RU2303597C1 - Pharmaceutical composition, method for its preparing and using - Google Patents

Abstract

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

Description

The invention relates to a pharmaceutical composition for drugs for humans and warm-blooded animals used to treat diseases and conditions associated with excessive activity (secretion) of adrenocorticotropic hormone (ACTH), in particular congenital or acquired adrenal cortical hyperplasia, Cushing's syndrome and disease. The invention also relates to new "molecular pharmacological tools" for research (in vitro and in vivo) of the biochemical mechanisms of action of corticosteroid hormones and their specific receptors, in particular melanocortin receptor-2 (MC2R), the ACTH agonist of which.

More specifically, the present invention relates to a pharmaceutical composition containing, as active substances, compounds comprising a fragment of 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydroisoquinoline, and also to a method for producing of these compositions and the method of using these compositions for the treatment and prevention of the development of various diseases associated with increased activation of adrenocorticotropic hormone (ACTH), as well as the use of compounds including the fragment 1-oxo-3- (1H-indol-3-yl) -1 , 2,3,4-tetrahydroisoquinoline, as a "mole ulyarnyh pharmacological tools "for studies (in vitro and in vivo) biochemical mechanisms of action of corticosteroids and their specific receptors, particularly melanocortin receptor-2 (MC2R), which is an agonist of CRF.

The adrenal cortex produces steroid hormones that play an exceptional role in human and animal physiology [a) Silverman M.L., Lee A.K. Anatomy and pathology of the adrenal glands. Urol. Clin. North Am. 1989; 16: 417-32; b) Rosol T.J., Yarrington J.T., Latendresse J., Capen C.C. Adrenal gland: structure, function, and mechanisms of toxicity. Toxicol. Pathol. 2001; 29: 41-8]. These steroids include the mineralocorticoid aldosterone, glucocorticides 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 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 to its receptor, the so-called melanocortin receptor MC-2, which leads to increased steroidogenesis [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]. Decreased ACTH secretion caused by congenital or acquired pituitary dysfunction leads to hypoadrenalism. Excessive secretion of ACTH leads to congenital or acquired hyperplasia of the adrenal cortex, Cushing's syndrome and disease, as well as ectopic production of ACTH.

Congenital adrenal cortical hyperplasia (aka adrenogenital syndrome) is a clinical symptom complex, the development of which is associated with impaired corticosteroid secretion due to a congenital defect in the enzymes responsible for the biosynthesis of these hormones [Collett-Solberg P.F. Congenital adrenal hyperplasia: from genetics and biochemistry to clinical practice, part 2. Clin. Pediatr. (Phila) 2001; 40: 125-32]. The reduced formation of cortisol leads to increased secretion of ACTH followed by the development of hyperplasia of the cortical layer of the adrenal cortex. Congenital hyperplasia of the adrenal cortex is not so rare and ranges from 1: 10,000 to 1: 20,000 newborns in the United States [New M.I., Newfield R.S. Congenital adrenal hyperplasia. Curr. Ther. Endocrinol. Metab. 1997; 6: 179-87], which makes it one of the most common congenital metabolic diseases [New M.I. Inborn errors of adrenal steroidogenesis. Mol. Cell. Endocrinol. 2003; 211: 75-83]. Currently, there is no effective medication for treating this disease, almost the only 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 constantly elevated levels of free cortisol in the blood, while Cushing's disease (Itsenko-Cushing's disease) 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 there are 3 new cases of Cushing's disease per 100,000 population [Cavagnini F., Pecori Giraldi F. Epidemiology and follow-up of Cushing's disease. Ann. Endocrinol. (Paris) 2001; 62: 168-72]. The main methods of treatment for Itsenko-Cushing's disease 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]. There are no effective methods of drug treatment.

Thus, at present, there is not a single drug in clinical practice, not a single developed drug candidate capable of selectively and effectively blocking the effect of excessively secreted ACTH. In fact, no low molecular weight non-peptide MC2R receptor antagonist has been discovered so far. At the same time, the discovery of such antagonists can lead to the creation of fundamentally new drugs for the treatment of endocrine and other diseases of humans and animals associated with excessive ACTH activity.

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

As a result of studies aimed at searching for new biologically active compounds capable of selectively and effectively blocking the action of excessively secreted ACTH, the inventors first discovered non-peptide antagonists of the MC2R receptor, namely azaheterocyclic compounds, including a 4'-carbamoyl-1'-carbonyl fragment [1, 4 '] bipiperidinyl, indole or 2- (4-oxo-5-sulfamoyl-4H-thieno [2,3-d] pyrimidin-3-yl) acetamide.

More specifically, this invention relates to a new pharmaceutical composition comprising azaheterocyclic compounds comprising a 4'-carbamoyl-1'-carbonyl [1,4 '] bipiperidinyl, indole or 2- (4-oxo-5-sulfamoyl-4H-thieno [ 2,3-d] pyrtiidin-3-yl) acetamide, in the form of active substances, as well as to a method for its preparation and its use for the treatment and prevention of various diseases associated with the action of excessively secreted ACTH (congenital or acquired adrenal hyperplasia) , Kushi syndrome and disease n et al.).

The following are definitions of terms that are used in the description of this invention.

“Azaheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing in the cycle at least one nitrogen atom, the meanings of which are given in this section. An azaheterocycle may have one or more “cyclic” substituents.

“Aliphatic” radical means a radical obtained by removing a hydrogen atom from a non-aromatic CH bond. An aliphatic radical may additionally contain substituents — aliphatic or aromatic radicals defined in this section. aliphatic radicals Representatives include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkiloksialkil, aralkiloksikarbonilalkil, aralkyl, aralkynyl, aralkiloksialkenil, heteroaralkenyl, heteroaralkyl, geteroaralkiloksialkenil, geteroaralkiloksialkil, heteroaralkenyl, anelirovanny arylcycloalkyl, anelirovanny heteroarylcycloalkyl, anelirovanny arylcycloalkenyl, anelirovanny heteroarylcycloalkenyl, anelated arylheterocyclyl, anelated heteroarylheterocyclyl, and unlated arylheterocyclenyl, anelated heteroarylheterocyclenyl.

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

Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. An alkyl group may have one or more substituents, for example, such as halogen, alkenyloxy, cycloalkyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroaralkyloxy, heterocyclyl, heterocyclylalkyloxyalkyloxycarbonyl ¹ G ² N-, G ¹ G ² NC (= O) -, G ¹ G ² NSO ₂ -, where G ¹ and G ² independently represent a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or G ¹ and G ² together with the N atom to which they svjaza s, form through G ¹ and G ² 4-7-membered heterocyclyl or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, benzyloxycarbonylmethylmethyl and pyridine. Preferred alkenyl groups are ethenyl, propenyl, n-butenyl, iso-butenyl, 3-methylbut-2-enyl, n-pentenyl and cyclohexylbutenyl.

“Alkenyloxy” means an alkenyl-O— group in which alkenyl is defined in this section. Allenyloxy and 3-butenyloxy are preferred alkenyloxy groups.

“Alkenyloxyalkyl” means an alkenyl-O-alkyl group in which alkyl and alkenyl are defined in this section.

"Alkyl" means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in a chain in which alkyl groups. Branched means that the alkyl chain has one or more "lower alkyl" substituents. Alkyl may have one or more identical or different substituents (“alkyl substituents”), including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonylheteroaralkyloxy, anelated heteroarylcycloalkenyl, anelated heteroarylcycloalkyl, anelated heteroarylheterocyclenyl, anelated heteroaryl heterocyclyl, anelated arylcyclo enyl, anelirovanny arylcycloalkyl, arylheterocyclenyl anelirovanny, anelirovanny arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or G ¹ G ² N-, G ¹ G ² NC (= O) -, G ¹ G ² NC (= S) -, G ¹ G ² NSO ₂ -, where G ¹ and G ² independently represent a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or G ¹ and G ² together with the N atom to which they are bonded form through G ¹ and G ² 4-7 membered heterocyclyl or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethylene . The preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or G ¹ G ² N-, G ¹ G ² NC (= O) -, anelated arylheterocyclenyl, anelated arylheterocyclyl.

“Alkyloxyalkyl” means an alkyl-O-alkyl group in which the alkyl groups are independent of each other and are defined in this section. Preferred alkyloxyalkyl groups are methoxyethyl, ethoxymethyl, n-butoxymethyl, methoxypropyl and isopropyloxyethyl.

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

“Alkoxy” means an alkyl-O— group in which alkyl is defined in this section. Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy.

“Alkoxycarbonyl” means alkyl-O — C (= O) —the group in which alkyl is defined in this section. Preferred alkoxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl and tert-butyloxycarbonyl.

“Alkoxycarbonylalkyl” means an alkyl-O — C (═O) -alkyl group in which alkyl is defined in this section. Preferred alkoxycarbonylalkyl groups are methoxycarbonylmethyl and ethoxycarbonylmethyl and methoxycarbonylethyl and ethoxycarbonylethyl.

“Amino group” means a G ¹ G ² N- group substituted or unsubstituted with an “amino substituent”, G ¹ and G ² , the meanings of which are defined in this section, for example amino (H ₂ N-), methylamino, diethylamino, pyrrolidine, morpholine, benzylamino or phenethylamino.

“Amino acid” means a natural amino acid or a non-natural amino acid, the meaning of the latter is defined in this section. Preferred amino acids are amino acids containing an α or β amino group. Examples of natural amino acids are α-amino acids, such as alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine and cysteine.

“Anelated cycle” (condensed cycle) means a bi- or polycyclic system in which the anelated cycle and the cycle or polycycle with which it is “anelated” have at least two atoms in common.

“Anelated arylheterocycloalkenyl” means anelated aryl and heterocycloalkenyl, the meanings of which are defined in this section. Anelated arylheterocycloalkenyl can bind through any possible atom of the cyclic system. The prefix "aza", "oxa" or "thia" before "heterocycloalkenyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Anelated arylheterocycloalkenyl may have one or more “cyclic system substituents,” which may be the same or different. The nitrogen and sulfur atoms in the heterocyclenyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of anelated arylheterocycloalkenyls are indolinyl, 1H-2-oxoquinolinyl, 2H-1-oxoisoquinolinyl, 1,2-dihydroquinolinyl, and the like.

“Anelated arylheterocycloalkyl” means anelated aryl and heterocycloalkyl, the meaning of which is defined in this section. Anelated arylheterocycloalkyl can bind through any possible atom of the cyclic system. The prefix "aza", "oxa" or "thia" before "heterocycloalkyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Anelated arylheterocycloalkyl may have one or more “cyclic system substituents,” which may be the same or different. The nitrogen and sulfur atoms in the heterocyclyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of anelated arylheterocycloalkyls are indolyl, 1,2,3,4-tetrahydroisoquinoline, 1,3-benzodioxol, and the like.

“Anelated arylcycloalkenyl” means anelated aryl and cycloalkenyl, the meanings of which are defined in this section. Anelated arylcycloalkenyl can bind through any possible atom of the cyclic system. Anelated arylcycloalkenyl may have one or more “cyclic system substituents,” which may be the same or different. Representatives of anelated arylcycloalkenyls are 1,2-dihydronaphthalene, indene, etc.

“Anelated arylcycloalkyl” means anelated aryl and cycloalkyl, the meanings of which are defined in this section. Anelated arylcycloalkyl can bind through any possible atom of the cyclic system. Anelated arylcycloalkyl may have one or more “cyclic system substituents,” which may be the same or different. Representatives of anelated arylcycloalkenyls are indanine, 1,2,3,4-tetrahydronaphthalene, 5,6,7,8-tetrahydronaphth-1-yl, and the like.

“Anelated heteroarylcycloalkenyl” means anelated heteroaryl and cycloalkenyl, the meanings of which are defined in this section. Anelated heteroarylcycloalkenyl can bind through any possible atom of the cyclic system. The prefix "aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Anelated heteroarylcycloalkenyl may have one or more “cyclic system substituents,” which may be the same or different. The nitrogen atom in the heteroaryl moiety may be oxidized to N-oxide. Representatives of anelated heteroarylcycloalkenyls are 5,6-dihydroquinolinyl, 5,6-dihydroisoquinolinyl, 4,5-dihydro-1H-benzimidazolyl, and the like.

“Anelated heteroarylcycloalkyl” means anelated heteroaryl and cycloalkyl, the meanings of which are defined in this section. Anelated heteroarylcycloalkyl can bind through any possible atom of the cyclic system. The prefix "aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Anelated heteroarylcycloalkyl may have one or more “ring system substituents”, which may be the same or different. The nitrogen atom in the heteroaryl moiety may be oxidized to N-oxide. Representatives of anelated heteroarylcycloalkenyls are 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, and the like.

“Anelated heteroaryl heterocyclenyl” means anelated heteroaryl and heterocyclenyl, the meanings of which are defined in this section. Anelated heteroarylheterocyclenyl can bind through any possible atom of the ring system. The prefix "aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Anelated heteroarylheterocyclenyl may have one or more “cyclic system substituents,” which may be the same or different. The nitrogen atom located in the heteroaryl part may be oxidized to N-oxide. The nitrogen and sulfur atoms located in the heterocyclenyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of anelated heteroarylcycloalkenyls are 1,2-dihydro [2,7] naphthyridinyl, 7,8-dihydro [1,7] naphthyridinyl, 6,7-dihydro-3H-imidazo [4,5-c] pyridyl and the like.

“Anelated heteroaryl heterocyclyl” means anelated heteroaryl and heterocyclyl, the meanings of which are defined in this section. Anelated heteroaryl heterocyclyl can bind through any possible atom of the cyclic system. The prefix "aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Anelated heteroaryl heterocyclyl may have one or more “cyclic system substituents,” which may be the same or different. The nitrogen atom in the heteroaryl moiety may be oxidized to N-oxide. The nitrogen and sulfur atoms in the heterocyclyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of anelated heteroarylcycloalkenyls are 2,3-dihydro-1H-pyrrolo [3,4-b] quinolin-2-yl, 2,3-dihydro-1H-pyrrolo [3,4-b] indol-2-yl, 1, 2,3,4-tetrahydro [1,5] naphthyridinyl and the like.

“Aralkenyl” means an arylalkenyl group in which the meanings of aryl and alkenyl are defined in this section. For example, 2-phenethenyl is an aralkenyl group.

“Aralkyl” means an alkyl group substituted with one or more aryl groups, in which the meanings of aryl and alkyl are defined in this section. Examples of aralkyl groups are benzyl, 2,2-diphenylethyl or phenethyl.

"Aralkylamino" means aryl-alkyl-NH-, in which the meanings of aryl and alkyl are defined in this section.

“Aralkylsulfinyl” means an aralkyl-SO— group in which the meaning of aralkyl is defined in this section.

“Aralkylsulfonyl” means an aralkyl-SO ₂ group in which the meaning of aralkyl is defined in this section.

“Aralkylthio” means an aralkyl-S group in which the meaning of aralkyl is defined in this section.

“Aralkoxy” means an aralkyl-O-group in which the meaning of aralkyl is defined in this section. For example, benzyloxy or 1- or 2-naphthylenemethoxy are aralkyl groups.

“Aralkoxyalkyl” means an aralkyl-O-alkyl group in which the meanings of aralkyl and alkyl are defined in this section. An example of an aralkyl-O-alkyl group is benzyloxyethyl.

“Aralkoxycarbonyl” means an aralkyl-O — C (= O) group in which the meaning of aralkyl is defined in this section. An example of an aralkoxycarbonyl group is benzyloxycarbonyl.

“Aralkoxycarbonylalkyl” means an aralkyl-O — C (= O) -alkyl group in which aralkyl and alkyl are defined in this section. An example of an aralkoxycarbonylalkyl group is benzyloxycarbonylmethyl or benzyloxycarbonylethyl.

“Aryl” means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. Aryl may contain one or more “cyclic system substituents”, which may be the same or different. Representative aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be anelated with a non-aromatic ring system or heterocycle.

“Arylcarbamoyl” means aryl-NHC (= O), the group in which the meaning of aryl is defined in this section.

“Aryloxy” means an aryl-O— group in which the meaning of aryl is defined in this section. Representative aryloxy groups are phenoxy and 2-naphthyloxy.

“Aryloxycarbonyl” means aryl-O — C (= O) —the group in which the meaning of aryl is defined in this section. Representative aryloxycarbonyl groups are phenoxycarbonyl and 2-naphthoxycarbonyl.

“Arylsulfinyl” means an aryl-SO— group in which the meaning of aryl is defined in this section.

"Arylsulfonyl" means aryl-SO ₂ - a group in which the meaning of aryl is defined in this section.

“Arylthio” means an aryl-S— group in which the meaning of aryl is defined in this section. Representative arylthio groups are phenylthio and 2-naphthylthio.

“Aroylamino” means aroyl-NH— group in which the meaning of aroyl is defined in this section.

“Aroyl” means aryl-C (= O) —the group in which the meaning of aralkyl is defined in this section. Examples of aroyl groups are benzoyl, 1- and 2-naphthoyl.

“Aromatic” radical means a radical obtained by removing a hydrogen atom from an aromatic C — H bond. An “aromatic" radical includes aryl and heteroaryl rings defined in this section. Aryl and heteroaryl rings may additionally contain substituents — aliphatic or aromatic radicals defined in this section. Representatives of aromatic radicals include aryl, anelated cycloalkenylaryl, anelated cycloalkylaryl, anelated heterocyclylaryl, anelated heterocyclylaryl, heteroaryl, anelated cycloalkylheteroaryl, anelated cycloalkenylheteroaryl, anelated heterocyclenylheteroaryl and.

“Aromatic cycle” means a planar cyclic system in which all atoms of the cycle participate in the formation of a single conjugation system, which, according to the Hückel rule, includes (4n + 2) π-electrons (n is a non-negative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene, and the like. In the case of “heteroaromatic cycles”, π-electrons and p-electrons of heteroatoms participate in the conjugation system; their total number is also equal to (4n + 2). Examples of such cycles are pyridine, thiophene, pyrrole, furan, thiazole and the like. An aromatic ring may have one or more “cyclic substituents” and can be anelated with a non-aromatic ring, heteroaromatic or heterocyclic ring.

“Acyl” means HC (= O) - or alkyl-C (= O) -, cycloalkyl-C (= O) -, heterocyclyl-C (= O) -, heterocyclylalkyl-C (= O) -, aryl -C (= O) - arylalkyl-C (= O) - or heteroaryl-C (= O) -, heteroarylalkyl-C (= O) - a group in which alkyl-, cycloalkyl-, heterocyclyl-, heterocyclylalkyl, aryl- , arylalkyl, heteroaryl-, heteroarylalkyl are defined in this section.

“Acylamino” means an acyl-NH— group in which the acyl value is defined in this section.

"Bifunctional reagent" means a chemical compound having two reaction centers participating simultaneously or sequentially in the reactions. Examples of bifunctional reagents are reagents containing a carboxyl group and an aldehyde or ketone group, for example 2-formylbenzoic acid, 2- (2-oxoethylcarbamoyl) benzoic acid, 2- (3-formylthiophen-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 “alkyl substituents”, the meaning of which is defined in this section.

“Halogen” means fluoro, chloro, bromo and iodo. Fluorine, chlorine and bromine are preferred.

“Heteroanelated cycle” means that a cycle that attaches (annelates or condenses) to another cycle or polycycle contains at least one heteroatom.

“Heteroaralkenyl” means a heteroarylalkenyl group in which heteroaryl and alkenyl are defined in this section. Preferably, heteroaralkenyl includes a lower alkyl group. Representatives of heteroaralkenyls are 4-pyridylvinyl, thienylethenyl, imidazolylethenyl, pyrazinylethenyl, and the like.

“Heteroaralkyl” means a heteroarylalkyl group in which heteroaryl and alkyl are defined in this section. Representatives of heteroaralkyls are pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, pyrazinylmethyl, and the like.

“Heteroaralkyloxy” means a heteroarylalkyl-O— group in which heteroarylalkyl is defined in this section. Representatives of heteroaralkyloxy groups are 4-pyridylmethyloxy, 2-thienylmethyloxy and the like.

“Heteroaroyl” means heteroaryl-C (= O), the group in which heteroaryl is defined in this section. Representative heteroaroyls are nicotinoyl, thienoyl, pyrazoloyl, etc.

“Heteroaryl” means an aromatic monocyclic or polycyclic system comprising from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are substituted with heteroatoms or heteroatoms such as nitrogen, sulfur or oxygen. The prefix "aza", "oxa" or "thia" before heteroaryl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. The nitrogen atom in the heteroaryl may be oxidized to N-oxide. Heteroaryl may have one or more “ring system substituents”, which may be the same or different. Representative heteroaryl compounds are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, isoxazolyl, isothiazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinazole, quinazole -a] pyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanil, indolyl, azaindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridine, imidazoinazole, azidazinoidinazole thienopyrrolyl, furopyrrolyl. and etc.

“Heteroarylsulfonylcarbamoyl” means heteroaryl-SO ₂ —NH — C (= O) —the group in which heteroaryl is defined in this section.

“Heterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one heteroatom in the ring, the meaning of which in this section. Preferred heteroatoms are nitrogen, oxygen and sulfur. An azaheterocycle may have one or more “cyclic” substituents.

“Heterocyclenyl” means a non-aromatic monocyclic or polycyclic system comprising from 3 to 13 carbon atoms, preferably from 5 to 13 carbon atoms, in which one or more carbon atoms are replaced by a hetero atom, 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" in front of heterocyclenyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Heterocyclenyl may have one or more “ring system substituents”, which may be the same or different. The nitrogen and sulfur atoms in heterocyclenyl can be oxidized to N-oxide, S-oxide or S-dioxide. Representative heterocyclenyls are 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolyl, 2-pyrazolinyl, dihydrofuranyl, dihydrothiophenyl and the like.

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

“Heterocyclyloxy” means a heterocyclyl-O— group in which heterocyclyl is defined in this section.

"Hydrate" means a solvate in which water is a molecule or molecules of a solvent.

“Hydroxyalkyl” means a HO-alkyl group in which alkyl is defined in this section.

“Substituent” means a chemical radical that is attached to a scaffold (fragment), for example, “substituent alkyl”, “substituent of an amino group”, “substituent carboxyl”, “substituent carbamoyl”, “substituent of the cyclic system”, the meanings of which are defined in this section.

“Substituent alkyl” means a substituent attached to alkyl, alkenyl, the meaning of which is defined in this section. Alkyl substituent is hydrogen, alkyl, halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkilsulfonilgeteroaralkiloksi, anelirovanny heteroarylcycloalkenyl , gelled heteroarylcycloalkyl, gelled heteroarylheterocyclenyl, gelled heteroarylheterocyclyl, gelled arylcycloalkenyl, gelled arylcycloalkyl, gelled ar lgeterotsiklenil, anelirovanny arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or G ¹ G ² N-, G ¹ G ² NC (= O) -, G ¹ G ² NSO ₂ -, where G ¹ and G ² each independently represent an atom hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or G ¹ and G ² together with the N atom to which they are bonded form 4-7 membered heterocyclyl or heterocyclenyl through G ¹ and G ² . 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, benzyloxycarbonyl. The preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or G ¹ G ² N-, G ¹ G ² NC (= O) -, anelated arylheterocyclenyl, anelated arylheterocyclyl. The meaning of “alkyl substituents” is defined in this section.

“Acyl substituent” means a substituent selected from the group of alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl attached to the carbon atom of the carbonyl group of the acyl in which acyl, alkyl, cycloalkyl, heterocyclyl, heterocyclyl, heteroaryl, heteroarylalkyl are defined in this section.

“Substituent amino group” means a substituent attached to an amino group. Amino group substituent represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, geterotsiklilaminokarbonil, alkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, anelirovanny heteroarylcycloalkenyl, anelirovanny heteroarylcycloalkyl, anelirovanny heteroarylheterocyclenyl , anelated heteroaryl heterocyclyl, anelated arylcycloalkenyl, anelated arylcycloalkyl, anelated arylheterocyclenyl, anelated arylheterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl.

“Urea carbamoyl” means a substituent attached to a carbamoyl group, the meaning of which is defined in this section. The carbamoyl substituent is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or G ¹ G ² N-, G ¹ G ² NC (= O) -alkyl, anelated heteroaryl aryl-aryl, gelled heteroarylheterocyclyl, gelled arylcycloalkenyl, gelled arylcycloalkyl, gelled arylheterocyclenyl, gelled arylheterocyclyl. Preferred “carbamoyl substituents” are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroalkyloxycarbonylalkyl or G ¹ G ² N-, G ¹ G ² NC (= O) -alkyl, anelated aryl heterocyclic.

"Carboxyl substituent" means a substituent attached to the oxygen of the carboxyl group, the meaning of which is defined in this section. The carboxy substituent is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or G ¹ G ² N-, G ¹ G ² NC (= O) -alkyl, anelated heteroarylcycloalkylalkylalkenyl, , anelated arylcycloalkenyl, anelated arylcycloalkyl, anelated arylheterocyclenyl, anelated arylheterocyclyl. Preferred “carboxy substituents” are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or G ¹ G ² N-alkyl, G ¹ G ² NC (= O) -alkyl, anelated aryl aryl.

“Nucleophilic substituent” means a chemical radical that attaches to scaffold by reaction with a nucleophilic reagent, for example, selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thiophenols.

"Substituent cyclic system" means a substituent attached to an aromatic or non-aromatic cyclic system, including hydrogen, alkylalkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, acyl, aroyl, genogen, nitro, cyano, carboxy , alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, cycloalkyl kenil, heterocyclyl, heterocyclenyl, amidino, G ¹ G ² N-, G ¹ G ² N-alkyl, G ¹ G ² NC (= O) - or G ¹ G ² NSO ₂ -, where G ¹ and G ² represent independently from each other hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl, or a substituent G ¹ G ² N-, in which one of G ¹ and G ² may be acyl or aroyl, and the value the other of G ¹ and G ^{2 is} defined above, or “cyclic system substituents” are G ¹ G ² NC (= O) - or G ¹ G ² NSO ₂ -, in which G ¹ and G ² together with the nitrogen atom with which they are connected oh 4-7 membered heterocyclyl or heterocyclenyl is formed via G ¹ and G ² . Preferred “cyclic substituents” are alkoxycarbonyl, alkoxy, halogen, aryl, aralkoxy, alkyl, hydroxy, aryloxy, nitro, cyano, alkylsulfonyl, heteroaryl or G ¹ G ² N-. If the cyclic system is saturated or partially saturated, then “substituents of the cyclic system” may be methylene (CH ₂ =), oxo (O =) or thioxo (S =).

“Electrophilic substituent” means a chemical radical that attaches to scaffold by reaction with an electrophilic reagent, for example, organic acids or their derivatives (anhydrides, imidazolides, halides), organic sulfonic acid esters or organic sulfonyl chlorides, organic haloformates, organic isocyanates and organic isothiocyanates.

“Protecting group” (PG) means a chemical radical that is attached to a scaffold or intermediate to synthesize the amino group in multifunctional compounds, including, but not limited to: an amide substituent such as formyl, optionally substituted acetyl (eg trichloroacetyl, trifluoroacetyl, 3 -phenylpropionyl and others), optionally substituted benzoyl and others; a carbamate substituent, such as optionally substituted C ₁ -C ₇ alkyloxycarbonyl, for example methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), etc .; an optionally substituted C ₁ -C ₇ alkyl substituent, for example tert-butyl, benzyl, 2,4-dimethoxybenzyl, 9-phenylfluorenyl, etc .; sulfonyl substituent, for example benzenesulfonyl, p-toluenesulfonyl, etc. For more details, “Protective groups” are described in the book: Protective groups in jrganic synthesis. Third Edition Greene, TW and Wuts, PGM 1999, p. 494-653. John Wiley & Sons, Inc., New York, Chichester, Weinheim, Brisbane, Toronto, Singapore.

"Protected primary or secondary amine" means a group of formula G ¹ G ² N-, in which one of G ¹ and G ² represents a protective group PG, and the value of the other of G ¹ and G ² represents hydrogen, alkenyl, alkyl, aralkyl , aryl, anelirovanny, arylcyloalkenyl, anelirovanny arylcycloalkyl, anelirovanny arylheterocyclenyl, anelirovanny arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroaryl, anelirovanny heteroarylcycloalkenyl, anelirovanny heteroarylcycloalkyl, roarilgeterotsiklil, heterocyclenyl or heterocyclyl.

"Inert substituent" (or "non-interfering", "Non-interfering substituent") means a low or non-reactive radical, including but not limited to C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C7 alkynyl, C ₁ -C ₇ alkoxy. C ₇ -C ₁₂ aralkyl substituted with inert aralkyl substituents, C ₇ -C ₁₂ heterocyclylalkyl substituted with inert substituents heterocyclylalkyl, C ₇ -C ₁₂ alkaryl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C ₂ -C ₁₂ acoxyalkyl, C ₂ -C ₁₀ alkylsulfinyl, C ₂ -C ₁₀ alkylsulfonyl, (CH ₂ ) _m -O- (C ₁ -C ₇ alkyl), - (CH ₂ ) _m —N (C ₁ -C ₇ alkyl) _n , aryl substituted with halogens, inert substituents aryl substituted with inert substituents alkoxy, fluoroalkyl, aryloxyalkyl, heterocyclyl substituted with inert substituents hetero alkyl and nitroalkyl, where m and n are from 1 to 7. Preferred “inert substituents” are C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkoxy, C ₇ -C ₁₂ aralkyl, C ₇ -C ₁₂ alkaryl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl substituted with inert substituents C ₁ -C ₇ alkyl, phenyl substituted with inert substituents phenyl, ((CH ₂ ) _m -O- (C ₁ -C ₇ alkyl), - (CH ₂ ) _m -N (C ₁ -C ₇ alkyl) _n , aryl substituted with inert substituents aryl, heterocyclyl and substituted with inert substituents heterocyclyl.

"Carbamoyl" means G ¹ G ² NC (= O) - group. Carbamoyl may have one or more of the same or different "carbamoyl substituents" G ¹ and G ² , including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.

“Carbamoylaseheterocycle” means an azaheterocycle containing as “substituent of the cyclic system” at least one carbamoyl group, the meaning of “azaheterocycle”, “substituent of the cyclic system” and “carbamoyl group” are defined in this section.

“Carboxy” means HOC (= O) - (carboxyl) group.

“Carboxyalkyl” means an HOC (= O) -alkyl group in which the meaning of alkyl is defined in this section.

“Carbocycle” means a mono- or polycyclic system consisting only of carbon atoms. Carbocycles can be either aromatic or alicyclic. Alicyclic polycycles may have one or more common atoms. In the case of one common atom, spiro-carbocycles are formed (for example, spiro [2.2] pentane), in the case of two, various condensed systems (for example, decalin), in the case of three, bridge systems (for example, bicyclo [3.3.1] nonane), in the case of a larger number, various polyhedral systems (for example, adamantane). Alicycles can be “saturated”, for example, as cyclohexane, or “partially saturated”, for example, as tetralin.

“Combinatorial library” means a collection of compounds obtained by parallel synthesis designed to search for a hit or leader compound, as well as to optimize the physiological activity of a hit or leader, each library compound corresponding to a common scaffold and the library is a collection of related homologues or analogues.

“Methylene radical” means —CH ₂ - a group that contains one or two identical or different “alkyl substituents”, the meaning of which is given in this section.

“Non-aromatic cycle” (saturated cycle or partially saturated cycle) means a non-aromatic cyclic or polycyclic system formally formed as a result of complete or partial hydrogenation of unsaturated C = C or C = N bonds. A non-aromatic ring may have one or more “cyclic substituents” and can be anelated with aromatic, heteroaromatic or heterocyclic systems. Examples of non-aromatic rings are cyclohexane or piperidine, examples of a partially saturated ring are cyclohexene or piperidine.

“Unnatural amino acid” means an amino acid of a non-nucleic nature. Examples of unnatural amino acids include the D-isomers of natural α-amino acids, aminobutyric acid, 2-aminobutyric acid, γ-aminobutyric acid, N-α-alkylated amino acids, 2,2-dialkyl-α-amino acids, 1-aminocycloalkylcarboxylic acids, β- alanine, 2-alkyl-β-alanines, 2-cycloalkyl-β-alanines, 2-aryl-β-alanines, 2-heteroaryl-β-alanines, 2-heterocyclyl-β-alanines and (1-aminocycloalkyl) acetic acids, in which the meanings of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are defined in this section.

“Optional aromatic cycle” means a cycle, which can be either an aromatic cycle or a non-aromatic cycle, the meanings of which are defined in this section.

“Optionally substituted radical” means a radical without substituents or containing one or more substituents.

“Optional anelated (condensed) cycle” means a condensed or non-condensed cycle, the meanings of which are defined in this section.

"Lower alkyl" means a linear or branched alkyl with 1-4 carbon atoms. “Parallel synthesis” means a method for conducting chemical synthesis of a combinatorial library of individual compounds.

“1,3-Propylene radical” means —CH ₂ —CH ₂ —CH ₂ - a group that contains one or more identical or different “alkyl substituents”, the meaning of which is given in this section.

“Leader compound” (“leader”) means a compound with outstanding (maximum) physiological activity associated with a particular biotarget related to a specific (or several) pathology or disease.

“Hit compound” (“hit”) means a compound that exhibits the desired physiological activity during the initial screening process.

“Sulfamoyl group” means G ¹ G ² NSO ₂ - a group substituted or unsubstituted by “amino substituent” G ¹ and G ² , the meanings of which are defined in this section.

"Sulfonyl" means G ³ -SO ₂ - a group in which G ³ represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, anelated heteroarylcycloalkyl, anelated heteroaryl heterocyclylenyl, anelated heteroaryl heterocyclylalkyl, anelated heteroaryl heterocyclyl, aryl, arylheterocyclyl, the meaning of which is defined in this section.

“Template” means the general structural formula of a group of compounds or compounds included in a “combinatorial library”.

"Thiocarbamoyl" means G ¹ G ² NC (= S) - group. Carbamoyl may have one or more of the same or different “thiocarbamoyl substituents” G ¹ and G ² , including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined 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 “ring system substituents”, which may be the same or different. Representative cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl and the like. Cycloalkyl can be anelated with an aromatic ring or heterocycle. Preferred “cyclic system substituents” are alkyl, aralkoxy, hydroxy or G ¹ G ² N, the meaning of which is defined in this section.

“Cycloalkylcarbonyl” means cycloalkyl-C (═O) —the group in which the meaning of cycloalkyl is defined in this section. Representatives of cycloalkylcarbonyl groups are cyclopropylcarbonyl or cyclohexylcarbonyl.

“Cycloalkoxy” means a cycloalkyl-O— group in which the meaning of cycloalkyl is defined in this section.

"Pharmaceutical composition" means a composition comprising a compound of formula I and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceiving agents, agents delivery, such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, such as parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugar, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and distributors are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. A pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration, an active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers . Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

“Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared specifically based on the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like. (A detailed description of the properties of such salts is given in Berge S.M. et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19.). Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have 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, tetraalkylammonium hydroxides, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine.

“Focused library” means a combinatorial library or a collection of several combinatorial libraries, or a collection of libraries and substances specially organized in order to increase the likelihood of finding hits and leaders or to increase the efficiency of their optimization. The design of focused libraries, as a rule, is associated with a directed search for effectors (inhibitors, activators, agonists, antagonists, etc.) of specific biological targets (enzymes, receptors, ion channels, etc.).

“Fragment” (scaffold) means the structural formula of a part of a molecule characteristic of a group of compounds or a molecular framework characteristic of a group of compounds or compounds included in a “combinatorial library.

“1,2-Ethylene radical” means —CH ₂ —CH ₂ - a group that contains one or more identical or different “alkyl substituents”, the meaning of which is defined in this section.

An object of the present invention is to provide a new pharmaceutical composition in the form of tablets, capsules or injections in a pharmaceutically acceptable package.

This goal is achieved by a pharmaceutical composition having an inhibitory effect on the MC2R receptor for the preparation of pharmaceutical preparations in the form of tablets, granules, capsules, suspensions, solutions or injections, placed in a pharmaceutically acceptable package containing, as an active substance, an azaheterocyclic compound of the general formula 1.1.1 and / or 1.2.1, and / or 1.3.1:

where R ¹ in the general formula 1.1.1 is substituted alkyl, aryl, heteroaryl, heterocyclyl or in the general formula 1.2.1, R ¹ is an amino substituent selected from hydrogen or optionally substituted lower alkyl or lower acyl;

R ² , R ³ and R ⁴ independently of one another represent a cyclic system substituent selected from hydrogen, azaheterocycle, optionally substituted lower alkyl, optionally substituted hydroxy, optionally substituted carboxy, cycloalkyl, or R ³ and R ⁴ together with carbon atoms, with which they are bonded, short the azaheterocycle through R ³ and R ⁴ , or R ¹ together with the nitrogen atom to which it is bonded, and R ³ and R ⁴ together with the carbon atoms with which they are bonded, short-circuited through R ¹ , R ³ and R ⁴ azaheterocycle;

R ¹⁸ and R ¹⁹ independently represent amino substituents selected from hydrogen or lower alkyl substituted with azaheterocycle in the form of their racemates, optically active isomers or their pharmaceutically acceptable salts and / or hydrates, R ²⁰ and R ²¹ , together with the nitrogen atom to which they are attached form a possibly substituted azaheterocycle.

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

where R ¹ , R ² and R ⁴ have the above meaning; R ⁵ represents an azaheterocycle.

According to the invention, a more preferred pharmaceutical composition having an inhibitory effect on the MC2R receptor is a composition containing, as an active substance, 11- (1H-indol-3-yl) -2,3,4,5,10,11-hexahydrodibenzo [b , e] [1,4] diazepin-1-one of the general formula 1.2.1.2 or its racemates, or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates:

where R ¹ and R ² have the above meaning; R ⁶ represents alkyl or cycloalkyl; R ⁷ and R ⁸ independently from each other represent a hydrogen atom, alkyl or aryl.

According to the invention, a more preferred pharmaceutical composition having an inhibitory effect on the MC2R receptor is a composition containing, as an active substance, 7-acyl-6- (1H-indol-3-yl) -3-sulfanyl-6,7,8,9 Tetrahydro-1,2,4-triazino [5,6-f] [1,3] oxazepine of the general formula 1.2.1.3 or its racemates, or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates:

where R ¹ and R ² have the above meaning; R ⁹ represents alkyl or alkenyl.

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

where R ¹ and R ² have the above meaning; R ¹⁰ represents a substituent of the cyclic system; R ¹¹ , R ¹² and R ¹³ independently of each other represent an amino substituent.

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

where R ¹ , R ² , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ have the above meaning.

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

where R ¹ represents hydrogen or methyl; R ¹⁰ , R ¹¹ and R ¹³ have the above meaning.

According to the invention, a more preferred pharmaceutical composition having an inhibitory effect on the MC2R receptor is a composition containing 1,2,3,8-tetrahydro-1-oxo-pyrrolo [3,4-b] indole of the general formula 1.2 as an active substance. 1.5 or its racemates, or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates:

where R ¹ and R have the above meaning; R ¹⁴ represents a substituent of an amino group; R ¹⁵ represents aryl or heteroaryl.

According to the invention, a more preferred pharmaceutical composition having an inhibitory effect on the MC2R receptor is a composition containing, as an active substance, 2,3,4,5-tetrahydro-1H-pyrido [3,4-b] indole of the general formula 1.2.1.6 or its racemates, or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates:

where R ¹ and R ² have the above meaning; R ¹⁶ represents an amino group substituent.

According to the invention, a more preferred pharmaceutical composition having an inhibitory effect on the MC2R receptor is a composition containing, as an active substance, an azaheterocyclic compound of the general formula 1.2.1.7 or its racemates, or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates:

where R ² has the above meaning; R ¹⁷ represents an amino group substituent.

According to the invention, a more preferred pharmaceutical composition having an inhibitory effect on the MC2R receptor is a composition containing as an active substance 2- [6-methyl-4-oxo-5- (4-pyrimidin-2-ylpiperazin-1-sulfonyl) - 4H-thieno [2,3-d] pyrimidin-3-yl] acetamide of the general formula 1.3.1.1 or its racemates, or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates:

where R ¹⁸ and R ¹⁹ have the above meaning.

The aim of the present invention is also a method for producing a pharmaceutical composition.

The goal is achieved by a method of obtaining a pharmaceutical composition, which consists in mixing the active substance with inert excipients and / or solvents with respect to the substance, followed by tableting, granulation, encapsulation, suspension, dissolution or dilution and placed in a suitable package, the distinctive feature of which consists in that, as an active substance, any of the azaheterocyclic compounds of the general formula 1.1.1 and / or 1.2.1, and / or 1.3.1 or their racemate is used Or the optical isomers thereof, or pharmaceutically acceptable salts and / or hydrates.

Inert excipients and / or solvents (excipients) refers to pharmaceutical diluents, auxiliary agents and / or carriers of azaheterocyclic compounds of the general formula 1.1.1, 1.2.1, 1.3.1 of 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 it is necessary to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed for the manufacture of various forms, and they may include traditional pharmaceutical carriers, for example, oral forms (such as tablets, gelatine capsules, pills, solutions or suspensions); injection forms (such as injectable solutions or suspensions, or dry powder for injection, which only requires the addition of water for injection before use); local forms (such as ointments or solutions).

The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to obtain common forms, including oral agents using binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless agents flavoring agents of taste; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used. Pharmaceutical preparations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically). If any medicinal substance is not stable under the conditions of the stomach, it can be used to make tablets coated with a film of a substance soluble in the stomach or intestines.

In accordance with the invention, a new pharmaceutical composition is used to prepare 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 the development of various diseases of warm-blooded animals and people associated with increased activation of adrenocorticotropic hormone (ACTH).

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

The clinical dosage of a pharmaceutical composition containing the aforementioned azaheterocyclic compounds as an active ingredient in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as on the age, sex and stage of the patient’s disease. while the daily dose in adults is usually 10 ~ 500 mg, preferably 50 ~ 300 mg. Therefore, during the preparation of the pharmaceutical compositions of the present invention in dosage units, the above effective dosage must be taken into account, with each dosage unit containing 10 ~ 500 mg of an azaheterocyclic compound of the general formula 1.1.1, 1.2.1 or 1.3.1, preferably 50 ~ 300 mg In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).

The aim of the present invention is also the creation of new "pharmacological tools" for experimental studies of processes associated with increased activation of adrenocorticotropic hormone (ACTH). This goal is achieved by the use of physiologically active azaheterocyclic compounds of the general formula 1.1.1, 1.2.1 or 1.3.1, or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates having properties to inhibit the MC2R receptor, for the preparation of medicinal agents for the treatment and / or prevention of diseases associated with increased activation of adrenocorticotropic hormone (ACTH) or for experimental (in vitro or in vivo) studies of processes associated with increased activation of address okortikotropnogo hormone (ACTH), as the "pharmacological tool".

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

The following are specific examples that illustrate but do not limit the invention.

The drawing shows the dependence of the inhibition of the induction of cAMP by the test compounds caused by adrenocorticotropic hormone (100 nM) in Y1 cells.

Example 1. Inhibition of the MC2R receptor by azaheterocyclic compounds of the general formula 1.1.1, 1.2.1, 1.3.1. For high-throughput screening of large quantities of substances on their potential ability to block the action of adrenocorticotropic hormone, a mouse cell culture (Y1 cells) is used, which is known [Heisler S, Tallerico-Melnyk T, Yip C, 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 a melanocorticotropic receptor type 2 (MC2R). In a preferred embodiment, cells (hereinafter referred to as Yl-CRE-lu) were transfected with a pHTS-CRE vector obtained from Biomyx Technology (San Diego, CA), with a luciferase reporter gene and a cyclic AMP-sensitive transcription element. Upon stimulation of MC2R with adrenocorticotropic hormone (ACTH), the level of cyclic AMP increases, which leads to stimulation of luciferase gene expression and, as a result, increased luminescence of expressed luciferase, which can be detected using a luminescent spot reader in 96- or 384-well formats. Screening was carried out as follows. Stably transfected with the luciferase gene cells were planted in the wells of 96-well plates (5000-7000 cells / well) and incubated at 37 ° C in an atmosphere of 5% CO ₂ for 24 hours. Test compounds were added to the plate cells at a final concentration of 1 μM, the cells were incubated for an additional 15 minutes, after which ACTH was added to them at a concentration of 100 nM, and the incubation continued for an additional 4 hours. Luciferase activity was measured using a kit of reagents manufactured by Biotium, Inc., (USA), and in accordance with their protocol. In particular, the incubation medium was removed from the wells by aspiration, and the cells were washed with physiological saline with phosphate buffer. 20 μl of the reagent kit lysate buffer was added to the wells and the plates were shaken at room temperature for 15 minutes. For measurement, a 96-well VICTOR ² V reader (PerkinElmer, USA) was used in the luminescence mode. 100 μl of the luciferase reagent containing luciferin is injected into each well and the developing luminescence generated by the catalytic oxidation of luciferin with oxygen is integrated for 10 sec. Tables 1-3 show some examples of the percent inhibition of the luminescent signal in the presence of the tested azaheterocyclic compounds of the general formula 1.1.1 (Table 1), 1.2.1 (Table 2) and 1.3.1 (Table 3), in relation to the signal developing in the presence of one ACTH. The presented examples confirm the inhibition of the MC2R receptor by azaheterocyclic compounds, including a fragment of the formula 1.1, 1.2 and 1.3, which in many cases reaches more than 50%.

Example 2. An example illustrating the preparation of tablets containing 100 mg of the active ingredient. 1600 mg of starch, 1600 mg of ground lactose, 400 mg of talc and 1000 mg of azaheterocyclic compound 1.1 (9) or 1.2.1.4 (183), or 1.3.10 are mixed and pressed into a block. The resulting bar is crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The granules obtained are tabletted into a suitable tablet form weighing 560 mg each. According to the invention, pharmaceutical compositions in the form of tablets are likewise obtained in the form of tablets containing other azaheterocyclic compounds as an active ingredient, including a fragment of formula 1.1 or 1.2, or 1.3.

Example 3. Capsules containing 200 mg of azaheterocyclic compound 1.1 (9) or 1.2.1.4 (183), or 1.3.10, according to the invention can be obtained by thoroughly mixing compound 1.1 (9) or 1.2.1.4 (183), or 1.3. 10 with lactose powder in a ratio of 2: 1. The resulting powder mixture is packaged in 300 mg in a suitable size gelatin capsule.

Example 4. Injectable compositions for intramuscular, intraperitoneal or subcutaneous injection can be prepared by mixing 500 mg of the active ingredient with suitable solvents, for example, azaheterocyclic hydrochloride 1.2.1.4 (183) with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injection 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 of melatonin receptor blockers (MC2R), Y1 cells naturally expressing this receptor were used. Receptor stimulation with adrenocorticotropic hormone (ACTH) causes increased production of cyclic AMP (cAMP), which was measured using the TR-FRET fluorescence method using LANCE cAMP PerkinElmer [Hemmila I. (1999). LANCE: Homogenous Assay Platform for HTS. J. Biomol Screen, 4 (6). 303-308]. Cells were plated in wells of 96-cell dies and left overnight at 37 ° C in an incubator with 100% humidity and 5% CO ₂ . The next day, compounds at various concentrations obtained by serial dilution of stock solutions were added to the cells. After 15 minutes of incubation, ACTH was added to the cells at a concentration of 100 nM and incubation continued for 45 minutes. After incubation, a lysis solution contained in the detection kit was added to the cells, and the reaction to determine the resulting cAMP was carried out in strict accordance with the procedure recommended by the kit manufacturer (PerkinElmer). Fluorescence reflecting the amount of cAMP formed was measured using a VICTOR ² V fluorometer (PerkinElmer) and converted to the amount of cAMP formed using a calibration curve obtained by adding a known amount of cAMP. The activity of the compounds was determined by the concentration of compounds that cause half-maximal inhibition of cAMP stimulation by adrenocorticotropic hormone (IC ₅₀ ). Table 4 shows the activity values of some inhibitors of MC2 receptor, allowing their use as pharmacological tools.

Table 4.
IC ₅₀ values for test compounds Compound IC ₅₀ , nM 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

Claims (15)

1. A pharmaceutical composition having an inhibitory effect on the MC2R receptor for the preparation of pharmaceutical preparations in the form of tablets, granules, capsules, suspensions, solutions or injections, placed in a pharmaceutically acceptable package containing, as an active substance, an azaheterocyclic compound of the general formula 1.1.1 , 1.2.1 or 1.3.1

where R ¹ in the general formula 1.1.1 is substituted alkyl, aryl, heteroaryl, heterocyclyl, or in the general formula 1.2.1, R ¹ is an amino substituent selected from hydrogen or optionally substituted lower alkyl or lower acyl; R ² , R ³ and R ⁴ independently of one another represent a cyclic system substituent selected from hydrogen, azaheterocyclyl, optionally substituted lower alkyl, optionally substituted hydroxy, carboxy, cycloalkyl; or R ³ and R ⁴ together with the carbon atoms to which they are bonded form an azaheterocycle, or R ¹ together with the nitrogen atom to which it is bonded and R ³ and R ⁴ together with the carbon atoms to which they are bonded form through R ¹ , R ³ and R ⁴ azaheterocycle; R ¹⁸ and R ¹⁹ independently represent amino substituents selected from hydrogen or lower alkyl substituted with azaheterocycle in the form of their racemates, optically active isomers or their pharmaceutically acceptable salts and / or hydrates, R ²⁰ and R ²¹ together with the atom the nitrogen to which they are attached form a possibly substituted azaheterocycle. 2. The pharmaceutical composition according to claim 1, containing as an active substance N- [2- (1H-indol-3-yl) ethyl] acylamide of the general formula 1.2.1.1 or its racemates or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates

where R ¹ , R ² and R ⁴ have the above meaning; R ⁵ represents an azaheterocycle. 3. The pharmaceutical composition according to claim 1, containing as an active substance 11- (1H-indol-3-yl) -2,3,4,5,10,11-hexahydro-dibenzo [b, e] [1,4 ] diazepin-1-one of general formula 1.2.1.2 or its racemates or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates

where R ¹ and R ² have the above meaning; R ⁶ represents alkyl or cycloalkyl; R ⁷ and R ⁸ independently from each other represent a hydrogen atom, alkyl or aryl. 4. The pharmaceutical composition according to claim 1, containing as an active substance 7-acyl-6- (1H-indol-3-yl) -3-sulfanyl-6,7,8,9-tetrahydro-1,2,4- triazino [5,6-f] [1,3] oxazepine of the general formula 1.2.1.3 or its racemates or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates

where R ¹ and R ² have the above meaning; R ⁹ represents alkyl or alkenyl. 5. The pharmaceutical composition according to claim 1, containing as active substance 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline of the general formula 1.2.1.4 or its racemates or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates

where R ¹ and R ² have the above meaning; R ¹⁰ represents a substituent of a cyclic system selected from hydrogen; R ¹³ represents an amino group substituent selected from optionally substituted alkyl, each of R ¹¹ , R ¹² independently of each other represents an amino group substituent selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, in which the heteroatoms are selected from nitrogen, oxygen or sulfur, or R ¹¹ and R ¹² together with the nitrogen atom to which they are attached can 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 an active substance 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline of the general formula 1.2.1.4.1 or its racemates or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates

where R ¹ , R ² , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ have the above meaning. 7. The pharmaceutical composition according to claim 5, containing as an active substance 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline of the general formula 1.2.1.4.2 or its racemates or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates

where R ¹ represents hydrogen or methyl; R ¹¹ , R ¹² and R ¹³ have the above meaning. 8. The pharmaceutical composition according to claim 1, containing as the active substance 1,2,3,8-tetrahydro-1-oxo-pyrrolo [3,4-b] indole of the general formula 1.2.1.5 or its racemates or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates

where R ¹ and R ² have the above meaning; R ¹⁴ represents an amino group substituent selected from optionally substituted aryl; R ¹⁵ represents aryl or heteroaryl. 9. The pharmaceutical composition according to claim 1, containing, as an active substance, 2,3,4,5-tetrahydro-1H-pyrido [3,4-b] indole of the general formula 1.2.1.6 or its racemates or its optical isomers, or pharmaceutically acceptable salts and / or hydrates

where R ¹ and R ² have the above meaning; R ¹⁶ is an amino group substituent selected from an acyl group. 10. The pharmaceutical composition according to claim 1 or 3, containing as an active substance an azaheterocyclic compound of the general formula 1.2.1.7 or its racemates or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates

where R ¹ and R ² have the above meaning; R ¹⁷ is an amino substituent selected from an acyl group. 11. The pharmaceutical composition according to claim 1, containing as an active substance 2- [6-methyl-4-oxo-5- (4-pyrimidin-2-yl-piperazin-1-sulfonyl) -4H-thieno [2,3 -d] pyrimidin-3-yl] -acetamide of the general formula 1.3.1.1 or its racemates or its optical isomers, or its pharmaceutically acceptable salts and / or hydrates

where R ¹⁸ and R ¹⁹ have the above meaning. 12. A method of obtaining a pharmaceutical composition according to any one of claims 1 to 11 by mixing the active substance with excipients and / or diluents inert with respect to the active substance, followed by tableting, granulation, encapsulation, suspension, dissolution or dilution and placing in a suitable packaging, characterized in that any of the azaheterocyclic compounds of the general formula 1.1.1, 1.2.1, 1.3.1 or their racemates or their optical isomers, or their pharmaceutically acceptable salts, are used as the active substance and / or hydrates. 13. The use of the pharmaceutical composition according to any one of claims 1 to 11 for the preparation of drugs for the treatment and prevention of diseases associated with increased activation of adrenocorticotropic hormone (ACGT). 14. A method of treating and preventing the development of various diseases of warm-blooded animals and people associated with increased activation of adrenocorticotropic hormone (ACTH) by administering to the warm-blooded animal or human a pharmaceutical composition according to any one of claims 1 to 11. 15. The use of physiologically active azaheterocyclic compounds of the formula 1.1.1, 1.2.1 or 1.3.1, or their racemates or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates of claim 1, having properties to inhibit the MC2R receptor, in the preparation of drugs for the treatment and / or prevention of diseases associated with increased activation of adrenocorticotropic hormone (ACTH), or for experimental studies of in vitro or in vivo processes associated with increased activation of adrenocorticotropic mountains Mona (ACTH), as a "pharmacological tool."

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