Pharmaceutical composition, method for its preparing and using

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions possessing inhibitory effect with respect to MC2R-receptors, for preparing medicinal preparations as tablets, granules, capsules, suspensions, solutions or injections placed into pharmaceutically acceptable package. As active substance the composition comprises azaheterocyclic compound of general formulas (1.1.1) , (1.2.1) or (1.3.1) , wherein R1 in the general formula (1.1.1) represents substituted alkyl, aryl, heteroaryl, heterocyclyl, or R1 in the general formula (1.2.1) represents a substitute of amino-group chosen from hydrogen atom or possibly substituted lower alkyl or lower acyl; each R2, R3 and R4 represents independently of one another a substitute of cyclic system chosen from hydrogen atom, azaheterocyclyl, possibly substituted lower alkyl, possibly substituted hydroxy-group, carboxy-group, cycloalkyl; or R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle, or R1 in common with nitrogen atom to which it is bound, and R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle through R1, R3 and R4; R18 and R19 represent independently of one another substitutes of amino-group chosen from hydrogen atom or lower alkyl substituted with azaheterocycle as their racemates, optically active isomers or their pharmaceutically acceptable salts and/or hydrates; R20 and R21 in common with nitrogen atom to which they are bound form possibly substituted azaheterocycle. Also, invention relates to a method for preparing a pharmaceutical composition and using compounds and compositions for preparing medicinal preparations and for treatment or prophylaxis of diseases associated with enhanced activation of adrenocorticotropic hormone for compounds of general formulas (1.1.1), (1.2.1) and (1.3.1), and for using compounds for experimental investigations of indicated processes in vitro or in vivo also.

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

15 cl, 1 dwg, 4 tbl, 5 ex

 

The invention relates to pharmaceutical compositions for medicinal products for humans and warm-blooded animals used for the treatment of diseases and conditions associated with excessive activity (secretion) of adrenocorticotropic hormone (ACTH), in particular congenital or acquired hyperplasia of the adrenal cortex syndrome and Cushing's disease. The invention relates to new molecular pharmacological tools for studies (in vitro and in vivo biochemical mechanisms of action of steroid hormones and their specific receptors, in particular melanocortin receptor 2 (MC2R), an agonist which is ACTH.

More specifically, the present invention relates to pharmaceutical compositions containing as active ingredients compounds, including the fragment 1-oxo-3-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline, as well as for obtaining these compositions and method of use of these compositions for the treatment and prevention of the development of various diseases associated with increased activation of adrenocorticotropic hormone (ACTH), as well as to the use of compounds comprising a fragment of 1-oxo-3-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline as "molecular pharmacology tools for studies (in vitro and in vivo biochemical mechanisms of action of Corti is isteroidnyh hormones and their specific receptors, in particular melanocortin receptor 2 (MC2R), an agonist which is ACTH.

The adrenal cortex produces steroid hormones that play a crucial role in the physiology of human and animals [a) Silverman M.L., Lee A.K. Anatomy and pathology of the adrenal glands. Urol. Clin. North. Am. 1989; 16:417-32; (b) Rosol TJ, Yarrington J.T., J. Latendresse, Capen C.C. Adrenal gland: structure, function, and mechanisms of toxicity. Toxicol. Pathol. 2001; 29:41-8]. These steroids are mineralocorticoid aldosterone, glucocorticoid cortisone and corticosterone, as well as a number of androgens. The production of these steroids is regulated by ACTH, the secretion of which is controlled by the corticotropin-releasing hormone [Brodish, A., Lymangrover J.R. The hypothalamic-pituitary-adrenocortical system. Int. Rev. Physiol. 1977; 16:93-149]. ACTH produced by the pituitary gland, acts by binding specifically with its receptor, the so-called melanocortin receptor MC-2, which leads to increased steroidogeneza [Schioth H.B., Chhajlani V, Muceniece R., Klusa V., Wikberg J.E. Major pharmacological distinction of the ACTH receptor from other melanocortin receptors. Life Sci. 1996; 59:797-801]. Hyposecretion of ACTH caused by congenital or acquired dysfunction of the pituitary gland leads to hypoadrenalism. Excessive secretion of ACTH leads to congenital or acquired hyperplasia of the adrenal cortex, the syndrome and Cushing's disease, and ectopic development ACTH.

Congenital adrenal hyperplasia (otherwise adrenogenital syndrome) is a clinically is a mere symptom, development is associated with impaired secretion of corticosteroids due to a congenital defect of the enzymes responsible for the biosynthesis of these hormones [Collett-Jong Clemente P.F. Congenital adrenal hyperplasia: from genetics and biochemistry to clinical practice, part 2. Clin. Pediatr. (Phila) 2001; 40:125-32]. Reduced formation of cortisol leads to increased secretion of ACTH and subsequent hyperplasia of cortical layer of the adrenal cortex. Congenital adrenal hyperplasia is not infrequent and is from 1:10000 to 1:20000 births in the U.S. [New M.I., Newfield RS Congenital adrenal hyperplasia. Curr. Ther. Endocrinol. Metab. 1997; 6:179-87], making it one of the most common congenital metabolic diseases [New M.I. Inborn errors of adrenal steroidogenesis. Mol. Cell. Endocrinol. 2003; 211:75-83]. There is currently no effective medical treatment for this disease, virtually the only method of treatment is surgical [Merke D.P., Camacho C.A. Novel basic and clinical aspects of congenital adrenal hyperplasia. Rev. Endocr. Metab. Disord. 2001; 2:289-96].

Cushing's syndrome combines the symptoms caused by the constantly high level of free cortisol in the blood, at the same time, the Cushing disease (Itsenko-Cushing syndrome) is a special pituitary ACTH-dependent subtype of this syndrome [Giraldi P.P., Putignano p, Cavagnini F. Cushing''s syndrome. Lancet 2001; 357:2138]. According to statistics, every year, 3 new cases of Cushing's disease per 100,000 population [Cavagnini F., Pecori Giraldi f Epideiology and follow-up of Cushing''s disease. Ann. Endocrinol. (Paris) 2001; 62:168-72]. The main metodami treatment Itsenko-Cushing remain adrenalectomy and irradiation of the pituitary gland, which can be combined with adrenalectomy. Typically, these methods are accompanied by painful side effects [Semple P.L., Laws E.R. Complications in a contemporary series of patients who underwent transsphenoidal surgery for Cushing''s disease. J. Neurosurg. 1999; 91:175-9]. Effective methods of medical treatment are not available.

Thus currently there is no drug in clinical practice, none of the developed drug candidate is capable of selectively and effectively block the action of excessively secreted ACTH. In fact, so far found no low-molecular ones antagonist MC2R receptor. At the same time, the opening of such antagonists can lead to the creation of a fundamentally new drugs for the treatment of endocrine and other diseases of humans and animals associated with excessive activity of ACTH.

It should be noted that in the scientific and patent literature to date has no information about the activity of azaheterocyclic compounds in relation to MC2R receptor.

As a result of research aimed at finding new biologically active compounds capable of selectively and effectively blocks the SQL action excessively secreted ACTH, the inventors first discovered ones antagonists MC2R receptor, namely azaheterocyclic compounds, including the fragment 4'-carbarnoyl-1'-carbonyl[1,4']bipiperidine, indole or 2-(4-oxo-5-sulfamoyl-4H-thieno [2,3-d]pyrimidine-3-yl)ndimethylacetamide.

More specifically this invention relates to new pharmaceutical compositions containing azaheterocyclic compounds, including the fragment 4'-carbarnoyl-1'-carbonyl[1,4']bipiperidine, indole or 2-(4-oxo-5-sulfamoyl-4H-thieno[2,3-d]pertainin-3-yl)ndimethylacetamide, in the form of active substances, as well as to its preparation and method of its use for the treatment and prevention of the development of various diseases associated with the activity excessively secreted ACTH (congenital or acquired hyperplasia of the adrenal cortex, syndrome and disease Cushing and others).

Below are definitions of terms used in the description of this invention.

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

"Aliphatic" radical, means the radical obtained by removing a hydrogen atom from a non-aromatic C-H connection. Aliphati the definition of radical can optionally contain substituents - aliphatic or aromatic radicals, as defined in this section. Representatives of aliphatic radicals include alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, aralkyl, aralkylamines, uralelectromontrage, aralkyl, aralkyl, aralkylamines, heteroalkyl, heteroalkyl, heteroalicyclic, heteroalicyclic, heteroaryl, analyoung aristically, analyoung heteroalicyclic, analyoung arylchloroalkanes, analyoung heteroarylboronic, analyoung arylheteroacetic, analyoung heteroalicyclic, analyoung arylheteroacetic, analyoung heterooligomerization.

"Alkenyl" means aliphatic linear or branched hydrocarbon group containing 2 to 7 carbon atoms and including the carbon-carbon double bond.

Branched means that linear alkenylphenol chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl. The alkyl group may have one or more substituents, such as halogen, alkenylacyl, cycloalkyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroarylboronic, heterocyclyl, geterotsiklicheskikh, alkoxycarbonyl, and alkoxycarbonyl, heteroarylboronic or G1G2N-, G1G2NC(=O)-, G1G2NSO2-where G1and G2independently from each other represent a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or G1and G2together with the N atom to which they are bound, form a through G1and G24-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, benzyloxycarbonylation and pyridinedicarboxylate. Preferred alkenylamine groups are ethynyl, propenyl, n-butenyl, ISO-butenyl, 3-methylbut-2-enyl, n-pentenyl and cyclohexylmethanol.

"Alkenylacyl" means alkenyl-O - group in which alkenyl defined in this section. The preferred alkenylacyl are allyloxy and 3 butenyloxy.

"Alkenylacyl" means alkenyl-O-accelgroup, in which the alkyl and aeknil defined in this section.

"Alkyl" means an aliphatic hydrocarbon of linear or branched group with 1-12 carbon atoms in the chain, in which the alkyl groups. Branched means that the alkyl chain has one or more "lower skilnik" deputies. 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, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonates, analyoung heteroarylboronic, analyoung heteroalicyclic, analyoung heterooligomerization, analyoung heteroalicyclic, analyoung arylchloroalkanes, analyoung aristically, analyoung arylheteroacetic, analyoung arylheteroacetic, alkoxycarbonyl, arelaxation, heteroarylboronic or G1G2N-, G1G2NC(=O)-, G1G2NC(=S)-, G1G2NSO2-where G1and G2independently from each other represent a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or G1and G2together with the N atom to which they are bound, form a through G1and G24-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, meloxicam ylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation methoxycarbonylmethyl and pyridinedicarboxylate. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or G1G2N-, G1G2NC(=O)-, analyoung arylheteroacetic, analyoung arylheteroacetic.

"Alkyloxyalkyl" means alkyl-O-accelgroup, in which the alkyl groups are independent of each other and defined in this section. Preferred alkyloxyalkyl groups are methoxyethyl, ethoxymethyl, n-butoxymethyl, methoxypropyl and ISO-propylacetate.

"Alkylthio" means alkyl-S-group in which altergroup defined in this section.

"Alkoxy" means alkyl-O - group in which alkyl is defined in this section. The preferred alkyloxyaryl are methoxy, ethoxy, n-propoxy, ISO-propoxy and n-butoxy.

"Alkoxycarbonyl" means alkyl-O-C(=O)- group in which alkyl is defined in this section. Preferred alkoxycarbonyl groups are methoxycarbonyl, etoxycarbonyl and tert-butyloxycarbonyl.

"Alkoxycarbonyl" means Ala is l-O-C(=O)-accelgroup, in which alkyl is defined in this section. Preferred alkoxycarbonylmethyl groups are methoxycarbonylmethyl and ethoxycarbonylmethyl and methoxycarbonylethyl and ethoxycarbonylethyl.

"Amino group"means G1G2N - group, substituted or unsubstituted "Deputy amino group", G1and G2whose value is defined in this section, for example, amino (H2N-), methylamino, diethylamino, pyrrolidine, morpholine, benzylamine or phenethylamine.

"Amino acid" means a natural amino acid or unnatural amino acid, meaning the latter is defined in this section. Preferred amino acids are amino acids containing αor β-amino group. An example of natural amino acids are α-amino acids can serve as alanine, valine, leucine, isoleucine, Proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine and cysteine.

"Analyoung cycle" (condensed cycle) means of bi - or polycyclic system, where analyoung cycle and cycle or politics, with whom he "anaeroven have at least two common atom.

"Analyoung arylheteroacetic" means annelirovaniya aryl and geteroseksualen, the value of which is determined in this section. Analyoung arylheteroacetic can contact chartlabel possible atom of the cyclic system. The prefix "Aza", "oxa" or "thia" before "geteroseksualen" means the presence in the cyclic system, nitrogen atom, oxygen atom or sulfur atom, respectively. Analyoung arylheteroacetic may have one or more "cyclic system substituents"which may be the same or different. Atoms of nitrogen and sulfur, in heterocyclyl parts can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives analyoung of allgemeinreaktion are indolinyl, 1H-2-oxopyrrolidin 2N-1-oxoethylidene, 1,2-dihydroquinoline etc.

"Analyoung arylheteroacetic" means annelirovaniya aryl and heteroseksualci, the value of which is determined in this section. Analyoung arylheteroacetic can be contacted through any possible atom of the cyclic system. The prefix "Aza", "oxa" or "thia" before "heteroseksualci" means the presence in the cyclic system, nitrogen atom, oxygen atom or sulfur atom, respectively. Analyoung arylheteroacetic may have one or more "cyclic system substituents"which may be the same or different. Atoms of nitrogen and sulfur, in heterocyclyl part, can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives analyoung of analgeticalkie are in the of oil, 1,2,3,4-tetrahydroisoquinoline, 1,3-benzodioxol etc.

"Analyoung arylchloroalkanes" means annelirovaniya aryl and cycloalkenyl, the value of which is determined in this section. Analyoung arylchloroalkanes can be contacted through any possible atom of the cyclic system. Analyoung arylchloroalkanes may have one or more "cyclic system substituents"which may be the same or different. Representatives analyoung of arylcyclohexylamines are 1,2-dihydronaphthalene, inden, etc.

"Analyoung aristically" means annelirovaniya aryl and cycloalkyl, the value of which is determined in this section. Analyoung aristically can be contacted through any possible atom of the cyclic system. Analyoung aristically may have one or more "cyclic system substituents"which may be the same or different. Representatives analyoung of arylcyclohexylamines are indanan, 1,2,3,4-tetrahydronaphthalen, 5,6,7,8-tetrahedronal-1-yl, etc.

"Analyoung heteroarylboronic" means annelirovaniya heteroaryl and cycloalkenyl, the values of which are defined in this section. Analyoung heteroarylboronic can be contacted through any possible atom of the cyclic system. The prefix "Aza", "oxa" or "thia" before "heteroa the l" indicates a cyclic system, of nitrogen atom, oxygen atom or sulfur atom, respectively. Analyoung heteroalicyclic may have one or more "cyclic system substituents"which may be the same or different. The nitrogen atom located in the heteroaryl portion may be okisleniem to N-oxide. Representatives analyoung of heteroarylboronic are 5,6-dihydroxyindoline, 5,6-dihydroisoquinolyl, 4,5-dihydro-1H-benzimidazolyl etc.

"Analyoung heterokedasticity" means annelirovaniya heteroaryl and cycloalkyl, the values of which are defined in this section. Analyoung heteroalicyclic can be contacted through any possible atom of the cyclic system. The prefix "Aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. Analyoung heteroalicyclic may have one or more "cyclic system substituents"which may be the same or different. The nitrogen atom located in the heteroaryl portion may be okisleniem to N-oxide. Representatives analyoung of heteroarylboronic are 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, 4,5,6,7-tetrahydro-1H-benzimidazolyl etc.

"Analyoung heterooligomerization" means annelirovaniya hetero is the Rila and heterocyclyl, values are defined in this section. Analyoung heterooligomerization can be contacted through any possible atom of the cyclic system. The prefix "Aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system, nitrogen atom, oxygen atom or sulfur atom, respectively. Analyoung heterooligomerization may have one or more "cyclic system substituents"which may be the same or different. The nitrogen atom located in the heteroaryl portion may be okisleniem to N-oxide. Atoms of nitrogen and sulfur, in heterocyclyl part, can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives analyoung of heteroarylboronic are 1,2-dihydro[2,7]naphthyridines, 7,8-dihydro[1,7]naphthyridine, 6,7-dihydro-3H-imidazo[4,5-C]pyridyl and the like,

"Analyoung heteroalicyclic" means annelirovaniya heteroaryl and heterocyclyl, the values of which are defined in this section. Analyoung heteroalicyclic can be contacted through any possible atom of the cyclic system. The prefix "Aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system, nitrogen atom, oxygen atom or sulfur atom, respectively. Analyoung heteroalicyclic may have one or more substituents CEC is practical system", which may be the same or different. The nitrogen atom located in the heteroaryl portion may be okisleniem to N-oxide. Atoms of nitrogen and sulfur, in heterocyclyl part, can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives analyoung of heteroarylboronic are 2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-2-yl, 2,3-dihydro-1H-pyrrolo[3,4-b]indol-2-yl, 1,2,3,4-tetrahydro[1,5]naphthyridine etc.

"Aralkyl" means arylalkyl, in which values of aryl and alkenyl defined in this section. For example, 2-pentenyl is arlbergpass.

"Aralkyl" means an alkyl group substituted by one or more aryl groups, in which values of aryl and alkyl are defined in this section. Examples Uralkalij groups are benzyl, 2,2-diphenylether or phenethyl.

"Aralkylamines" means an aryl-alkyl-NH-, in which values of aryl and alkyl are defined in this section.

"Aralkylamines" means aralkyl-SO-group, which is aralkyl defined in this section.

"Aralkylamines" means aralkyl-SO2the group, which is aralkyl defined in this section.

"Uralkali" means aralkyl-S-group in which the value of aralkyl defined in this section.

"Arakaki" means aralkyl-O-group in which the value of aralkyl defined what this topic. For example, benzyloxy or 1 - or 2-naphthalenyloxy are Uralkalij groups.

"Alcoxialchil" means aralkyl-O-accelgroup, which is aralkyl and alkyl are defined in this section. An example of aralkyl-O-alkyl group is benzyloxyethyl.

"Arelaxation" means aralkyl-O-C(=O)group, which is aralkyl defined in this section. Example alcoxycarbenium group is benzyloxycarbonyl.

"Alcoxycarboxylates" means aralkyl-O-C(=O)-alkyl-group in which values aralkyl and alkyl are defined in this section. Example alcoxycarboxylates group is benzyloxycarbonyl or benzyloxycarbonyl.

"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 anaeroven with non-aromatic cyclic system or heterocycle.

"Arylcarbamoyl" means aryl-NHC(=O)- group, where aryl is defined in this section.

"Aryloxy" means aryl-O - group, where aryl about is designated in this section. Representatives of aryloxy are phenoxy and 2 naphthyloxy.

"Aryloxyalkyl" means aryl-O-C(=O)- group, where aryl is defined in this section. Representatives aryloxyalkyl groups are phenoxycarbonyl and 2-mattoxicator.

"Arylsulfonyl" means aryl-SO - group, where aryl is defined in this section.

"Arylsulfonyl" means aryl-SO2group, where aryl is defined in this section.

"Aristeo" means an aryl-S - group, where aryl is defined in this section. Representatives of aricioglu are phenylthio and 2 naphthylthio.

"Aroylamino" means aroyl-NH - group, which is aroyl defined in this section.

"Aroyl" means an aryl-C(=O)- group in which the value of aralkyl defined in this section. Examples rolnych groups are benzoyl, 1 - and 2-naphtol.

"Aromatic" radical, means the radical obtained by removing hydrogen atom from the aromatic C-H bond. "Aromatic" moiety includes aryl and heteroaryl cycles defined in this section. Aryl and heteroaryl cycles can optionally contain substituents is an aliphatic or aromatic radicals, as defined in this section. Representatives of aromatic radicals include aryl, analyoung recloak melaril, analyoung cycloalkenyl, analyoung heterocyclisation, analyoung heterocultural, heteroaryl, analyoung cycloalkylcarbonyl, analyoung cycloalkylcarbonyl, analyoung heterocyclisation and analyoung heterocyclisation.

"Aromatic cycle" means a planar cyclic system in which all the atoms of the cycle involved in the formation of a unified system of conjugation, including according to the hückel rule (4n+2) π-electrons (n is a nonnegative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene, etc. In the case of heteroaromatic cycles in the system of the pairing involved πelectrons and p-electrons of heteroatoms, their total number is also equal to (4n+2). Examples of such cycles include pyridine, thiophene, pyrrole, furan, thiazole, etc. Aromatic cycle can have one or more cyclic substituents" of the system and can be anaeroven with non-aromatic cycle, heteroaromatic or heterocyclic system.

"Acyl" means an H-S(=O)- or alkyl-C(=O)-, cycloalkyl-C(=O)-, heterocyclyl-C(=O)-, geterotsiklicheskikh-C(=O)-, aryl-C(=O)- arylalkyl-C(=O)- or heteroaryl-C(=O)-, heteroallyl-C(=O)- group in which alkyl-, cycloalkyl-, heterocyclyl, geterotsiklicheskikh, aryl-arylalkyl, heteroaryl, heteroaromatic defined in this section./p>

"Acylamino" means acyl-NH - group, where the acyl is defined in this section.

"Bifunctional reagent" means a chemical compound having two reaction centre involved simultaneously or sequentially in reakciyakh. An example of a bifunctional reagents can serve as reagents containing carboxyl group and aldehyde or ketone group, such as 2-formylbenzoate acid, 2-(2-oxoethylidene)benzoic acid, 2-(3-formylthiophene-2-yl)benzoic acid or 2-(2-formylphenyl)thiophene-3-carboxylic acid.

"1,2-Vinyl radical" means-CH=CH - group, which contains one or more identical or different "Deputy alkyl", the value of which is determined in this section.

"Halogen" means fluorine, chlorine, bromine and iodine. Preferred are fluorine, chlorine and bromine.

"Heteroarylboronic cycle" means a cycle, which is attached (Anneliese or condensed) to another cycle or polycycle, contains at least one heteroatom.

"Heteroalkyl" means heteroaromatics in which heteroaryl and alkenyl defined in this section. Preferably heteroalkyl includes lower alkyl group. Representatives of heteroarenes are 4-pyridalyl, trilateral, imidazolidinyl, personalemail etc.

"Goethe is aralkyl" means heteroallyl, in which heteroaryl and alkyl are defined in this section. Representatives of heteroalkyl are pyridylmethyl, thienylmethyl, furylmethyl, imidazolidinyl, personality etc.

"Heteroaromatics" means heteroallyl-O - group in which heteroaromatic defined in this section. Representatives of heteroeroticism are 4 pyridylmethylene, 2-thienylmethyl etc.

"Heteroaryl" means heteroaryl-C(=O)- group in which heteroaryl defined in this section. Representatives of heteroaryl are nicotinoyl, thienoyl, pyrazolyl etc.

"Heteroaryl" means an aromatic monocyclic or polycyclic system containing from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms replaced by a heteroatom or heteroatoms, such as nitrogen, sulfur or oxygen. The prefix "Aza", "oxa" or "thia" before heteroaryl means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. The nitrogen atom located in heteroaryl, can be oxidized to N-oxide. Heteroaryl may have one or more "cyclic system substituents"which may be the same or different. Representatives of heteroaryl are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, isooxazolyl, isothiazol the sludge, tetrazolyl, oxazolyl, thiazolyl, pyrazolyl, furutani, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, honokalani, phthalazine, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofuranyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, chinoline, imidazolyl, cyanopyridyl, hintline, thienopyrimidines, pyrrolopyridine, imidazopyridine, ethenolysis, benzoxazinones, 1,2,4-triazinyl, thienopyrrole, properly. and other

"Heteroarylboronic" means heteroaryl-SO2-NH-C(=O)- group in which heteroaryl defined in this section.

"Heterocycle" means an aromatic or non-aromatic monocyclic or polycyclic system containing a loop at least one heteroatom, which is in this section. Preferred heteroatoms are nitrogen, oxygen and sulfur. Azaheterocycle can have one or more cyclic substituents" of the system.

"Heterocyclyl" means a non-aromatic monocyclic or polycyclic system containing from 3 to 13 carbon atoms, mainly from 5 to 13 carbon atoms, in which one or several carbon atoms replaced by a heteroatom, such as nitrogen, oxygen, sulfur, which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. The prefix "Aza", "oxa" or "thia" before Goethe what ocalenia means the presence of cyclical nitrogen atom, oxygen atom or sulfur atom, respectively. Heterocyclyl may have one or more "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 of heterocyclyl are 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridines, 1,4-dihydropyridines, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 2-pyrazoline, dihydrofurane, dihydrothiophene etc.

"Heterocyclyl" means a 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 several 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 may have one or more "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.

"Heterocyclic" means heterocyclyl-O - group, in which heterocyclyl defined in this section.

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

"Hydroxyalkyl" means BUT accelgroup, in which alkyl is defined in this section.

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

"Deputy alkyl" means a Deputy, attached to the alkyl, alkenyl, the value of which is determined in this section. Deputy alkyl represents hydrogen, alkyl, halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonates, analyoung heteroarylboronic, analyoung heteroalicyclic, analyoung heterooligomerization, analyoung heteroalicyclic, analyoung arylchloroalkanes, analyoung aristically, analyoung arylheteroacetic, analyoung arylheteroacetic, alkoxycarbonyl, arelaxation, gets ruraltransitions or G 1G2N-, G1G2NC(=O)-, G1G2NSO2-where G1and G2independently from each other represent a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl or G1and G2together with the N atom to which they are bound, form a through G1and G24-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation and pyridinedicarboxylate. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or G1G2N-, G1G2NC(=O)-, analyoung arylheteroacetic, analyoung arylheteroacetic. The significance of the "alkyl substituents" defined in this section.

"Deputy acyl" means a Deputy chosen from the series alkyl, cycloalkyl, heterocyclyl, geterotsiklicheskikh, aryl, arylalkyl, heteroaryl, heteroaromatic attached to the atom is gerada carbonyl group of the acyl, in which the acyl, alkyl, cycloalkyl, heterocyclyl, geterotsiklicheskikh, aryl, arylalkyl, heteroaryl, heteroaromatic defined in this section.

"Deputy amino group" means the Deputy attached to the amino group. Deputy amino group represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, analyoung heteroarylboronic, analyoung heteroalicyclic, analyoung heterooligomerization, analyoung heteroalicyclic, analyoung arylchloroalkanes, analyoung aristically, analyoung arylheteroacetic, analyoung arylheteroacetic, alkoxycarbonylmethyl, alcoxycarboxylates, heteroarylboronic.

"Deputy carbamoyl" means the Deputy attached to carbamoyl group, the value of which is defined in this section. Deputy carbamoyl represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic or G1 G2N-, G1G2NC(=O)-alkyl, analyoung heteroarylboronic, analyoung heteroalicyclic, analyoung heterooligomerization, analyoung heteroalicyclic, analyoung arylchloroalkanes, analyoung aristically, analyoung arylheteroacetic, analyoung arylheteroacetic. Preferred substituents carbamaepine" are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic or G1G2N-, G1G2NC(=O)-alkyl, analyoung arylheteroacetic, analyoung arylheteroacetic.

"Deputy carboxyl" means the Deputy attached to the oxygen of the carboxylic group, the value of which is defined in this section. Deputy carboxyl represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic or G1G2N-, G1G2NC(=O)-alkyl, analyoung heteroarylboronic, analyoung heteroalicyclic, analyoung heterooligomerization, analyoung heteroalicyclic, analyoung arylchloroalkanes, analyoung aristically, analyoung arylheteroacetic, analyoung allgeric the L. Preferred carboxyl substituents are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic or G1G2N - alkyl, G1G2NC(=O)-alkyl, analyoung arylheteroacetic, analyoung arylheteroacetic.

"Deputy nucleophilic" means a chemical moiety that is attached to scaffold in the reaction with the nucleophilic reagent, for example, selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thiophenols.

"Deputy cyclic system" means the Deputy attached to aromatic or non-aromatic cyclic system, including hydrogen, alkylaryl, quinil, aryl, heteroaryl, aralkyl, heteroalkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, acyl, aroyl, glogan, nitro, cyano, carboxy, alkoxycarbonyl, aryloxyalkyl, arelaxation, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylthio, aaltio, heteroaromatic, Uralkali, heteroalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, amidino, G1G2N-, G1G2N-alkyl-, G1G2NC(=O) -, or G1G2NSO2-where G1and G2represent independently researched the Simo from each other hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heteroalkyl, or Deputy G1G2N-, in which one of the G1and G2can be acyl or aroyl, and is different from G1and G2defined above, or "cyclic system substituents" are G1G2NC(=O) -, or G1G2NSO2-in which G1and G2together with the nitrogen atom to which they are bound, form a through G1and G24-7-membered heterocyclyl or heterocyclyl. Preferred "cyclic system substituents" are alkoxycarbonyl, alkoxy, halogen, aryl, Alcoxy, alkyl, hydroxy, aryloxy, nitro, cyano, alkylsulfonyl, heteroaryl or G1G2N-. If the cyclic system is saturated or partially saturated, the "cyclic system substituents" may have a value of methylene (CH2=), oxo (O=) or thioxo (S=).

"Deputy electrophilic" means a chemical moiety that is attached to scaffold as a result of reaction with an electrophilic reagent, for example, organic acids or their derivatives (anhydrides, imidazolides, halides, esters of organic sulfonic acids or organic sulfochlorides, organic halogenfree, organic isocyanates and the content of inorganic fillers isothioscyanates.

"Protective group" (PG) means a chemical moiety that is attached to scaffold or semi-synthesis for the temporary protection of amino groups in multifunctional compounds, including, but not limited to: amide Deputy, such as formyl, optionally substituted acetyl (for example, trichloroacetyl, TRIFLUOROACETYL, 3-phenylpropionyl and others), optionally substituted benzoyl and others; urethane Deputy, such as optionally substituted C1-C7allyloxycarbonyl, such as methyloxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc), and others; optionally substituted C1-C7alkyl substituent, such as tert-butyl, benzyl, 2,4-dimethoxybenzyl, 9-phenylfluorene and others; sulfanilic Deputy, for example benzazolyl, p-toluensulfonyl and other More "Protective groups described in Protective groups in jrganic synthesis. Third Edition, Greene, T.W. and Wuts, P.G.M. 1999, p.494-653. Publisher John Wiley & Sons, Inc., New York, Chichester, Weinheim, Brisbane, Toronto, Singapore.

"Protected primary or secondary amine" means a group of the formula G1G2N-, in which one of the G1and G2represents a protective group PG, and is different from G1and G2represents hydrogen, alkenyl, alkyl, aralkyl, aryl, analyoung, killller, analyoung oryzicola is, analyoung arylheteroacetic, analyoung arylheteroacetic, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, analyoung heteroarylboronic, analyoung heteroalicyclic, analyoung heterooligomerization, analyoung heteroalicyclic, heterocyclyl or heterocyclyl.

"Inert Deputy" (or "not interfering", "Non-interfering substituent"means low or directionspanel radical, including, but not limited to C1-C7alkyl, C2-C7alkenyl,2C7 quinil, C1-C7alkoxy. With7-C12aralkyl substituted with inert substituents, aralkyl,7-C12geterotsiklicheskikh substituted with inert substituents, geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-C12alkoxyalkyl,2-C10alkylsulfonyl,2-C10alkylsulfonyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted by Halogens, inert substituents aryl, substituted with inert substituents, alkoxy, foralkyl, aryloxyalkyl, heterocyclyl substituted with inert substituents heterocyclyl and nitroalkyl, where m and n have a value from 1 to 7. Pre is reverent "inert substituents are C 1-C7alkyl, C2-C7alkenyl, C2-C7quinil, C1-C7alkoxy, C7-C12aralkyl,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl substituted with inert substituents C1-C7alkyl, phenyl, substituted by inert substituents phenyl, ((CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted with inert substituents aryl, heterocyclyl and substituted with inert substituents heterocyclyl.

"Carbarnoyl" means G1G2NC(=O)- group. Carbarnoyl may have one or more identical or different "Vice carbamoyl" G1and G2including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the value of which is determined in this section.

"Carbamoylaspartate" means azaheterocycle containing as samestyle cyclic system, at least one karbamoilnuyu group, is "azaheterocycle", "semester cyclic system" and "carnemolla group" is defined in this section.

"Carboxy" means the NOSE(=O)- (carboxyl) group.

"Carboxylic" means the NOSE(=O)-accelgroup, where alkyl is defined in this section.

"Carbocycle" means a mono - or polycyclic system, SOS is ojasuu only of carbon atoms. Carbocycle can be aromatic, and alicyclic. Alicyclic politicly can have one or more common atoms. In the case of a single atom are formed Spiro-carbocyclic (for example, Spiro[2.2]pentane), in the case of two - varied kondensirovannye system (for example, decalin), in the case of three - bridge systems (for example, bicyclo[3.3.1]nonan), in case a greater number of different polyhedral systems (e.g., adamantane). Alicycle can be "saturated", such as cyclohexane, or partially saturated, for example, as tetralin.

"Combinatorial library" means a collection of compounds obtained by parallel synthesis, designed to search for connections-hit or leader, as well as to optimize the physiological activity of hit or leader, each compound of the library meets the General scaffold and the library is a collection of related homologues or analogues.

"Methylene radical" sachet-CH2group, which contains one or two identical or different "Deputy alkyl", the meaning of which in this section.

"Nah cycle (saturated cycle or partially saturated cycle) refers to non-aromatic cyclic or polycyclic system, formally educated as a result of full or partial hydrogenation of nepredel is s C=C or C=N bonds. Non-aromatic cycle can have one or more cyclic substituents" of the system and can be anaeroven with aromatic, heteroaromatic or heterocyclic systems. Examples of non-aromatic cycles are cyclohexane or piperidine, examples of partially nasyshenno cycle - cyclohexen or piperideine.

"Unnatural amino acid" means an amino acid nucleic not nature. An example of unnatural amino acids can serve as D-isomers of natural α-amino acid, aminobutyric acid, 2-aminobutyric acid, γ-aminobutyric acid, N-α-alkylated amino acid, 2,2-dialkyl-α-amino acids, 1-aminocyclopropane acid, β-alanine, 2-alkyl-β-alanine, 2-cycloalkyl-β-alanine, 2-aryl-β-alanine, 2-heteroaryl-β-alanine, 2-heterocyclyl-β-alanine and (1-aminocyclohexane)acetic acid in which the alkyl values, cycloalkyl, aryl, heteroaryl and heterocyclyl defined in this section.

"Optional aromatic cycle" means a cycle, which can be either aromatic cycle, and non-aromatic cycle, the values of which are defined in this section.

"Optionally substituted radical" means a radical without substituents or with one or more substituents.

"Optional analyoung (condensed) cycle"means a condensed or unfused cycle, values are defined in this section.

"Lower alkyl" means a linear or branched alkyl with 1-4 carbon atoms. "Parallel synthesis" means a method for chemical synthesis of combinatorial libraries of individual connections.

"1,3-Propylene radical" means-CH2-CH2-CH2- the group that contains one or more identical or different "Deputy alkyl", the meaning of which in this section.

"Connection-leader" ("leader") means the connection is outstanding (maximum) physiological activity associated with a specific biomechani relating to a particular (or several) of pathology or disease.

"Connection-hit" ("hit") means a compound expressed during primary screening desired physiological activity.

"Altamarena group" means G1G2NSO2group, substituted or unsubstituted "Deputy amino group" G1and G2whose values are defined in this section.

"Sulfonyl" means G3-SO2- the group in which G3represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, analyoung heteroarylboronic, analyoung heteroalicyclic, analyoung heterooligomerization, analyoung heteroalicyclic, anilinov the hydrated arylchloroalkanes, analyoung aristically, analyoung arylheteroacetic, analyoung arylheteroacetic, the value of which is determined in this section.

"Template" means the General structural formula of a group of compounds or compounds included in "combinatorial library".

"Thiocarbamoyl" means G1G2NC(=S)- group. Carbarnoyl may have one or more identical or different "Vice thiocarbamoyl" G1and G2,including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the value of which is determined in this section.

"Cycloalkyl" means a non-aromatic mono - or polycyclic system containing from 3 to 10 carbon atoms. Cycloalkyl may have one or more "cyclic system substituents"which may be the same or different. Representatives cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl, etc. Cycloalkyl can be anaeroven with aromatic cycle or a heterocycle. Preferred "cyclic system substituents" are alkyl, Alcoxy, hydroxy or GlG2N, the value of which is determined in this section.

"Cycloalkylcarbonyl" means cycloalkyl-C(=O)- group in which the value of cycloalkyl defined in this section. Representatives of C is Gloucestershire groups are cyclopropanecarbonyl or cyclohexylcarbonyl.

"Cycloalkane" means cycloalkyl-O - group in which the value of cycloalkyl defined in this section.

"Pharmaceutical composition" means a composition comprising a compound of formula I and at least one component selected from the group consisting 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, polyoxyethylenesorbitan 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 from onionskin 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 mixtures thereof, 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, alginic 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 administration, the active principle, one or in combination with other active early, 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, javate the performance communications 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.

"Pharmaceutically acceptable salt" refers to 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 these salts is given in S.M. Berge 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 the amines. The metal include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, the most desirable 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.

"Focused library" means a combinatorial library, or a combination of several combinatorial bi is leotek, or a set of libraries and substances, specially organized for the purpose of increasing the probability of finding hits and leaders, or to improve the efficiency of their optimization. The design of focused libraries, typically associated with directional search effectors (inhibitors, activators, agonists, antagonists, etc.) certain biological targets (enzymes, receptors, ion channels, and so on).

"Fragment" (scaffold) means the structural formula of the molecule, characteristic of a group of compounds or molecular frame, characteristic of a group of compounds or compounds included in the combinatorial library.

"1,2-Ethylene radical" means-CH2-CH2- the group that contains one or more identical or different "Deputy alkyl", the value of which is determined in this section.

The aim of the present invention is to provide new pharmaceutical compositions in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing.

This goal is achieved by a pharmaceutical composition having inhibitory activity against MC2R receptor, for the preparation of medicinal products in the form of tablets, granules, capsules, suspensions, solutions or injections, placed in pharmaceutically acceptable packing containing ka is este active substance azaheterocyclic compound of General formula 1.1.1 and/or 1.2.1, and/or 1.3.1:

where R1in the General formula 1.1.1 is a substituted alkyl, aryl, heteroaryl, heterocyclyl or in the General formula 1.2.1 R1is a Deputy amino group selected from a hydrogen or a possibly substituted lower alkyl or lower acyl;

R2, R3and R4independently from each other represent a Deputy cyclic system selected from hydrogen, azaheterocycle, possibly substituted lower alkyl, possibly substituted hydroxy-group, possibly substituted carboxypropyl, cycloalkyl, or R3and R4together with the carbon atoms to which they are linked, through close R3and R4azaheterocycle, or R1together with the nitrogen atom to which it is linked, and R3and R4together with the carbon atoms to which they are linked, through close R1, R3and R4azaheterocycle;

R18and R19independently from each other, represent substituents of the amino group selected from hydrogen or lower alkyl, substituted azaheterocycles, in the form of their racemates, optically active isomers or pharmaceutically acceptable salts and/or hydrates, R20and R21together with the nitrogen atom to which they are bound, form a possible C is displaced azaheterocycle.

According to the invention preferred pharmaceutical composition having inhibitory activity against MC2R receptor, is a composition containing as active substance N-[2-(1H-indol-3-yl)ethyl]acylamide General formula 1.2.1.1 or racemates, or optical isomers, or pharmaceutically acceptable salts and/or hydrates:

where R1, R2and R4have the above meaning; R5is azaheterocycle.

According to the invention preferred pharmaceutical composition having inhibitory activity against MC2R receptor, is a composition containing as active substance 11-(1H-indol-3-yl)-2,3,4,5,10,11-hexahydrobenzo[b,e][1,4]diazepin-1 he General formula 1.2.1.2 or racemates, or optical isomers, or pharmaceutically acceptable salts and/or hydrates:

where R1and R2have the above meaning; R6represents an alkyl or cycloalkyl; R7and R8independently from each other represent a hydrogen atom, alkyl or aryl.

According to the invention preferred pharmaceutical composition having inhibitory activity against MC2R receptor, is a composition containing as the active substance 7-acyl-6-(1H-indol-3-yl)-3-effect-free remedy 6,7,8,9-tetrahydro-1,2,4-triazino[5,6-f][1,3]oxazepan General formula 1.2.1.3 or its racemate, or its optical isomer, or its pharmaceutically acceptable salts and/or hydrates:

where R1and R2have the above meaning; R9represents an alkyl or alkenyl.

According to the invention preferred pharmaceutical composition having inhibitory activity against MC2R receptor, is a composition containing as the active substance 1-oxo-3-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline General formula 1.2.1.4 or racemates, or optical isomers, or pharmaceutically acceptable salts and/or hydrates:

where R1and R2have the above meaning; R10is a Deputy cyclic system; R11, R12and R13independently from each other represent a Deputy amino group.

According to the invention preferred pharmaceutical composition having inhibitory activity against MC2R receptor, is a composition containing as the active substance 1-oxo-3-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline General formula 1.2.1.4.1 or racemates, or optical isomers, or pharmaceutically acceptable salts and/or hydrates:

where R1, R2, R10, R11, R 12and R13have the above value.

According to the invention preferred pharmaceutical composition having inhibitory activity against MC2R receptor, is a composition containing as the active substance 1-oxo-3-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline General formula 1.2.1.4.2 or racemates, or optical isomers, or pharmaceutically acceptable salts and/or hydrates:

where R1represents hydrogen or methyl; R10, R11and R13have the above value.

According to the invention preferred pharmaceutical composition having inhibitory activity against MC2R receptor, is a composition containing as active substance 1,2,3,8-tetrahydro-1-oxo-pyrrolo[3,4-b] indole of General formula 1.2.1.5 or racemates, or optical isomers, or pharmaceutically acceptable salts and/or hydrates:

where R1and R have the above significance; R14is a Deputy amino group; R15represents aryl or heteroaryl.

According to the invention preferred pharmaceutical composition having inhibitory activity against MC2R receptor, is a composition containing in the quality of the ve active substance 2,3,4,5-tetrahydro-1H-pyrido[3,4-b]indole of General formula 1.2.1.6 or its racemate, or its optical isomer, or its pharmaceutically acceptable salts and/or hydrates:

where R1and R2have the above meaning; R16is a Deputy amino group.

According to the invention preferred pharmaceutical composition having inhibitory activity against MC2R receptor, is a composition containing as active substance azaheterocyclic compound of General formula 1.2.1.7 or racemates, or optical isomers, or pharmaceutically acceptable salts and/or hydrates:

where R2has the above meaning; R17is a Deputy amino group.

According to the invention preferred pharmaceutical composition having inhibitory activity against MC2R receptor, is a composition containing as the active substance 2-[6-methyl-4-oxo-5-(4-(pyrimidine-2-reparation-1-sulfonyl)-4H-thieno[2,3-d]pyrimidine-3-yl]ndimethylacetamide General formula 1.3.1.1 or racemates, or optical isomers, or pharmaceutically acceptable salts and/or hydrates:

where R18and R19have the above value.

The aim of the present invention is also a method of obtaining Pharma is eticheskoi composition.

This goal is achieved by a method of obtaining a pharmaceutical composition, which consists in mixing the active substance with an inert, with respect to substance, excipients and/or solvents, followed by pelletizing, granulating, kapsulirovaniem, suspendirovanie, dissolution or dilution and placing them in suitable packaging, the distinctive feature of which is that as the active substance use any of azaheterocyclic compounds of the General formula 1.1.1 and/or 1.2.1, and/or 1.3.1 or their racemates, or optical isomers, or their pharmaceutically acceptable salts and/or hydrates.

Under inert fillers and/or solvents (experiencemy) means used in the field of pharmaceutical diluents, auxiliary agents and/or carriers of azaheterocyclic compounds of the General formula 1.1.1, 1.2.1, 1.3.1 the present invention, which can be used in combination with other active ingredients provided that they do not cause unwanted effects, such as allergic reactions.

If you want to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed to produce different forms, however, they can include traditional pharmaceutical but Italy, for example, oral formulations such as tablets, gelatin capsules, pills, solutions or suspensions); forms for injection (such as solutions or suspensions for injection or dry powder for injection, which requires only the addition of water for injection before use); local forms such as ointments or solutions).

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 pharmaceutical preparations can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally or topically). If any of the medicinal substance in the conditions of the stomach is not stable, you can use it for the manufacture of tablets, film-coated substance, soluble in the stomach or intestines.

In accordance with the invention of a new pharmaceutical compositions which ia used for the preparation of drugs for the treatment and prevention of diseases, associated with increased activation of adrenocorticotropic hormone (ACTH).

The aim of the present invention is also a method of treating and preventing various diseases of warm-blooded animals and humans associated with increased activation of adrenocorticotropic hormone (ACTH).

This goal is achieved by a method of treating and preventing various diseases of warm-blooded animals and humans associated with increased activation of adrenocorticotropic hormone (ACTH), by introducing a warm-blooded animal or human pharmaceutical compositions containing as active substance azaheterocyclic compound of General formula 1.1.1, 1.2.1 and 1.3.1, or their racemates, or optical isomers, or their pharmaceutically acceptable salts and/or hydrates in the required therapeutic doses.

The clinical dosage of the pharmaceutical compositions containing as active ingredient the above-mentioned azaheterocyclic compounds, 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, predpochtitel is about 50˜ 300 mg. Therefore, during the preparation of pharmaceutical compositions of 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 of azaheterocyclic compounds of General formula 1.1.1, 1.2.1 and 1.3.1, 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 aim of the present invention is the creation of new pharmacological tools for investigating processes associated with increased activation of adrenocorticotropic hormone (ACTH). This goal is achieved by the application of physiologically active azaheterocyclic compounds of the General formula 1.1.1, 1.2.1 and 1.3.1, or their racemates, or optical isomers, or their pharmaceutically acceptable salts and/or hydrates having properties to inhibit MC2R receptor, for the preparation of drugs for the treatment and/or prevention of diseases associated with increased activation of adrenocorticotropic hormone (ACTH) or experimental (in vitro or in vivo) studies of the processes associated with increased activation adrenocorticotropin what about hormone (ACTH), as pharmacological tools.

Azaheterocyclic compounds of General formula 1.1.1, 1.2.1 and 1.3.1, or their racemates, or optical isomers, or their pharmaceutically acceptable salts and/or hydrates are known compounds and are commercially available, for example, by ChemDiv, Inc [San Diego, CA: www. Chemdiv.com].

The following are specific examples which illustrate, but not limit the invention.

The drawing shows the dependence of inhibition of the test compounds induction of camp induced adrenocorticotropic hormone (100 nm) in Y1 cells.

Example 1. Inhibition of MC2R receptor azaheterocyclic compounds of the General formula 1.1.1, 1.2.1, 1.3.1. To conduct high-throughput screening of large quantities of substances for their potential ability to block the action of adrenocorticotropic hormone use culture murine cells (Y1 cells), which, as is well known [Heisler's, Tallerico-Melnyk T, Yip S, Schimmer BP. Y-1 adrenocortical tumor cells contain atrial natriuretic peptide receptors which regulate cyclic nucleotide metabolism and steroidogenesis. Endocrinology 1989; 725:2235-43], Express melanocortin receptor type 2 (MC2R). In a preferred execution of the cells (hereinafter referred to as Yl-CRE-lu) were transliterowany vector pHTS-CRE obtained from Biomyx Technology (San Diego, CA), with a reporter luciferase gene and transcriptional element. who inym to cyclic AMP. During stimulation of the MC2R adrenocorticotropic hormone (ACTH) level of cyclic AMP increases, which leads to stimulation of the expression of the luciferase gene and, as a consequence, the enhancement of luminescence downregulation of luciferase, which can be registered using fluorescent spot reader in 96 - or 384-well formats. The screening was carried out as follows. Stable transfetsirovannyh luciferase gene cells were planted in 96 wells-hole boards (5000-7000 cells/well) and maintained in a thermostat at 37°C in an atmosphere of 5% CO2within 24 hours. In cells dice was added compound at a final concentration of 1 μm, the cells were additionally incubated for 15 minutes, and then thereto was added ACTH concentration of 100 nm and the incubation continued for an additional 4 hours. Measurement of luciferase activity was performed using the kit reagents produced Biotium, Inc., (USA), and in accordance with their Protocol. In particular, the incubation medium was removed from the wells by aspiration and cells were washed with saline phosphate buffer. The wells were made in 20 µl lisanova buffer from a set of reagents and die rocking at room temperature for 15 minutes To measure the used 96-well reader VICTOR2V (PerkinElmer, USA) using luminescence. 100 μl of luciferase Rea is Teva, containing luciferin, is injected into each cell and developing the luminescence generated by the catalytic oxidation of luciferin oxygen, integrated within 10 seconds. In tables 1-3 presents some examples of the percentage inhibition of fluorescent signal in the presence of the subjects of azaheterocyclic compounds of the General formula 1.1.1 (table 1), 1.2.1 (table 2) and 1.3.1 (table 3), with respect to the signal developing in the presence of one ACTH. Presents examples confirm the inhibition of MC2R receptor azaheterocyclic compounds comprising a fragment of formulas 1.1, 1.2 and 1.3, reaching in many cases more than 50%.

Example 2. An example illustrating the preparation of tablets containing 100 mg of active ingredient. Mix 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 m is azaheterocyclic compounds 1.1(9) or 1.2.1.4(183), or 1.3.10 and pressed together in 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. According to the invention likewise receive pharmaceutical composition in the form of tablets containing as active ingredient other azaheterocyclic compounds, including the fragment of the formula 1.1 or 1.2, or 1.3.

Example 3. Capsules containing 200 mg of azaheterocyclic compounds 1.1(9) or 1.2.1.4(183), or 1.3.10, according to the invention can be obtained by thorough mixing of compounds 1.1(9) or 1.2.1.4(183), or 1.3.10 with lactose powder in a 2:1 ratio. The obtained powder mixture is Packed 300 mg in gelatin capsules of suitable size.

Example 4. Injectable compositions for intramuscular, intraperitoneal or subcutaneous injection can be prepared by mixing 500 mg of the active ingredient with suitable solvents, such as hydrochloride of azaheterocyclic compounds 1.2.1.4(183) 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 and sterilized in an autoclave.

Example 5. To determine the inhibitory activity blockers melatonindosage receptor (MC2R) used to EDI Y1, naturally expressing the receptor. Stimulation of the receptor adrenocorticotropic hormone (ACTH) causes increased production of cyclic AMP (camp), which was measured using the method TR-FRET fluorescence when using the LANCE cAMP PerkinElmer [Hemmila I. (1999). LANCE: Homogenous Assay Platform for HTS. J Biomol Screen 4(6). 303-308]. Cells were planted in 96 wells-cell plates and left overnight at 37°C incubator with 100% humidity and 5% CO2. The next day cells were added compound in various concentrations, obtained by serial dilution of the original solution. After 15 minutes incubation, the cells were added ACTH concentration of 100 nm and continued incubation for 45 minutos incubation, the cells were added to lyse the solution contained in the composition of the detecting set, and response to determining formed of camp was carried out in strict accordance with the methodology recommended by the manufacturer of the kit (PerkinElmer). Fluorescence, reflecting the number of the resulting currents were measured using fluorometry VICTOR2V (PerkinElmer) and were converted into the number of the resulting currents using a calibration curve obtained by adding known amounts of camp. The activity of compounds was determined by the concentration of the compounds that cause premaxillae inhibition of stimulation of camp, adrenocortico Repnin hormone (IC 50). Table 4 shows the values of the activity of certain inhibitors MC2 receptor, allowing their use as pharmacological tools.

Table 4.

The value of the IC50for the tested compounds
ConnectionIC50nm
1.2.1.4.1(8)25,1
1.2.1.4.1(9)10
1.2.1.4.1(46)398
1.2.1.4.1(79)126
1.2.1.4.1(183)12,6
1.2.1.4.1(187)10
1.2.1.4.1(190)631

1. Pharmaceutical composition having inhibitory activity against MC2R receptor, for the preparation of medicinal products in the form of tablets, granules, capsules, suspensions, solutions or injections, placed in pharmaceutically acceptable packing, containing as active substance azaheterocyclic compound, of General formula 1.1.1, 1.2.1 and 1.3.1

where R1in the General formula 1.1.1 is a substituted alkyl, aryl, heteroaryl, heterocyclyl, or in the General formula 1.2.1 R1represents C is the election agent of an amino group, selected from hydrogen or a possibly substituted lower alkyl or lower acyl;

R2, R3and R4independently from each other represent a Deputy cyclic system selected from hydrogen, azaheterocycle, possibly substituted lower alkyl, possibly substituted hydroxy-group, carboxypropyl, cycloalkyl; or R3and R4together with Tomomi carbon to which they are linked, form azaheterocycle, or R1together with the nitrogen atom to which it is linked and R3and R4together with the carbon atoms to which they are linked, form a through R1, R3and R4azaheterocycle;

R18and R19independently from each other, represent substituents of the amino group selected from hydrogen or lower alkyl, substituted azaheterocycles, in the form of their racemates, optically active isomers or pharmaceutically acceptable salts and/or hydrates, R20and R21together with the nitrogen atom to which they are bound, form a possibly substituted azaheterocycle.

2. The pharmaceutical composition according to claim 1, containing as active substance N-[2-(1H-indol-3-yl)-ethyl]-acylamide General formula 1.2.1.1 or its racemates or optical isomers, or pharmaceutically acceptable salts and/or hydrates

where R1, R2and R4have the above meaning;

R5is azaheterocycle.

3. The pharmaceutical composition according to claim 1, containing as active substance 11-(1H-indol-3-yl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1 he General formula 1.2.1.2 or its racemates or optical isomers, or pharmaceutically acceptable salts and/or hydrates

where R1and R2have the above meaning;

R6represents an alkyl or cycloalkyl;

R7and R8independently from each other represent a hydrogen atom, alkyl or aryl.

4. The pharmaceutical composition according to claim 1, containing as active substance 7-acyl-6-(1H-indol-3-yl)-3-effect-free remedy 6,7,8,9-tetrahydro-1,2,4-triazino[5,6-f][1,3]oxazepan General formula 1.2.1.3 or its racemates or optical isomers, or pharmaceutically acceptable salts and/or hydrates

where R1and R2have the above meaning;

R9represents an alkyl or alkenyl.

5. The pharmaceutical composition according to claim 1, containing as the active substance 1-oxo-3-(1H-indol-3-yl)-1,2,3,4-tetrahydro-isoquinoline General formula 1.2.1.4 or its racemates or optical isomers, or pharmaceutically acceptable solii/or hydrates

where R1and R2have the above meaning;

R10is a Deputy cyclic system selected from hydrogen; R13is a Deputy amino group selected from a possibly substituted alkyl,

each of R11, R12independently from each other represents a Deputy amino group selected from hydrogen, possibly substituted alkyl, possibly substituted aryl, possibly substituted heteroaryl, in which the heteroatoms are selected from nitrogen, oxygen, or sulfur, or

R11and R12together with the nitrogen atom to which they are attached, may form a possibly substituted azaheterocycle, which may contain a second heteroatom selected from nitrogen, oxygen or sulfur.

6. The pharmaceutical composition according to claim 5, containing as active substance 1-oxo-3-(1H-indol-3-yl)-1,2,3,4-tetrahydro-isoquinoline General formula 1.2.1.4.1 or its racemates or optical isomers, or pharmaceutically acceptable salts and/or hydrates

where R1, R2, R10, R11, R12and R13have the above value.

7. The pharmaceutical composition according to claim 5, containing as active substance 1-oxo-3-(1H-indol-3-yl)-1,2,3,tetrahydro-isoquinoline General formula 1.2.1.4.2 or its racemates or optical isomers, or its pharmaceutically acceptable salts and/or hydrates

where R1represents hydrogen or methyl;

R11, R12and R13have the above value.

8. The pharmaceutical composition according to claim 1, containing as active substance 1,2,3,8-tetrahydro-1-oxo-pyrrolo[3,4-b]indole of General formula 1.2.1.5 or its racemates or optical isomers, or pharmaceutically acceptable salts and/or hydrates

where R1and R2have the above meaning;

R14is a Deputy amino group selected from a possibly substituted aryl;

R15represents aryl or heteroaryl.

9. The pharmaceutical composition according to claim 1, containing as active substance 2,3,4,5-tetrahydro-1H-pyrido[3,4-b]indole of General formula 1.2.1.6 or its racemates or optical isomers, or pharmaceutically acceptable salts and/or hydrates

where R1and R2have the above meaning; R16is a Deputy amino group selected from acyl group.

10. The pharmaceutical composition according to claim 1 or 3, containing as active substance azaheterocyclic compound of General formula 1.2.1.7 and the and its racemates or optical isomers, or its pharmaceutically acceptable salts and/or hydrates

where R1and R2have the above meaning;

R17is a Deputy amino group selected from acyl group.

11. The pharmaceutical composition according to claim 1, containing as the active substance 2-[6-methyl-4-oxo-5-(4-(pyrimidine-2-yl-piperazine-1-sulfonyl)-4H-thieno[2,3-d]pyrimidine-3-yl]-ndimethylacetamide General formula 1.3.1.1 or its racemates or optical isomers, or pharmaceutically acceptable salts and/or hydrates

where R18and R19have the above value.

12. A method of obtaining a pharmaceutical composition according to any one of claims 1 to 11 by mixing the active substances with inert to the active substances, fillers and/or diluents, followed by pelletizing, granulating, kapsulirovaniem, suspendirovanie, dissolution or dilution and placing them in suitable packaging, characterized in that the active substance used any of azaheterocyclic compounds of the General formula 1.1.1, 1.2.1, 1.3.1 or their racemates or optical isomers, or their pharmaceutically acceptable salts and/or hydrates.

13. The use of the pharmaceutical composition according to any one of claims 1 to 11 for the preparation of medicines is the R drugs for the treatment and prevention of diseases, associated with increased activation of adrenocorticotropic hormone (ACGT).

14. A method of treating and preventing various diseases of warm-blooded animals and humans associated with increased activation of adrenocorticotropic hormone (ACTH) by introducing a warm-blooded animal or human pharmaceutical composition according to any one of claims 1 to 11.

15. The application of physiologically active azaheterocyclic compounds of the formula 1.1.1, 1.2.1 and 1.3.1, or their racemates or optical isomers, or their pharmaceutically acceptable salts and/or hydrates specified in claim 1, having the properties to inhibit MC2R receptor, in the preparation of medicines for the treatment and/or prevention of diseases associated with increased activation of adrenocorticotropic hormone (ACTH), or for experimental studies in vitro or in vivo, associated with increased activation of adrenocorticotropic hormone (ACTH), as pharmacological tools.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel 4-phenyl-substituted tetrahydroisoquinolines of the formulae: (IA) , (IB) , (IIA) , (IIB) , (IIIA) and (IIIC) wherein values X and R1-R7 are given in the invention description. Proposed compounds show selective binding of neurotransmitters and therefore they can be used in treatment of different neurological or psychological disorders, for example, ADHD. Also, invention relates to a pharmaceutical composition based on proposed compounds and to a method for treatment.

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

36 cl, 1 dwg, 16 tbl, 131 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing properties of inhibitors of protein kinase p38. In the formula (I) A means nitrogen atom (N) or -CH; R1 means hydrogen atom, alkyl or aralkyl; R2 means (C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, (R'')2NCO-alkylene- (wherein each R'' means independently hydrogen atom or (C1-C6)-alkyl), (C3-C7)-cycloalkyl substituted optionally with hydroxy-group, 6-membered heterocyclyl comprising nitrogen, oxygen or sulfur atom or its oxides as heteroatoms and wherein nitrogen-containing heterocyclyl can be substituted with (C1-C4)-alkylsulfonyl group, optionally substituted phenyl wherein substitutes are chosen from halogen atoms and lower alkoxy-group; X means oxygen atom (O), -NR3 or sulfur atom (S) wherein R3 means (C1-C6)-alkyl or phenyl; Y means a chemical bond, O, C(=O), -CH(OR'), -CHR' or S wherein R' means hydrogen atom; R means phenyl optionally substituted with one or some substitutes chosen from halogen atoms, lower alkyl and lower alkoxy-group. Proposed compounds can be used, for example, in treatment of inflammatory diseases, among them intestine disease, Alzheimer's disease, Crohn's disease, cerebrospinal sclerosis, asthma and can be used in development of viral diseases also.

EFFECT: valuable medicinal properties of compounds.

11 cl, 5 sch, 1 tbl

FIELD: organic chemistry, biology, pharmacy.

SUBSTANCE: invention relates to derivatives of thieno[2,3-d]pyrimidine of the general formula (I): or their pharmaceutically acceptable salts wherein R1 and R2 in common with nitrogen atom to which they are added form a ring comprising from 2 to 6 carbon atoms and optionally comprising one or more heteroatoms chosen from nitrogen (N), oxygen (O) and/or sulfur (S) atoms. Proposed compounds possess ability to activate both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and can be used in therapy in aims for regulating fertility. Also, invention describes a pharmaceutical composition based on compounds of the formula (I).

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical composition.

6 cl, 1 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1): wherein each R1 and R2 represents independently (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-cycloalkyl-(C1-C3)-alkyl or (C3-C6)-cycloalkyl wherein each of them can be substituted possibly with halogen atom in the amount from 1 to 3; R3 represents isoxyzolydine-2-ylcarbonyl or tetrahydroisoxazine-2-ylcarbonyl wherein each ring is substituted possibly with one hydroxy-group; Q represents -CO- or -C(R4)(R5)- (wherein R4 represents hydrogen atom or (C1-C4)-alkyl, and R5 represents hydrogen atom or hydroxy-group); Ar represents 5-10-membered aromatic ring system wherein up to 4 ring atoms can be represented by heteroatoms chosen independently from nitrogen, oxygen and sulfur atoms and wherein this ring system is substituted possibly with one or more substitute. Proposed compounds can be used for modulation of autoimmune disease. Also, invention describes methods for synthesis of compounds of the formula (1) and pharmaceutical composition based on compounds of the formula (1).

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

14 cl, 44 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes glycine-substituted thieno[2,3-D]-pyrimidines of the formula (I): wherein X represents oxygen atom (O) or H,H; A represents sulfur atom (S), -NH, -N(R6), O or a bond; R1 represents (C1-C4)-alkyl, (C2-C4)-alkenyl, unsubstituted or substituted phenyl, thienyl, pyridyl; R2 represents hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkoxy-(C2-C4)-alkyl or hydroxy-(C2-C4)-alkyl; R3 and R4 are chosen independently from H, (C1-C4)-alkyl and hydroxy-(C1-C4)-alkyl; R5 represents H or (C1-C4)-alkyl, and R6 represents (C1-C4)-alkyl. Compound possess agonistic activity with respect to glycoprotein hormone, in particular, to compounds possessing agonist activity with respect to luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Also, invention describes pharmaceutical compositions containing such compounds and using these compounds in medicinal therapy, in particular, for fertilization control.

EFFECT: valuable biological and medicinal properties of compounds.

11 cl, 1 tbl, 27 ex

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

SUBSTANCE: invention describes compounds of the formula (I):

wherein R1 means hydrogen atom; R2 means phenyl or phenyl mono- or di-substituted substituted with the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, perfluoro-(lower)-alkyl; R3 and R4 in common with carbon atoms to which they are bound form phenyl optionally and independently mono-, di- or tri-substituted with halogen atom or perfluoro-(lower)-alkyl, or form 5-, 6- or 7-membered saturated cycle optionally comprising heteroatom chosen from oxygen (O) and sulfur (S) atom and optionally and independently mono-substituted with (lower)-alkyl wherein indicated saturated cycle is condensed in ortho-position with 5-membered aromatic cycle optionally comprising S atom as a heteroatom, or with phenyl optionally and independently mono- di-substituted with the group: halogen atom, (lower)-alkyl, perfluoro-(lower)-alkyl or (lower)-alkoxy-group, and their pharmaceutically acceptable salts. Also, invention describes a method for synthesis of compounds, a pharmaceutical composition and using compounds for treatment and/or prophylaxis of DPP-IV-associated diseases. Compounds are used in treatment of such diseases as diabetes mellitus being first of all non-insulin dependent diabetes mellitus and damaged tolerance to glucose.

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

16 cl, 1 tbl, 39 ex

FIELD: agriculture, organic chemistry.

SUBSTANCE: invention relates to application of 2-[N-(2'-iodophenyl)carboxamido]-3-amino-4,6-dimethylthieno[2,3-b]pyridine of formula as stimulator of sunflower growth.

EFFECT: stimulation of sunflower seed germination; increased sunflower productivity.

2 tbl, 3 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing properties of inhibitors of protein kinase p38. In the formula (I) A means nitrogen atom (N) or -CH; R1 means hydrogen atom, alkyl or aralkyl; R2 means (C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, (R'')2NCO-alkylene- (wherein each R'' means independently hydrogen atom or (C1-C6)-alkyl), (C3-C7)-cycloalkyl substituted optionally with hydroxy-group, 6-membered heterocyclyl comprising nitrogen, oxygen or sulfur atom or its oxides as heteroatoms and wherein nitrogen-containing heterocyclyl can be substituted with (C1-C4)-alkylsulfonyl group, optionally substituted phenyl wherein substitutes are chosen from halogen atoms and lower alkoxy-group; X means oxygen atom (O), -NR3 or sulfur atom (S) wherein R3 means (C1-C6)-alkyl or phenyl; Y means a chemical bond, O, C(=O), -CH(OR'), -CHR' or S wherein R' means hydrogen atom; R means phenyl optionally substituted with one or some substitutes chosen from halogen atoms, lower alkyl and lower alkoxy-group. Proposed compounds can be used, for example, in treatment of inflammatory diseases, among them intestine disease, Alzheimer's disease, Crohn's disease, cerebrospinal sclerosis, asthma and can be used in development of viral diseases also.

EFFECT: valuable medicinal properties of compounds.

11 cl, 5 sch, 1 tbl

FIELD: organic chemistry, medicine, hepatology.

SUBSTANCE: invention relates to using 2-methylthiopyrimido[4,5-b]indole of the formula (1): showing melting point at 243°C (with decomposition) and value LD50 > 1000 mg/kg used in liver protection from poisoning with carbon tetrachloride. Proposed compound exceeds activity of the "Essentiale" as a comparison preparation.

EFFECT: valuable medicinal property of compound, enhanced effectiveness.

1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): possessing properties of inhibitor of inflammatory cytokines release from cells. In compound of the formula (I) R is chosen from: (a) fragment of the formula -OR3 wherein R3 is chosen from group consisting of phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3-N-acetylaminophenyl, 2-methoxyphenyl, 4-methoxyphenyl and 3-benzo[1,3]dioxol-5-yl; (b) fragment of the formula: wherein R6 is chosen from group consisting of hydrogen atom, methyl, ethyl, vinyl, cyclopropyl, cyclohexyl, methoxymethyl, methoxyethyl, 1-hydroxy-1-methylethyl, carboxy-group, 4-fluorophenyl, 2-aminophenyl, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-(propanesulfonyl)phenyl, 3-benzo[1,3]dioxol-5-yl, pyridine-2-yl, pyridine-3-yl, or (c) fragment of the formula: wherein R6 is chosen from group consisting of hydrogen atom, methyl, ethyl, vinyl, cyclopropyl, cyclohexyl, methoxymethyl, methoxyethyl, 1-hydroxy-1-methylethyl, carboxy-group, phenyl, 4-fluorophenyl, 2-aminophenyl, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-(propanesulfonyl)phenyl, 3-benzo[1,3]dioxol-5-yl, pyridine-2-yl, pyridine-3-yl; each radical R2 is chosen independently from group consisting of (a) hydrogen atom; (b) -(CH2)jO(CH2)nR8; (c) -(CH2)jNR9aR9b; (e) -(CH2)OCO2R10; (g) -(CH2)jOCON(R10)2 wherein each radical R8, R9a, R9b and R10 represents independently hydrogen atom, (C1-C4)-alkyl; or R9a and R9b can form in common 5-6-membered heterocyclic ring comprising 1-2 heteroatoms chosen from nitrogen and/or oxygen atoms; or two radicals R10 can form in common 5-6-membered heterocyclic ring comprising 1-2 heteroatoms chosen from nitrogen and/or oxygen atoms; j represents index 0; n represents index 0. Also, invention relates to a pharmaceutical composition and a method for inhibition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 2 sch, 8 tbl, 13 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of sulfamide-substituted imidazotriazinones represented by the general formula (I): Method involves interaction of compound of the formula (II): with sulfuric acid followed by treatment of synthesized substances with thionyl chloride and interaction with amine without their isolation to yield the end compound that is converted if necessary to the corresponding salts or hydrates. Method provides the development of a simple realization of synthesis of sulfamide-substituted imidazotriazinones in large-scale and high yield being without isolation of hydrolysis-sensitive imidazotriazinone sulfonyl chloride in intermediate step with exception of variations in yield at intermediate step of synthesis.

EFFECT: improved method of synthesis.

5 cl, 2 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel condensed derivatives of imidazole that are inhibitors of dipeptidyl peptidase IV. Invention describes compound represented by the following formula (I): or its salt or hydrate wherein T1 represents monocyclic 5-6-membered heterocyclic group comprising one or two nitrogen atoms in ring that can comprise one or more amino-groups as substitutes; X represents (C2-C6)-alkenyl group that can comprise one or more substitutes, (C2-C6)-alkynyl group, phenyl group that can comprise one or some substitutes chosen from alkyl group or halogen atom or phenyl-(C1-C6)-alkyl group; each Z1 and Z2 represents independently nitrogen atom or group of the formula -CR2=; each R1 and R2 represents independently group of the formula -A0-A1-A2 wherein A0 represents a single bond or (C1-C6)-alkylene group that can comprise 1-3 substitutes chosen from group B consisting of given below substitutes; A1 represents a single bond, oxygen atom, sulfur atom, sulfinyl group, sulfonyl group, carbonyl group, group represented by formula -O-CO-, group represented by formula -CO-O-, group represented by formula -NRA-, group represented by formula -CO-NRA-, group represented by formula -NRA-CO-, group represented by formula -SO2-NRA-, or group represented by formula -NRA-SO2-; each A2 and RA represents independently hydrogen atom, halogen atom, cyano-group, (C1-C6)-alkyl group, (C3-C8)-cycloalkyl group, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, (C6-C10)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocyclic group, 5-10-membered heteroaryl-(C1-C6)-alkyl group, (C6-C10)-aryl-(C1-C6)-alkyl group or (C2-C7)-alkylcarbonyl group wherein each A2 and RA can comprise independently 1-3 substitutes chosen from the given below group of substitutes D: when Z2 represents group of the formula -CR2= then R1 and R2 can form in common 5-7-membered ring with exception cases when: [1] R1 represents hydrogen atom; Z1 represents nitrogen atom, and Z2 represents group -CH=; and [2] Z1 represents nitrogen atom and Z2 represents group -C(OH)=; <group of substitutes B>. Group of substitutes B represents group comprising: hydroxyl group, mercapto-group, cyano-group, nitro-group, halogen atom, trifluoromethyl group, (C1-C6)-alkyl group that can comprise one or some substitutes, (C3-C8)-cycloalkyl group, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, (C6-C10)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocyclic group, (C1-C)-alkoxy-group, (C1-C6)-alkylthio-group, group represented by formula -SO2-NRB1-RB2, group represented by formula -NRB1-CO-RB2, group represented by formula -NRB1-RB2 (wherein each RB1 and RB2 represents independently hydrogen atom or (C1-C6)-alkyl group), group represented by formula -CO-RB3 (wherein RB3 represents 4-8-membered heterocyclic group), group represented by formula -CO-RB4-RB5, and group represented by formula -CH2-CO-RB4-RB5 wherein RB4 represents a single bond, oxygen atom or group represented by formula -NRB6- wherein each RB5 and RB6 represents independently hydrogen atom, (C1-C6)-alkyl group, (C3-C8)-cycloalkyl group, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, (C6-C10)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocycle-(C1-C6)-alkyl group, (C6-C10)-aryl-(C1-C6)-alkyl group or 5-10-membered heteroaryl-(C1-C6)-alkyl group. Also, invention describes inhibitor, pharmaceutical composition, method of treatment and using based on thereof. Invention describes novel compounds possessing useful biological properties.

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

33 cl, 3 tbl, 352 ex

FIELD: organic chemistry, heterocyclic compounds, medicine.

SUBSTANCE: invention relates to dihydropyrimidine compounds of the formula (I*): their enantiomers, diastereoisomers and pharmaceutically acceptable salts wherein X1, X2 and X3 in common with atoms to which they are added form ring of the formula: or ; R1 represents hydrogen atom; R2, R3*, R4, R5, R6 and R7 have values given in cl. 1 of the invention claim. Also, invention relates to separate dihydropyrimidine compounds. Proposed compounds are inhibitors of calcium channel function being especially inhibitors of Kv1 subfamily of potential-overlapping K+-channels and especially inhibitors of Kv 1.5 that associated with super-rapid activating delayed cleaning K+-flow of Ikur and can be used in treatment of arrhythmia and Ikur-associated diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 589 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for improved synthesis of pharmacologically active compound of the formula (A): Method involves the following steps: (a) interaction of compound of the formula (I): with alkaline metal nitrite in the presence of suitable acid to yield compound of the formula (VII): (b) coupling compound of the formula (VII) with compound of the formula (VI): to yield compound of the formula (V): and (c) removal of protection from compound of the formula (V) to yield compound of the formula (A). Compound of the formula (A) possesses property of antagonist of R2T receptors, high metabolic stability and bioavailability. Also, invention relates to a novel intermediate substance of the formula (I) and methods for its synthesis, and to novel intermediate substances used in its synthesis.

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

12 cl, 4 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to biologically active compounds and concerns the development of a novel substance - 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazine-7-(4H)-one sodium salt dihydrate of the formula: . This compound is designated for treatment and prophylaxis of diseases caused by viruses that are pathogenic form humans and animals. Proposed compound protects against infections caused by Rift Valley fever virus. Also, it shows activity against viruses of WEE(West Equine Encephalomyelitis), parainfluenza, respiratory-syncytium, Aujeszky's disease virus, avian infectious laryngotracheitis virus, avian influenza virus - totally against above 10 RNA- and DNA-containing viruses. The proposed compound is active in curative schedule of its using that is especially valuable.

EFFECT: valuable medicinal properties of compound.

1 cl, 6 tbl, 2 dwg, 7 ex

FIELD: organic chemistry, medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to novel 3,7-diazabicyclo[3.3.0]octanes of the formula (I): wherein wavy lines mean the possible relative cis- or trans-stereochemistry; R means (C1-C12)-alkyl (possibly substituted and/or terminating by one or more groups chosen from aryl, Het1, -C(O)R5a, -OR5b, -N(R6)R5c, -C(O)XR7, -C(O)N(R8)R5d and -S(O)2R9), Het2, -C(O)R5a, -C(O)XR7 or -S(O)2R9 wherein R5a - R5d in each case mean independently hydrogen atom (H), (C1-C6)-alkyl (possibly substituted and/or terminating by one or more substitute chosen from -OH, (C1-C6)-alkoxy-group, cyano-group, aryl, Het3 and -NHC(O)R10), aryl or Het4; R10means H, (C1-C4)-alkyl; R6 means H, aryl; X means oxygen atom (O); R7 means in each case (C1-C12)-alkyl (wherein alkyl group can be substituted and/or terminating by one substitute chosen from -OH, cyano-group, (C1-C6)-alkoxy-group, -SO2R13a, -C(O)R13b and Het5) wherein R13a and R13b mean independently (C1-C6)-alkyl; R8 means in each case H, (C1-C12)-alkyl, (C1-C6)-alkoxy-group (wherein two latter groups are substituted possibly and/or terminating by one substitute chosen from -OH, (C1-C4)-alkyl and (C1-C4)-alkoxy-group), -D-aryl, -D-Het6, -D-S(O)2R15a wherein R15a means independently aryl; D means a direct bond or (C1-C6)-alkylene; R9 means in each case (C1-C6)-alkyl (possibly substituted and/or terminating by one substitute chosen from aryl) or aryl; R2 means H, -E-OR16, -E-N(R17)R18 or in common with R3 represent =O; R3 means H or in common with R2 represent =O; R16 means H, (C1-C6)-alkyl or -E-aryl; R17 means H; R18 means H; E means in each case a direct bond or (C1-C4)-alkylene; A means -G-; B means -Z-, -Z-N(R22)-Z-, -Z-S(O)n-. -Z-O- (wherein in two latter groups Z is bound to carbon atom carrying R2 and R3); G means a direct bond or (C1-C6)-alkylene; Z means a direct bond or (C1-C4)-alkylene; R22 means independently H; R4 means aryl or het13 wherein both these groups are substituted possibly with one or more substitute chosen from -OH, cyano-group, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -C(O)R24c or -S(O)nR23c; Het13 means 5-6-membered heterocyclic group comprising one or more heteroatoms chosen from oxygen, nitrogen and/or sulfur; Het1 - Het6 in each case mean independently 5-6-membered heterocyclic groups comprising one or more heteroatoms chosen from oxygen, nitrogen and/or sulfur wherein these heterocyclic groups are substituted possibly with one or more substitutes comprising (C1-C6)-alkyl or -C(O)R24c wherein R23c means in each case independently (C1-C6)-alkyl; R24c means in each case H or (C1-C6)-alkyl; n means 0, 1 or 2 in each case; Ra - R1 mean independently H or (C1-C4)-alkyl wherein each aryl or aryloxy-group (if not indicated otherwise) is substituted possibly with one or more substitutes chosen from -OH, cyano-group, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -C(O)R24c or -S(O)nR23c; or it pharmaceutically acceptable derivative under condition that: (a) when R2 means -E-OR16 or -E-N(R17)R18 wherein E means a direct bond then: (1) A can't mean a direct bond; and (2) B doesn't mean -N(R22)-, -S(O)n-. -O- or -N(R22)-Z- (wherein in the latter group -N(R22) is bound to carbon atom carrying R2 and R3; (b) this compound is not 3,7-bis-(1-phenylethyl)-3,7-diazabicyclo[3.3.0]octane, 3-methyl-7-benzyl-3,7-diazabicyclo[3.3.0], 3-cyclohexyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(thiazol-2-yl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(2-pyrimidyl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(5,5-dimethoxy)pentyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane; (c) when R in common with R3 represent =O, and B means -Z-N(R22)- or -N(R22)-Z- then G is not a direct bond. Compounds of the formula (I) can be used as components of a pharmaceutical composition in treatment or prophylaxis of arrhythmia. Also, invention describes methods for its synthesis and intermediate compounds used in these methods.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

38 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel compound 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]-1,3,5-triazine of the formula (I):

, its steroisomeric forms or pharmaceutically acceptable salts, pharmaceutical composition comprising thereof and its using for preparing pharmaceutical composition used in treatment of anxiety in mammals.

EFFECT: valuable medicinal property of compound and pharmaceutical composition.

7 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel polycyclic compounds of the formula (I): wherein radicals and symbols have values given in the invention claim. Compounds of the formula (I) possess properties of H3 receptors antagonist. Also, invention relates to a pharmaceutical composition containing compounds of the formula (I). Also, invention relates to a method for treatment of disease of group comprising difficulty in nasal breath, obesity, somnolence, narcolepsy, attention deficiency with hyperactivity, Alzheimer's disease and schizophrenia that involves using compounds of the formula (I) and, optionally, in combination of H receptor antagonist.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

39 cl, 3 tbl, 31 ex

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