidine-7-amine;

compound 3: 2-(4-forfinal)-3-(4-chinoline)imidazo[1,2-a]pyrimidine-7-amine;

compound 4: 2-(3-chloro-4-forfinal)-3-(4-pyridinyl)imidazo [1,2-a]pyrimidine-7-amine;

compound 5: 2-phenyl-3-(4-pyridinyl)imidazo[1,2-a]pyrimidine-7-amine;

compound 6: 2-(4-forfinal)-3-[2-[(phenylmethyl)amino]-4-pyridinyl]imidazo[1,2-a]pyrimidine-7-a is in;

compound 7: 3-(4-pyridinyl)-2-[3-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine-7-amine;

compound 8: 3-[2-[(phenylmethyl)amino]-4-pyridinyl]-2-[3-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine-7-amine;

compound 9: 3-[2-[[(1S)-l-phenylethyl]amino]-4-pyrimidinyl]-2-[3-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine-7-amine;

compound 10: 2-(4-forfinal)-3-[2-(methylthio)-4-pyrimidinyl]imidazo[1,2-a]pyrimidine-7-amine;

compound 11: 3-[2-(methylthio)-4-pyrimidinyl]-2-[3-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine-7-amine;

compound 12: 2-(3-forfinal)-3-[2-(methylthio)-4-pyrimidinyl]imidazo[1,2-a]pyrimidine-7-amine;

the connection 13: 3-(4-pyrimidinyl)-2-[3-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine-7-amine;

compound 14: 2-phenyl-3-[2-(1-piperidinyl)-4-pyrimidinyl]imidazo[1,2-a]pyrimidine-7-amine;

compound 15: 3-[2-(methylthio)-4-pyrimidinyl]-2-phenylimidazo[1,2-a]pyrimidine-7-amine;

compound 16: 2-phenyl-3-(4-pyrimidinyl)imidazo[1,2-a]pyrimidine-7-amine;

compound 17: 3-[2-(methylsulphonyl)-4-pyrimidinyl]-2-phenylimidazo[1,2-a]pyrimidine-7-amine;

compound 18: 3-[2-(methylsulphonyl)-4-pyrimidinyl]-2-[3-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine-7-amine;

compound 19: 2-phenyl-3-[2-[[(1S)-1-phenylethyl]amino]-4-pyrimidinyl]imidazo[1,2-a]pyrimidine-7-amine;

compound 20: 3-[[[(4-methoxyphenyl)methyl]amino]-4-pyrimidinyl]-2-phenylimidazo[1,2-a]pyrimidine-7-amine;

compound 21: 2-(4-forfinal)-3-[3-[[(1S)-1-phenylethyl]amino]-4-pyridinyl]imidazo[1,2-a]pyrimidine-7-amine;

compound 22: 3-[2-[[(1S)-1-cyclohexylethyl]amino]-4-pyrimidinyl]-2-(4-forfinal)imidazo[1,2-a]pyrimidine-7-amine;

compound 23: 3-(2-methoxy-4-pyrimidinyl)-2-phenylimidazo [1,2-a]pyrimidine-7-amine;

compound 24: 2-(4-forfinal)-3-(4-pyrimidinyl)imidazo[1,2-a]pyrimidine-7-amine;

compound 25: 2-(3-chlorophenyl)-3-(4-pyridinyl)imidazo[1,2-a]pyrimidine-7-amine;

compound 26: 3-(2-bromo-4-pyridinyl)-2-(4-forfinal)imidazo [1,2-a]pyrimidine-7-amine and

compound 27: 3-(2-bromo-4-pyridinyl)-2-[3-(trifluoromethyl) phenyl]imidazo[1,2-a]pyrimidine-7-amine

This invention also relates to a headlamp is aseptically composition, containing the specified connection and a pharmaceutically acceptable carrier.

Pharmaceutical compositions containing the compound of the present invention as an active ingredient in a homogeneous mixture with a pharmaceutical carrier, you can get the usual methods adopted in pharmacy. The media can take many different forms, depending on the form of preparation desired for administration, including such as local injection system and introduction, including, but not limited to, intravenous infusion, oral, nasal or parenteral administration. Upon receipt of the compositions in a dosage form for oral administration can be used any known conventional pharmaceutical carriers, such as water, glycerol, glycols, oils, alcohols, corrigentov, preservatives, dyes, syrup-like substance in the case of oral liquid preparations (for example, suspensions, elixirs and solutions); or carriers such as starches, sugar, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol and similar substances in the case of solid oral preparations (such as powders, capsules and tablets). All excipients can be mixed, if necessary, with substances that contribute to the scattering, thinners, substances that promote granulation, lubricating agents, binders and p, using conventional methods known to experts in the field of production of dosage forms.

The preferred method of administration is oral administration. Due to the simple introduction of tablets and capsules represent the best standard dosage form for oral administration, and in this case, obviously, are solid pharmaceutical carriers. If necessary, tablets conventional methods can be applied sugar coating or intersolubility floor. In the case of parenteral forms of media, as a rule, will contain sterile water, although you can add other ingredients, for example, contributing to the dissolution or for the purposes of preservation. You can also get a suspension for injection, and in this case you can use the appropriate liquid carriers, suspendresume tools, etc.

Used herein, the term "cytokine" refers to proteins TNF-α and IL-1β. Disorders associated with cytokine are diseases of humans and other mammals, where overproduction cytokines causes the symptoms of the disease. Overproduction cytokines TNF-α and IL-1β associated with a number of diseases.

Compounds of the present invention inhibit the production of TNF-α and IL-1βthus, the present invention also relates to a method of treatment of a subject article is daysago from the state, the relief which is achieved by reducing cytokines inflammation, which contributes to a specified condition, including the introduction of a specified subject a therapeutically effective dose of the pharmaceutical composition of the present invention. Used herein, the term "subject" includes, but is not limited to, any animal or artificially modified animal. In a preferred variant embodiment of the invention the subject is a person.

The invention also refers to a method of inhibiting the occurrence of the subject's condition, the relief which is achieved by reducing cytokines inflammation, which contributes to a specified condition, including the introduction of a specified subject prophylactically effective dose of the pharmaceutical composition of the present invention.

In one variation of the embodiment of the invention such a condition selected from the group which includes arthritis, an inflammatory disease of the digestive tract, septic shock, osteoporosis, osteoarthritis, neuropathic pain, HIV replication, dementia caused by HIV, viral myocarditis, insulin-dependent diabetes, non-insulin-dependent diabetes, periodontal disease, restenosis, alopecia areata, a fall in the number of T-lymphocytes during HIV infection or AIDS, psoriasis, acute pancreatitis, rejection of al is of transplantat, allergic lung inflammation, atherosclerosis, multiple sclerosis, cachexia, Alzheimer's disease, stroke, Crohn's disease, ischemia, congestive heart failure, pulmonary fibrosis, hepatitis, glioblastoma, Guillain-Barre syndrome and systemic lupus erythematosus. In a preferred variant embodiment of the invention this condition is rheumatoid arthritis.

Used herein, the term "treatment" refers to the elimination or weakening of the causes and/or its actions. "Inhibition" of the occurrence of the disorder means the prevention, containment or reduction of the likelihood of such occurrence. Similarly, the "therapeutically effective" and "prophylactically effective" doses are doses, enabling, respectively, the treatment and inhibition of the disorder. Methods for determining therapeutically and prophylactically effective dose of the pharmaceutical composition of the present invention are methods known in this field. Effective dose for administration of the pharmaceutical composition to a person, for example, can be determined mathematically from the results of animal studies.

In one variant embodiment of the invention, the oral dose of the compounds of the present invention are in the range of from about 0.05 to about 100 mg/kg per day. In another embodiment, the oral dose h is formed in the range of from about 0.05 to about 50 mg/kg per day, in one embodiment, from about 0.05 to about 20 mg/kg per day. Infusion doses can range, for example, from about 1.0 to 1.0×104mcg/kg/min compounds of the present invention, mixed with a pharmaceutically acceptable carrier, in the course of time in the range from several minutes to several days. In the case of local administration of the compound of the present invention can be admixed with a pharmaceutically acceptable carrier in a concentration of, for example, from about 0.1 to about 10% of the drug relative to the filler.

Finally, the invention relates to a method of producing compounds of the present invention. These compounds can be obtained as shown below, from readily available starting compounds and/or intermediate compounds according to methods known in this field.

The invention will be better understood with reference to the experimental details are described later, but experts in the art can easily imagine that they are only illustrative for the invention, which is more fully described in the claims below.

In addition, in this application cited various publications. All of these publications are included in the present description as a reference for a more complete description of the prior art, to which apply the this invention.

EXPERIMENTAL DETAILS

A. Schematic and synthesis

The compounds of formula I, where R1represents NH2and R3and Y represent H, can be obtained according to scheme I. the Original connection type 1A such as 4-methylpyridine or 4-methylinosine, can be mixed with the ester of benzoic acid type 1b and two equivalents of a suitable base, with spatial difficulties, such as hexamethyldisilazide sodium in a suitable solvent such as THF, at room temperature and get enolate 1, which is then bromilow to the connection Id. Then the intermediate connection type Id, you can enter into interaction with 2,6-diaminopirimidina and to obtain the compound of formula I, where R1represents NH2and Y is N.

Although the method shown in the diagram, get the compound of formula I, where R1represents NH2, X represents CH and Y represents N, the specified scheme can also be used to obtain other compounds of the invention.

Scheme II illustrates how to obtain the compounds of formula I where X is N, and Y, R2and R3have the values specified above.

Scheme III illustrates how to obtain the compounds of formula I where X is CH, Z' represents F, Cl or Br, and Y, R2and R 3have the values specified above.

Scheme IV illustrates how to obtain the compounds of formula I where X is CH, Y is other4and R4has the values listed above.

In the examples, below, describes more specifically the chemical synthesis of typical compounds of the present invention. Other compounds described herein, can be obtained in a similar manner in accordance with one or more of the following methods. Attempt to optimize yields in these reactions were not taken, and to a person skilled in the art it should be clear that changes in time, temperature, solvents and/or reagents reactions can raise such exits.

Example 1

3-[2-[(Phenylmethyl)amino]-4-pyridinyl]-2-[3-(trifluoromethyl) phenyl]imidazo[1,2-a]pyrimidine-7-amine

To 5,44 g (27,44 mmol) 2-benzylamino-4-methylpyridine in 40 ml of tert-butanol add 6,59 g (31,18 mmol) di-tert-BUTYLCARBAMATE. After 18 hours the solvent is removed in vacuum. The residue is triturated with hexane and FilterOutputStream concentrated in vacuo and get 4,25 g amine with a protecting group.1H NMR (300 MHz, DMSO-d6) δ by 8.22 (1H, d, J=5,1 Hz), of 6.99 (1H, d, J=5,1 Hz), 5,10 (2H, s), 2,31 (3H, s), 1,38 (N, C).

To a solution of 8,97 g (30,07 mmol) H-BOC-2-benzylamino-4-methylpyridine and to 6.58 g (30,07 mmol) ethyl 3-triftoratsetata in 60 ml of tetrahydrofuran using a dropping funnel under nitrogen atmosphere is added dropwise 61 ml (61 mmol) of 1.0 M solution of bis(trimethylsilyl)amide sodium in tetrahydrofuran. After eighteen hours the reaction is quenched with a saturated solution of ammonium chloride and removing the solvent in vacuo. The residue is extracted with 300 ml ethyl acetate and the extract washed with 2×200 ml of water, 1×100 ml of brine, dried over sodium sulfate, filtered and concentrated in vacuo, obtaining a brown oil. Column chromatography using a mixture of hexane/ethyl acetate, 5:1, gives 10.92 g of the reaction product as a thick yellow oil.1H NMR (300 MHz, DMSO-d6) δ to 7.59 (1H, s), 5,11 (2H, s), to 4.62 (2H, s), 1,33 (N, C).

Amine with a protecting group (10.92 g, 23,21 mmol) is refluxed for 1 hour in 100 ml of tetrahydrofuran containing 20 ml of 6 M HCl, the mixture is cooled, diluted with 220 ml of water and extracted with 2×250 ml of ethyl acetate. The organic layers separated, unite, washed with 200 ml of water, 2×100 ml of brine, dried over magnesium sulfate, filtered and concentrated in vacuo, getting to $ 7.91 g of a viscous red oil. MN+=371.

To 2,33 g (6,29 mmol) of the ketone in 10 ml of ice is kusnoy acid type of 1.30 ml (6,61 mmol) of a 30% solution of hydrogen bromide in acetic acid. Add dropwise a solution of 0.35 ml (6,79 mmol) of bromine 1.65 ml of glacial acetic acid and the reaction mixture is heated at 60°C for one hour, cooled to room temperature and diluted with ether. The resulting oily residue is washed with ether and gain of 2.27 g (4,28 mmol) of the crude bromide. MN+=450.

A solution of 1.89 g (17,13 mmol) of 2,4-diaminopirimidina in 20 ml of ethanol is heated to 80°C. using a dropping funnel is added dropwise a solution of 2.27 g (4,28 mmol) of the crude bromide in 50 ml of ethanol. The reaction mixture was stirred at 80°C for one hour and then cooled to room temperature. Removed in vacuo to approximately half the volume of the solvent. After cooling to room temperature the reaction mixture is filtered. The filtrate was concentrated in vacuo, the residue is diluted with 250 ml ethyl acetate and washed h ml of 0.5 M sodium hydroxide solution, dried over sodium sulfate, filtered and concentrated in vacuo, getting red-brown oil. Column chromatography using 2% solution of methanol in ethyl acetate gives 0,4161 g of compound 8 (3-[2-[(phenylmethyl)amino]-4-pyridinyl]-2-[3-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine-7-amine in the form of not-quite-white solid. MN+=461.

Example 2

1-Phenyl-2-(4-pyridinyl)Etalon and 1-phenyl-2-bromo-2-(4-shall original)alanon

To a solution of 1.8 g (0.02 mol) of 4-picoline and 3.0 g (0.02 mol) of ethylbenzoic in 60 ml of tetrahydrofuran using a dropping funnel under nitrogen atmosphere add 1.0 M solution of bis(trimethylsilyl)amide, sodium (40 ml, 0.04 mol) in tetrahydrofuran. After eighteen hours the reaction is quenched with a saturated solution of ammonium chloride and removing the solvent in vacuo. The residue is extracted with 100 ml ethyl acetate and the extract washed with 2×200 ml of water, 1×100 ml of brine, dried over sodium sulfate, filtered and concentrated in vacuo, obtaining oil. Rubbing with ether to give 1.6 g of the reaction product 1-Phenyl-2-(4-pyridinyl)ethanone. MN+198.

To 1.6 g (8.1 mmol) of the ketone in 10 ml of glacial acetic acid added 1.8 ml (8.9 mmol) of a 35% solution of hydrogen bromide in acetic acid. Add dropwise a solution and 0.46 ml (8.9 mmol) of bromine 1.65 ml of glacial acetic acid and the reaction mixture is heated at 60°C for one hour, cooled to room temperature and diluted with ether. The resulting solid is washed with ether and obtain 2.5 g of bromide in the form of HBr salt of 1-phenyl-2-bromo-2-(4-pyridinyl)ethanone. MN+=276.

Example 3

2-Phenyl-3-(4-pyridinyl)imidazo[1,2-a]pyrimidine-7-amine

A solution of 1.2 g (11 mmol) of 2,4-diaminopirimidina in 10 ml of ethanol is heated to 80°C. using a dropping funnel is added dropwise a solution of 1.0 g (2.8 mmol) of bromide in 20 ml of ethanol, the Reaction mixture was stirred at 80° C for 3 hours and then cooled to room temperature. Removed in vacuo to approximately half the volume of the solvent. After cooling to room temperature the reaction mixture is filtered. The filtrate was concentrated in vacuo, the residue is diluted with 250 ml ethyl acetate and washed with 2×100 ml of 0.5 M sodium hydroxide solution, dried over sodium sulfate, filtered and concentrated in vacuo, getting red-brown oil. Rubbing the residue with EtOAc followed by filtration to give to 0.108 g of compound 5 in the form of not-quite-white solid. MN+=288.

To a solution of 13,38 g (84,73 mmol) of the hydrochloride of 2-mercapto-4-methylpyrimidine and 7,46 g (186,4 mmol) of sodium hydroxide in 120 ml of water via syringe is added dropwise 13,23 g (93,2 mmol) iodomethane. After 2 hours the reaction mixture is extracted with 2×125 ml of dichloromethane. The organic layers separated, combined, dried over Na2SO4, filtered and concentrated in vacuo, getting 11,14 g (79,45 mmol) of 4-methyl-2-(methylthio) pyrimidine in the form of a red oil. MN+=140,9.

To a solution 6,03 g (43 mmol) of 4-methyl-2-(methylthio) pyrimidine and 6,46 g (43 mmol) of ethylbenzoic in 86 ml of tetrahydrofuran in a nitrogen atmosphere using a dropping funnel is added dropwise 86 ml (86 mmol) of 1.0 M solution of bis(trimethylsilyl)amide sodium tetrahydrofurane. After 2 hours the reaction is quenched with a saturated solution of ammonium chloride. A large part of the tetrahydrofuran removed in vacuo. The residue is diluted with 400 ml ethyl acetate and 200 ml of water. The organic layer is separated and washed with 2×100 ml of saturated sodium chloride solution, separated, dried over Na2SO4, filtered and concentrated in vacuo, getting 10,45 g (42,77 mmol) 2-[2-(methylthio)pyrimidine-4-yl]-1-phenylethanone in the form of a viscous red-brown oil that solidifies upon standing. MH+=244,9.

To 10,45 g (42,77 mmol) of the ketone in 80 ml of glacial acetic acid, add 9 ml (44,91 mmol) of a 30% solution of hydrogen bromide in acetic acid. Add dropwise a solution of 2.40 ml (46,19 mmol) of bromine in 2,60 ml of glacial acetic acid, and the reaction mixture is heated at 60°C for 45 minutes, cooled to room temperature and diluted with ether. The resulting suspension is filtered, washed with ether and dried in vacuum, obtaining 18,06 g (44,69 mmol) of the crude bromide. MN+=324,9.

The solution 18,83 g (171,08 mmol) of 2,4-diaminopirimidina in 150 ml of ethanol is heated to 80°C. using a dropping funnel is added dropwise a solution of 18,06 g (42,77 mmol) of the crude bromide in 350 ml of ethanol. The reaction mixture is stirred at the boil under reflux for two hours. PEFC is cooling to room temperature the reaction mixture is filtered. The residue is stirred with 150 ml of 0.5 M sodium hydroxide solution. The precipitate is collected by filtration, washed with water, ether and hexane, obtaining 6,72 g (21.1 mol) of the reaction product as a pale yellow solid. MN+=334,9.

A mixture of 0.60 g (1,79 mmol) dimethylpyrimidine, approximately 4 ml of 50% Raney Nickel in aqueous solution, 40 ml of ethanol and 20 ml of water is refluxed for eighteen hours in a nitrogen atmosphere. The reaction mixture is cooled to room temperature and filtered through celite. Celite was washed with ethanol. The combined filtrates concentrated in vacuo. The residue is triturated with ethanol, collected by filtration and washed with ether, receiving 0,2310 g pyrimidine as a yellow solid matter (compound 16). MH+=289,0.

The solution of 8.28 g (13,46 mmol) oxone in 75 ml of water using a dropping funnel is added dropwise to 1.50 g (4,49 mmol) dimethylpyrimidine in 77 ml of methanol. The resulting suspension is stirred at room temperature for eighteen hours, filtered and the filtrate was concentrated in vacuo, removing the methanol. The residue is diluted with 100 ml of water and neutralized with solid sodium bicarbonate. The resulting suspension is filtered and the precipitate washed with water, ether and dried, obtaining 1.27 g (3.46 mmol) of methylsulfonylmethane as altago solids (compound 17). MN+=367,0.

A mixture of 0.55 g (1.5 mmol) of methylsulfonylmethane and 1,82 g (15 mmol) of (S)-(-)-α-methylbenzylamine heated at 140°C for 30 minutes, cooled to room temperature, diluted with 100 ml ethyl acetate and washed 3×50 ml of water and 1×50 ml saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated in vacuo, receiving a yellow oil. Column chromatography using 100% ethyl acetate as eluent gives 0,3977 g (0.98 mmol) of the reaction product as a pale yellow solid (compound 19). MN+=408,1.

C. ANALYSIS

Example 4

Assays for inhibition of R

Biological activity of some compounds of the invention demonstrated using in vitro and in vivo. As indicated above, means, inhibiting the enzyme activity R, inhibit the production of cytokines inflammation TNF-α and IL-1β.

The list of selected compounds of the invention are given in table 1, which also shows the mass spectral analysis, and data showing the ability of each compound to inhibit R, as shown by inhibition of production of TNF-α. Analyses in which the received data, such as described below.

Table 1

Connected to the I, tested for their ability to inhibit R shown through the inhibition of production of TNF-α
Connection # MC, Cl (M+1)LPS/PBMC IC50nm (TNF-α)% inhibition of production of TNF-α in mice, 10 mg/kg
130649100
230655100
335633326
434021100
528855100
6411642
73563599
8461419
94760,597
103533768
114032738
123531051
1335727885
14372863
153352823
16 28930473
173673414-
1843552010
194080,40100
2042414-
21425297
22432174
233199087
2430719991
2532216247

Analysis of whole cells RVMS

Typical compounds of the present invention tested in in vitro assays of whole cells using mononuclear cells of peripheral blood ("RVS"), which is obtained from human blood as follows. In viewsat venous blood type anticoagulation tool heparin, dilute it with equal volumes of phosphate buffered saline ("PBS") and placed in a sterile tube or other container. Aliquots (30 ml) of this mixture is transferred into centrifuge tubes, which impose a sublayer of ficoll-vipaka (15 ml). Prepared tubes centrifuged at 400×g without brake for 30 minpro room temperature. Carefully removed with a pipette approximately 1/2-2/3 of the sediment layer above the layer of mononuclear cells. Carefully using a pipette, remove most of the layer of mononuclear cells, and these RUMS diluted PBS and centrifuged at 600×g for 15 min Obtained RVMS washed with another portion of PBS and centrifuged at 400×g for 10 min at room temperature. Retrieved precipitation diluted in culture medium RPMI/1% FCS with low content of endotoxins and get a cell concentration of 0.5-2.0×106RUMS/ml Extract a small amount of suspension to count on hemocytometer, and the rest of the preparation is centrifuged at 200×g for 15 min at room temperature. Retrieved besieged RVMS resuspended in RPMI/1% FCS to a concentration of 1,67×106/ml.

In order to carry out the analysis, the suspension RVMS transferred into dual cell 96-well tiralongo microplate with flat-bottomed wells and incubated for 1 hour at 37°S.V. each well add a solution of the test compound (10 μl, obtained as 20× the required final concentration) and the plate incubated for 1 hour at 37°C. Add a solution (10 ml) LPS in RPMI/1% FCS (200 ng/ml) and the plate incubated overnight at 37°C. Remove the supernatant (100 μl) from each well and diluted RPMI/1% FCS (400 µl). Samples of analysera the t on TNF-α using a commercial ELISA kit (Genzyme). The results are shown above in table 1.

Analysis of the in vivo rodent

The ability of the compounds of formula I to inhibit the production of TNF-αinduced by LPS, show in the following analyses in vivo in rodents. Mice (female BALB/cJ, Jackson Laboratories) not fed for 30 min before oral administration of a dose of 5-10 ml/kg 5-50 mg/kg of the test compounds. Thirty minutes after administration of the dose animals administered intraperitoneally injected LPS (1 mg/kg and return them to the cells for 1 hour. Animals give anesthesia CO2produce blood via cardiac puncture and collected whole blood (0.1 to 0.7 ml). Blood enable clotting and serum transferred into a centrifuge tube. The resulting sample is centrifuged and the serum collected, divided into aliquots and frozen at -80°C. the Samples experience using a commercial ELISA kit for TNF-α (endogen for murine TNF-α). Calculate the % inhibition of the test compounds using the formula

% ingibirovaniya=[1-(sample-BKG)/(RL-BKG)]×100.

The results are shown above in table 1.

Analysis of recombinant R

Compounds of the invention tested for their ability to inhibit the activity R using the following in vitro assays. Solution (38 ml) purified recombinant R (where the amount of enzyme on Radelet empirically, and considered the linear region of analysis and an acceptable ratio of signal and noise; 6×His-p38 expressed in E. coli), the main protein substrate myelin (also determined empirically) and buffer pH 7.5 (Hepes 25 mm; MgCl2- 10 mm; MnCl2- 10 mm) is added to 92 wells of 96-well polypropylene tablet with round-bottomed wells. Remaining wells are used for control ("CTRL") and background ("BKG"). CTRL get with enzyme buffer for substrate and 21% DMSO, a BKG receive buffer substrate and 2% DMSO. In the wells for testing add solution (12 μl) of the test compounds in DMSO (compound diluted to 125 μm with a mixture of 10% DMSO/N2Oh and assayed at 25 μm, where the final concentration of DMSO is 2%). To all wells add a solution of ATP/33P-ATP (10 μl, containing 50 ám its ATP and 1 µci33P-ATP), and filled with tablets all mixed and incubated at 30°C for 30 minutes In each well add chilled on ice, a solution of 50% TCA/10 mm sodium phosphate (60 μl) and tablets incubated on ice for 15 minutes, the Contents of each well is transferred into wells of 96-well filtration tablet (Millipore, MultiScreen-DP) and place the filtration plate in a vacuum installation, equipped with a drip tray waste. The wells are washed in a vacuum five times with a mixture of 10% TCA/10 mm sodium phosphate (200 μl). Add scintillate the R MicroScint-20, tablets sealed using sheets Topseal-S and shall count in scintillation counter Packard TopCount using for liquids with33P correction extinguishing color, where the result is expressed in chem./minutes with correction for quenching colors. Although connections have first at 10 μm, if there are grounds, connections tested at a 4-fold increase and decrease the specified concentration. In addition, some compounds calculate the IC50using the program selection 4-parametric curves Deltagraph. The results are not given.

Analysis of IL-1β in vitro

The ability of compounds of the invention inhibit the production of IL-1β can be determined using the following in vitro assays. From RVMS receive cells adherent to plastic. RVMS add to the wells of the 96-hole tablet, as described above, incubated for 1 hour at 37°and receive adherent cells, gently resuspended non-stick cells pipettors, removing and discarding them, and gently washing the wells 3 times with 200 μl of culture medium. After the last washing the wells again add culture medium (180 μl). Adding a connection, LPS stimulation, incubation and collection of the supernatant exercise as well as for TNF-α. Supernatant analyzed for interleukin-1βusing commercial is abortion practices ELISA (Genzyme). The results are not given.

1. Substituted 2-aryl-3-(heteroaryl)imidazo[1,2-a]pyrimidines of the formula I

or their pharmaceutically acceptable salts, where

(a) R1selected from the group consisting of NH2With1-5alkylamino, di-C1-5alkylamino, phenylethylamine,

(b) Y is chosen from the group consisting of H, halogen, piperidine, OR4, SR4, -SO2CH3, Other4and NR4R5where

R4and R5chosen, independently, from N, α-alkylphenyl-C1-5of alkyl, straight or branched alkyl, optionally substituted C3-5carbocycle, phenyl or substituted phenyl, where the specified phenyl may be substituted by one or more substituents selected from C1-5alkoxy;

(c) R2represents from one to five members independently selected from the group including H, halogen, trifluoromethyl;

(d) R3represents H, or the radicals R3taken together, form an aromatic ring;

(e) X is N or CH.

2. The compound according to claim 1, where X represents CH.

3. The compound according to claim 1, where R1represents NH2.

4. The compound according to claim 1, where Y is other4and R4is vinylmation.

5. The compound according to claim 1, where R2represented by the Deputy, wybran the th of halogen or trifloromethyl.

6. The compound according to claim 1, where Y is piperidine.

7. The compound according to claim 1, where R4selected from α-alkylphenyl-C1-5of alkyl, straight or branched alkyl, optionally substituted C3-5carbocycle or phenyl.

8. The compound according to claim 1, which represents a 2-(3-chloro-4-forfinal)-3-(4-pyridinyl)imidazo[1,2-a]pyrimidine-7-amine.

9. The compound according to claim 1, which represents a 2-phenyl-3-(4-pyridinyl)imidazo[1,2-a]pyrimidine-7-amine.

10. The compound according to claim 1, which represents a 2-(4-fluoro-phenyl)-3-[2-[(phenyl-methyl)amino]-4-pyridinyl]imidazo[1,2-a]pyrimidine-7-amine.

11. The compound according to claim 1, which represents a 3-(4-pyridinyl)-2-[3-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine-7-amine.

12. The compound according to claim 1, which represents a 3-[2-[(phenyl-methyl)amino]-4-pyridinyl]-2-[3-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine-7-amine.

13. The compound according to claim 1, which represents a 2-(4-fluoro-phenyl)-3-(4-chinoline)imidazo[1,2-a]pyrimidine-7-amine.

14. The compound according to claim 1, which represents a 2-(3-chloro-phenyl)-3-(4-pyridinyl)imidazo[1,2-a]pyrimidine-7-amine.

15. The compound according to claim 1, which represents a 2-(4-fluoro-phenyl)-3-[2-(methylthio)-4-pyrimidinyl]imidazo[1,2-a]pyrimidine-7-amine.

16. The compound according to claim 1, which represents a 3-[2-(methylthio)-4-pyrimidinyl]-2-[3-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine-7-amine.

17. The compound according to claim 1, which represents a 2-(3-fluoro-phenyl)-3-[2-(methyl) - Rev. IO)-4-pyrimidinyl]imidazo[1,2-a]pyrimidine-7-amine.

18. The compound according to claim 1, which represents a 3-(4-pyrimidinyl)-2-[3-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine-7-amine.

19. The compound according to claim 1, which represents a 3-[2-(methylthio)-4-pyrimidinyl]-2-phenylimidazo[1,2-a]pyrimidine-7-amine.

20. The compound according to claim 1, which represents a 2-phenyl-3-(4-pyrimidinyl)imidazo[1,2-a]pyrimidine-7-amine.

21. The compound according to claim 1, which represents a 3-[2-(methyl-sulfonyl)-4-pyrimidinyl]-2-phenylimidazo[1,2-a]pyrimidine-7-amine.

22. The compound according to claim 1, which represents a 3-[2-(methyl-sulfonyl)-4-pyrimidinyl]-2-[3-(trifluoromethyl)phenyl]imidazo [1,2-a]pyrimidine-7-amine.

23. The compound according to claim 1, which represents a 2-phenyl-3-[2-[[(1S)-1-phenylethyl]amino]-4-pyrimidinyl]imidazo[1,2-a]pyrimidine-7-amine.

24. The compound according to claim 1, which represents 3-[[[(4-methoxyphenyl)methyl]amino]-4-pyrimidinyl]-2-phenylimidazo[1,2-a]-pyrimidine-7-amine.

25. The compound according to claim 1, which represents a 3-(2-methoxy-4-pyrimidinyl]-2-phenylimidazo[1,2-a]pyrimidine-7-amine.

26. The compound according to claim 1, which represents a 2-(4-fluoro-phenyl)-3-(4-pyrimidinyl)imidazo[1,2-a]pyrimidine-7-amine.

27. The compound according to claim 1, which represents a 2-(3-fluoro-phenyl)-3-(4-pyridinyl)imidazo[1,2-a]pyrimidine-7-amine.

28. The compound according to claim 1, which represents a 2-(4-fluoro-phenyl)-3-(4-pyridinyl)imidazo[1,2-a]pyrimidine-7-amine.

29. The compound according to claim 1, which represents a 3-[2-[[(1S)-1-phenylethyl]amino]-4-pyrimidin the]-2-[3-(trifluoromethyl)phenyl] imidazo[1,2-a]pyrimidine-7-amine.

30. The compound according to claim 1, which represents a 2-phenyl-3-[2-(1-piperidinyl)-4-pyrimidinyl]imidazo[1,2-a]pyrimidine-7-amine.

31. The compound according to claim 1, which represents a 3-[2-[[(1S)-1-cyclohexylethyl]amino]-4-pyrimidinyl]-2-(4-forfinal)imidazo [1,2-a]pyrimidine-7-amine.

32. The compound according to claim 1, which represents a 2-(4-forfinal)-3-[3-[[(1S)-1-phenylethyl]amino]-4-pyrimidinyl]imidazo[1,2-a]pyrimidine-7-amine.

33. The method of treatment of a subject suffering from the condition, the relief which is achieved by reducing cytokines inflammation, which contributes to a specified condition, comprising administration to the subject a therapeutically effective dose of a compound according to claim 1.

34. Method of inhibiting the occurrence of the subject's condition, the relief which is achieved by reducing cytokines inflammation, which contributes to a specified condition, including an introduction to the subject prophylactically effective dose of a compound according to claim 1.

35. The method according to p or 34, where the condition is selected from the group comprising rheumatoid arthritis, an inflammatory disease of the digestive tract, septic shock, osteoporosis, osteoarthritis, neuropathic pain, HIV replication, dementia caused by HIV, viral myocarditis, insulin-dependent diabetes, non-insulin-dependent diabetes, periodontal disease, restenosis, alopecia alopecia, the fall in the number of T-lymphocytes in HIV-is Peccei or AIDS, psoriasis, acute pancreatitis, allograft rejection, allergic lung inflammation, atherosclerosis, multiple sclerosis, cachexia, Alzheimer's disease, stroke, Crohn's disease, ischemia, congestive heart failure, pulmonary fibrosis, hepatitis, glioblastoma, Guillain-Barre syndrome and systemic lupus erythematosus.

36. The method according to p, where the specified condition is a rheumatoid arthritis.

37. A method of producing a connection structure according to claim 1 2f

including

a) conversion of compound 2A in the presence of NaOH and CH3I in connection 2b

(b) coordination compounds 2b with compound 2c in the presence of NaHMDS and THF with the formation of compound 2d;

c) conversion of compound 2d in connection 2nd in the presence NVG, Br2and Asón;

d) the interaction of compounds 2E with compound 1e in the presence of EtOH with the formation of compound 2f.

38. The method according to clause 37, including additional transformation connection 2f 2g connection in the presence of Raney Ni and EtOH

39. The method according to clause 37, including the store additionally

(a) making the connections 2f in connection 2h in the presence Oksana and Meon;

b) interaction of the compounds of formula 2h with a compound Y,

where Y represents halogen, piperidine, OR4, SR4, Other4or NR4R5with the formation of the compounds of formula 2i.

40. A method of obtaining a compound according to claim 1, where X represents CH and Y represents other4including

a) the conversion of compounds of formula 4A in the compound of formula 4b in the presence of (BOC)2O and tert-BuOH;

b) interaction of the compounds of formula 4b with the compound of the formula 4 in the presence of NaHMDS and HCl with the formation of the compounds of formula 4d;

c) the conversion of compounds of formula 4A in the compound of formula 4 in the presence of 30% HBr/Asón, Br2and Asón; and

d) the interaction of the compounds of formula 4e with a compound of formula 1E in the presence of EtOH with the formation of the compounds of formula 4f.



 

Same patents:

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes derivatives of imidazo-3-ylamine of the general formula (I):

wherein X and Y mean CH or nitrogen atom (N) under condition that X and Y don't mean nitrogen atom (N) simultaneously; R1 means tert.-butyl, (CH2)nCN wherein n means 4, 5 or 6, phenyl substituted optionally with (C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C4-C8)-cycloalkyl, 1,1,3,3-tetramethylbutyl or CH2Ra wherein Ra represents hydrogen atom, branched or linear (C1-C8)-alkyl, phenyl substituted optionally with halogen atom, (C1-C4)-alkoxy-group, CO(OR') wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl, PO(OR')2 wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl; R2 means hydrogen atom, CORb wherein Rb represents branched or linear (C1-C4)-alkyl; R3 means methyl, ethyl, tert.-butyl, (C3-C8)-cycloalkyl, phenyl monosubstituted optionally at position 3, 5 or 6 or optionally multisubstituted at position 4 and additionally at position 2 and/or 3, and/or 5, and/or 6 with halogen atom, hydroxyl group (OH), (C1-C4)-alkyl or (C1-C4)-alkoxy-group, naphthyl, optionally substituted (C1-C4)-alkoxy-group, di-(C1-C4)-alkylamino-group, pyrrole substituted optionally with (C1-C4)-alkyl, benzylsulfonyl, COOCH3, pyridyl substituted optionally with (C1-C4)-alkyl, OH, hydroxy-(C1-C4)-alkyl, furan substituted optionally with (C1-C4)-alkyl, nitro-group (-NO2), halogen-substituted phenyl, CH2COOCH3, COOH, thiophene substituted optionally with halogen atom, (C1-C4)-alkyl, (C1-C4)alkylsulfanyl, -NO2, phenoxy-group, thiophene, alkynylphenyl, unsubstituted anthracene or quinoline substituted optionally with halogen atom under condition that R3 doesn't means cyclohexyl-unsubstituted phenyl or phenyl monosubstituted with carboxylic acid amide at position 3 if R1 means tert.-butyl, n-propyl, n-butyl, 1,1,3,3-tetramethylbutyl, cyclohexyl, monosubstituted phenyl, 2,6-dimethylphenyl or benzyl, and R2 means simultaneously hydrogen atom or -CO-(methyl) and under condition that R2 doesn't mean hydrogen atom if R1 means benzyl simultaneously and R3 means methyl or R1 means simultaneously CH2C(O)-tert.-butyl and R3 means unsubstituted phenyl, in forms of bases or pharmaceutically acceptable salts, and a method for their preparing and a medicinal agent based on thereof. Described compounds possess analgesic activity and can be used in medicine.

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

7 cl, 2 tbl, 33 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new derivatives of pyrrolopyrimidine of the formula (1) and their pharmaceutically acceptable salts possessing properties of selective inhibitor of specific cyclic guanosine 3',5'-monophosphate phosphodiesterase (specific cGMP PDE) (PDE V). In the formula (1) R1 represents hydrogen atom (H), (C1-C3)-alkyl substituted optionally with one or some fluorine atoms; R2 represents H, halogen atom, (C1-C6)-alkyl substituted optionally with hydroxyl group (-OH), (C1-C3)-alkoxy-group, (C3-C6)-cycloalkyl or one or some fluorine atoms, (C3-C6)-cycloalkyl; R3 represents (C1-C6)-alkyl substituted optionally with (C3-C6)-cycloalkyl or one or some fluorine atoms; R4 represents (C1-C6)-alkyl substituted optionally with one or some fluorine atoms; R5 represents -SO2NR6R, -NHSO2R8 or heterocyclyl such as tetrazolyl; each R6 and R7 represents independently H or (C1-C6)-alkyl substituted optionally with -CO2H or one or some fluorine atoms; or in common with nitrogen atom to which they are bound form monocylic ring, such as imidazole, pyrrolidine, piperidine, morpholine, piperazine and homopiperazine wherein indicated group is replaced optionally with R9 wherein R9 represents (C1-C6)-alkyl substituted optionally with one or some halogen atoms, hydroxyl group (OH), (C1-C3)-alkoxy-group that is replaced optionally with one or some fluorine atoms, -NR11R12, -C=NR13(NR14R15) or tetrazolyl group, 6-membered nitrogen-containing heteroaryl group; each R11 and R12 represents independently H or (C1-C4)-alkyl; R13represents H; each R14 and R15 represents independently H. Also, invention relates to intermediate compounds, methods for preparing compounds and pharmaceutical compositions. Proposed compounds can be used in treatment of impotency, sexual dysfunction in females, stable, nonstable and variant (Prinzmental) stenocardia and other diseases also.

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

15 cl, 1 tbl, 250 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a pyrrolopyridazine derivative of the following formula: wherein R1 represents (C3-C7)-cycloalkyl-(C1-C6)-alkyl group that can be substituted optionally with (C1-C6)-alkyl group; R2 represents (C1-C6)-alkyl group; R3 represents hydroxymethyl group, (C2-C6)-aliphatic acyloxymethyl group, (C6-C10)-arylcarbonyloxymethyl group, (C1-C6)-alkoxycarbonyloxymethyl group, formyl group, carboxyl group, (C1-C6)-alkoxycarbonyl group or (C6-C10)-aryloxycarbonyl group; R4 represents (C6-C10)-aryl group that can be substituted optionally with substitutes taken among the group consisting of (C1-C6)-alkyl groups, halogen-(C1-C6)-alkyl groups, (C1-C6)-alkoxy-groups, halogen-(C1-C6)-alkoxy-groups and halogen atoms; A represents imino-group, oxygen or sulfur atom, or its pharmaceutically acceptable salt. Pyrrolopyridazine derivatives elicit inhibitory activity with respect to gastric juice secretion and protective activity with respect to stomach mucosa and can be useful as a curative agent for prophylaxis or treatment of ulcer disease. Except for, invention relates to a pharmaceutical composition based on compounds of the invention and to a method for prophylaxis and treatment of ulcer disease.

EFFECT: valuable medicinal properties of compound.

25 cl, 1 tbl, 11 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: compounds satisfying the formula I 1 are disclosed, wherein each R1 and R2 independently to one another are H, OH, OA or Hal; or R1 and R2 together are -O-CH2-O- or -O-CH2-CH2-O-; R3 and R4 are A-group; X - group monosubstituted with R8, R5 or R7; R5 is linear or branched C1-C10-alkylene, wherein one or two CH2-groups may be substituted with oxygen atom; R7 is phenyl or phenylmethyl; R8 is COOH, COOA, CONH2, CONHA, CON(A)2 or CN; F is C1-C6-alkyl; and Hal is F, Cl, Br, or I, as well as physiologically acceptable salts or solvates thereof. Methods for production of claimed compounds (I) and pharmaceutical composition containing the same also are disclosed. Said compounds and pharmaceutical composition have activity as phosphodiesterase V inhibitors and are useful in treatment of cardiovascular diseases and potency disorders.

EFFECT: pharmaceutically applicable compounds and compositions.

7 cl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

FIELD: organic chemistry, vitamins, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.

EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

FIELD: chemistry of peptides, medicine.

SUBSTANCE: invention relates to compound of the structure: N-methyl-(D-Leu-D-Val-D-Phe-D-Phe-D-leu)-NH2 designated for using as an active component in manufacturing a medicinal agent used for inhibition of natural β-amyloid peptides aggregation in patients suffering with disorder associated with β-amyloidosis and in treatment of Alzheimer's disease. Also, invention relates to a pharmaceutical composition, a method for inhibition of natural β-amyloid peptides, a method for detection of natural β-amyloid, a method for detection for the presence or absence of natural β-amyloid peptides in biological sample and to a method for treatment of patient with disorder associated with β-amyloidosis.

EFFECT: improved method for detecting, valuable medicinal properties of agent.

14 cl, 5 tbl, 5 dwg, 9 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new lipoic acid derivatives of general formula Ia

1, wherein n = 0-4, integer; -X-Y represents -O(CH2)r-, -CO-N(R3)-(CH2)r-, -N(R4)-CO-(CH2)r; -X'-Y' represents -(CH2)r-, -(CH2)r-N(R3)-(CH2)r-, -(CH2)r-CO-N(R3)-(CH2)2-; R3 and R4 are the same or different and represent hydrogen or alkoxycarbonyl; r = 0-4, integer; Ω represents piperazinyl, piperidyl or phenyl. Also disclosed are method for production the claimed derivatives and pharmaceutical composition, containing the same. Compounds are useful as NO-syntase inhibitors and/or reagents mediating redox state of thiol groups.

EFFECT: new lipoic acid derivatives.

7 cl, 17 ex

FIELD: organic chemistry, chemical technology, biochemistry.

SUBSTANCE: invention relates to new substituted 6-sulfo-2-oxo-1,2-dihydroquinoline 4-carboxylic acids and their derivatives of the general formula (1):

eliciting physiological activity, in particular, capacity to inhibit activity of protein kinase, and also to intermediate compounds for their preparing and to the focused library, for search compound-leaders and medicinal candidates obtaining on the basis of screening combinatory libraries. In compounds of the general formula (1) R1 represents hydrogen atom or electrophilic substitute; R2 represents hydrogen atom or inert substitute; R3 represents optionally substituted hydroxyl group, optionally substituted amino-group and optionally substituted azaheterocycle; R4 represents optionally substituted amino-group and optionally substituted azaheterocycle. Also, invention relates to compounds of the general formula (1.1):

wherein R1, R2 and R3 have above given values; R5 represents hydroxyl or chlorine atom, and to their applying for preparing compounds of the general formula (1.2):

and (1.3):

wherein R1, R2 and R4 have above given values.

EFFECT: valuable medicinal and biochemical properties of compounds.

6 cl, 4 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: biology, biochemistry, science-practical pharmacology, molecular biology.

SUBSTANCE: invention relates to isolated DNA fragment with indicated nucleotide sequence encoding protein that elicits property of intramembrane endoprotease (IMPAS), and to a method for preparing this protein. Invention provides the possibility for development of preparations used for diagnosis of diseases associated with proteolysis of intracellular receptors. Invention provides expanding assortment of agents useful in treatment of different neurological, cardiovascular and other diseases associated with the disturbed proteolysis of proteins.

EFFECT: improved preparing method, valuable medicinal properties of protein.

3 cl, 4 dwg, 1 tbl, 3 ex

FIELD: medicine, neurology, homeopathy.

SUBSTANCE: the suggested method is based upon immunomodulating and restorative therapy and deals with introducing a homeopathic preparation as Renel at the dosage of 0.15 g/an intake sublingually to an empty stomach, twice daily for 10 d both in the morning and in the second half of the day. The method enables to restore excretory functions of pelvic organs in patients with multiple sclerosis due to manifestation of new properties of Renel preparation, that is restoration of regulating function of nervous system.

EFFECT: higher efficiency of correction.

3 cl, 3 ex

FIELD: medicine, phytotherapy, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to using Belamcanda chinensis extract for preparing organ-selective medicinal preparation without uterotropic effect or with minimal such effect that is used as estrogen-like preparation. This preparation is used in selective treatment and/or prophylaxis of cardiovascular diseases, in particular, atherosclerosis and osteoporosis, climacteric disturbances, especially for prophylaxis or softening congestions of blood. Extract is used in manufacturing a medicinal preparation in ready formulation for selective treatment and/or prophylaxis of cardiovascular diseases, in particular atherosclerosis, and for selective treatment and/or prophylaxis of osteoporosis, climacteric disturbances, especially for prophylaxis and softening congestions of blood. Extract promotes to effective prophylaxis and/or treatment of cardiovascular diseases, in particular, atherosclerosis, climacteric disturbances, especially for prophylaxis and softening congestions of blood.

EFFECT: valuable medicinal properties of extract.

4 cl, 4 ex

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