Azaheterocycles comprising fragment of piperidin-2-yl- focused libraries and pharmaceutical compositions

FIELD: organic chemistry, medicine, pharmacy.

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

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

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

 

This invention relates to the synthesis of new chemicals, the search for new physiologically active substances, compounds leaders and drug candidates that can be derived from the combinatorial or screening of focused libraries of compounds, and to pharmaceutical compositions, methods for their preparation and use.

More specifically, the present invention relates to azaheterocycles, including 3-(piperidine-2-yl)-pyridine fragment, in the form of the individual enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, oxides or hydrates of considerable interest as a potential physiologically active substance, to the focused library and pharmaceutical compositions comprising these compounds, to processes for their preparation and use.

There are a large number of physiologically active compounds leaders and medicine, the molecules of which consist of both pyridine and piperidinyl fragments. Among them a significant number of compounds are potential agonists, antagonists and modulators of nicotinic receptors. Although biological target, which are 2-heterocyclyl-piperidine, very diverse. This receptors (dopamine, acetylcholine, serotonin etc), enzymes (retamosa, glucosidase, acetylcholinesterase and so on), ion channels (e.g., sodium), etc.

Given the high potential physiological activity of substituted piperidino, it is important to develop new compounds of this type, and pharmaceutical compositions comprising these compounds, methods for their preparation and use.

As a result of research aimed at finding new physiologically active substances, compounds leaders, inventors received previously unknown azaheterocycle, including 3-(piperidine-2-yl)-pyridine fragment, in the form of the individual enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, oxides or hydrates, which possess physiological activity, has developed a pharmaceutical composition comprising these compounds, and proposed methods for their preparation and use.

It is known that compounds containing interconnected pyridine and piperidinyl cycles, have various physiological activities. So, nicotinic agonists are the alkaloid anabasine or 2-(3-pyridinyl)-piperidine [.Ghelardini, P.C.Lazareno, D.Wilkison, B.Collins - Pharmacol. Res., 1995, 31(Suppl.), p.51] and 2-(3-pyridyl)Hinkley [M. Bencherif, P.M. Lippiello, W.S. - Pat. Intern. WO 9607410, 1996; Drug Data Rep. 1998, 20(6), p.555], is presented below:

Substituted 4-(4-pyridyl)piperidine, made the Lenna below, shows high inhibitory activity against lanosterol synthesis, which ensures its antiatherosclerotic and hypocholesterolemic effect [AstraZeneca plc. EP 0966462, December 29, 1999]

Heterogeneously 4-(piperidine-3-yl)-pyridine, shown below, is a highly effective inhibitor of Kappa b kinase (IKK-beta), a very promising potential treatment for a wide range of allergic and inflammatory diseases [Bayer AG, US 6562811, May 13, 2003]. Spiro-piperidine derivative represented below, is effectivnes and selektivnym an antagonist of the chemokine MCP-1 receptor, which allows to consider it as a tool for the prevention and treatment of chronic inflammatory processes (atherosclerosis, etc.) [Daiichi Pharmaceutical Co., Ltd. WO 0157044, August 9, 2001]

It should be noted that we only know a few substituted, annelated, and heteroarylboronic 3-(piperidine-2-yl)-pyridines, basically it is a direct derivative of nicotinic agonist of anabasine, presented in the Table. It should be noted, however, that the replacement and minor variations in the structure of 3-(piperidine-2-yl)-pyridines can lead to a complete loss of affinity to the nicotinic receptor and the acquisition of new pharmacological properties. T is to, the substance obtained by the alkylation piperidino cycle of anabasine (shown below), shows properties of highly effective ligand dopamine D3 and D4 receptors [Mach R. et al. Bioorg.Med.Chem. 2003, 11(2):225-234]. Annulirovano derived anabasine is an antagonist of aldosterone [Yamanouchi Phannaceutical Co., Ltd. JP 1997071586, March 18, 1997].

Table

Known 3-(piperidine-2-yl)-pyridine
No.FormulaLiterature
1C. Ghelardini, P..Lazareno, D.Wilkison, B.Collins. Pharmacol. Res., 1995, 31 (Suppl.), p.51.
2Kurbatov; Zalyalieva. Chem. Heterocycl. Compd. 1977, 13, 1227.
3Prokai-Tatrai, K.; Zaltewicz J.A.; Rtm, W.R. Tetrahedron 1994, 50(33). 9909-9918.
4Prokai-Tatrai, K.; Zaltewicz J.A.; Rtm, W.R. Tetrahedron 1994, 50(33), 9909-9918.
5Kabatschnik; Kaznel'son. Zh. Obshch. Khim. 1935, 5,1289,1295, 1296; Chem. Zentralbl. 1936, 107(1), 3339.

Menschikoff et al. Chem. Ber. 1934, 67, 289, 290.
6
7Kabatschnik; Kaznel'son. Zh. Obshch. Khim. 1935, 5, 1289,1295, 1296; Chem. Zentralbl. 1936, 107(1), 3339.
8Menschikoff et al. Chem. Ber. 1934, 67, 289,290. Kabatschnik; Sizer. Zh. Obshch. Khim. 1940, 70, 1007, 1010, 1296; Chem. Zentralbl. 1941, 107(1), 781.
9Kabatschnik; Sizer. Zh. Obshch. Khim. 1940, 70, 1007, 1010, 1296; Chem. Zentralbl. 1941, 107(1), 781.
10Kabatschnik; Sizer. Zh. Obshch. Khim. 1940, 70,1289,1295,1296; Chem. Zentralbl. 1941, 107(1), 781.
11Otroschtschenko et. al. Uzb. Khim. Zh. 1974,18(5), 41.
12Leete. J. Org. Chem. 1979, 44, 165-167.
13F. Galinovsky; Sparatore F.; Langer H. Vonat. Monatsh. Chem. 1956, 87,100, 103.
14Wanner M.J.; Roomen G.-J. J. Org. Chem. 1996, 61(16), 5581-5586.

15Sworykina et al. Izv. Akad. Nauk SSSR Ser. Khim. 1958, 770
16Orechoff; Norkina. Chem. Ber. 1932, 65, 72, 726.
17Katznelson; Kabatschnik. Chem. Ber. 1935, 68, 1247, 1250.
18Kabatschnik; Sizer. Zh. Obshch. Khim. 1940, 70, 1007,1010,1296; Chem. Zentralbl. 1941, 107(1), 781
19Kabatschnik; Sizer. Zh. Obshch. Khim. 1940, 70, 1007, 1010, 1296; Chem. Zentralbl. 1941, 107(1), 781.
20Kabatschnik; Sizer. Zh. Obshch. Khim. 1940, 70,1007,1010,1296; Chem. Zentralbl. 1941, 107(1), 781.
21Kabatschnik; Sizer. Zh. Obshch. Khim. 1940, 70, 1007, 1010, 1296; Chem. Zentralbl. 1941, 107(1), 781.
22Kabatschnik; Kaznel'son. Zh. Obshch. Khim. 1935, 5, 1289,1295,1296; Chem. Zentralbl. 1936, 107(1), 3339.
23Kabatschnik; Sizer. Zh. Obshch. Khim. 1940, 70,1289,1295, 1296; Chem. Zentralbl. 1941, 107(1), 781.
24Chromow-Borisow; Watkina. Zh. Obshch. Khim. 1957, 27, 695, 697.
25Otroschtschenko et al. Uzb. Khim. Zh. 1974, 18(5), 41.

26Menschikoff et al. hem. Ber.1934,67, 289,290. Katznelso; Kabatschnik. Zh. Obshch. Khim. 1934, 4, 552, 554; Bull. Soc. Chim. Fr. 1935, 2, 521, 523, 576, 579.
27Mukhamedzhanov et al. Chem. Nat. Compd. 1968, 4, 136; Khim. Prir. Soedin. 1968, 4, 158.
28Katznelson; Kabatschnik. Chem. Ber. 1935, 68, 1247, 1250.
29Kabatschnik; Kaznel'son. Chem. Ber. 1935, 68, 399,402; Zh. Obshch. Khim. 1935, 5, 1289, 1295, 1296; Chem. Zentralbl. 1936, 107(1), 3339. Chalezkii; Gurewitsch. Zh. Obshch. Khim. 1954, 24, 369, 371.
30Kabatschnik; Kaznel'son. Chem. Ber. 1935, 68, 399, 402; Zh. Obshch. Khim. 1935, 5, 1289,1295, 1296; Chem. Zentralbl. 1936, 107(1), 3339. Chalezkii; Gurewitsch. Zh. Obshch. Khim. 1954, 24, 369, 371.
31Menschikoff et al. Chem. Ber. 1934, 67, 1398,1400. Kabatschnik; Kaznel'son. Chem. Ber. 1935, 68, 399, 402; Zh. Obshch. Khim. 1935, 5, 1289, 1295, 1296; Chem. Zentralbl. 1936, 107(1), 3339.
32Orechoff; Norkina. Chem. Ber. 1932, 65, 724, 726.
33Uzbek chem. W. 1963, 7(4), 64-67. Chem.Abstr. 59:15281(g-h)
34Uzbek chem. W. 1963, 7(4), 64-67. Chem.Abstr. 59:15281(g-h)

35 Patent US 5594011, 1997; US Patent 5677459, 1997; US Patent 5703100, 1997; US Patent 5723477, 1998; US Patent 5705512, 1998.
36Patent US 5594011, 1997; US Patent 5677459, 1997; US Patent 5703100, 1997; US Patent 5723477, 1998; US Patent 5705512, 1998.
37Patent US 5594011, 1997; US Patent 5677459, 1997; US Patent 5703100, 1997; US Patent 5723477, 1998; US Patent 5705512, 1998.
38Patent US 5594011, 1997; US Patent 5677459, 1997; US Patent 5703100, 1997; US Patent 5723477, 1998; US Patent 5705512, 1998.
39Patent US 5276043,1994. WO 92/15306, 1992. WO 94/05288, 1994

Below are definitions of terms used in the description:

"Combinatorial library" means a collection of compounds obtained by parallel synthesis, designed to search for a leader or optimize the biological activity of lead compounds, with each compound of the library meets the General scaffold and the library is a collection of related homologues or analogues.

"Focused library" means a combinatorial library, or a combination of several combinatorial library, or a set of libraries and substances, specially organized for the purpose of increasing the likelihood between the Denia 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).

"Lead compound" means a compound with outstanding activity related to a particular disease.

"Scaffold" means the General structural formula or molecular skeleton, or invariant connections area common to all compounds included in the combinatorial library.

"Gametip" means a series of compounds having a common structural formula and with a certain common property, such as some form fiziologicheskii activity. We can say, for example, "new gametip activators of potassium channels" or "known gametip kinase inhibitors", etc. As a rule, the presence of common structural fragment of compounds within one chemotype is a necessary and sufficient condition for the existence of common properties.

"Deputy" means a chemical moiety or group that is attached to another moiety or group to scaffold, including, but not limited to the halogen atom, the "inert Deputy", the nitrogroup, alphagraph, a sulfa group, hydroxyl group, amino group, carboxialkilnuyu group, alkoxycarbonyl group, to remolina group and others

"Inert Deputy" ("Non-interfering substituent"means low or directionspanel radical inert to further transformations and the environment, including, but not limited to C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C2-C12aralkyl, substituted aralkyl,2-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-C12alkoxyalkyl,2-C10alkylsulfonyl, C2-C10alkylsulfonyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted aryl, substituted alkoxy, foralkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl; where m and n have a value from 1 to 7. Preferred inert substituents are C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted aryl, heterotic the silt and substituted heterocyclyl.

"Electrophilic Deputy" means a chemical moiety that is attached to scaffold as a result of reaction with an electrophilic reagent, for example, selected from the group of organic halides (optionally substituted C1-C7alkyl halides, optionally substituted aryls1-C7alkyl halides, optionally substituted heterocyclyl1-C7alkyl halides, optionally substituted aryl halides, optionally substituted heterocyclyl halides), organic acids or their derivatives (anhydrides, imidazolides, halides, esters of organic sulfonic acids or organic sulfochlorides, organic halogenfree, organic isocyanates and organic isothiocyanatobenzene.

"NH-Protective Deputy" 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, tre is 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 "NH-Protective substituents" described in the book: Protective groups in jrganic synthesis, Third Edition, T.W. Greene and P.G.M. Wuts 1999, p.494-653. Publisher John Wiley & Sons, Inc., New York, Chichester, Weinheim, Brisbane, Toronto, Singapore.

"Substituted group, substituted radical or scaffold" means respectively the group, the radical or scaffold, have a Deputy, including, but not limited to inert Deputy, a halogen atom, a nitro-group, cyano, alphagraph, hydroxyl group, amino group, carboxialkilnuyu group, carboxyl group, carnemolla group, for example, substituted alkyl means alkyl with one or more substituents, such as hydroxyalkyl or methoxycarbonylethyl, amino-methoxycarbonyl-methyl, dimethylaminoethyl, 2-hydroxy-2-methoxycarbonyl-ethyl and others; substituted amino group means an amino group, which have one or two substituent, such as alluminare, N,N-dialkylamino group, N-acyl-N-aryl-amino group, acetyl-methoxycarbonylmethyl-amino group and others; substituted phenyl means phenyl, which has one or more Vice is her for example, 2-ethoxycarbonylphenyl, 4-amino-3-ethoxycarbonylphenyl, 3,4-diaminophenyl and other

"Optionally substituted group optionally substituted radical or scaffold" means respectively the group, the radical or scaffold, including groups, radicals or scaffold with deputies and without deputies. For example, the concept of optional substituted amino group includes an unsubstituted amino group and amino group containing any, not inconsistent with chemistry substituents, including, but not limited to acylamino group, N,N-dialkylamino groups, N-acyl-N-aryl-amino group, acyl-methoxycarbonylmethyl-amino group and others

"Aryl" means one or more aromatic cycles, each of which contains 5 or 6 carbon atoms. "Aryl" may be condensed political, such as naphthalene, or unfused, such as biphenyl. "Substituted aryl" has one or more "not interfering" deputies.

"Halogen" means fluorine atom, chlorine, bromine or iodine.

"Heterocycle" means one or more saturated or aromatic cycles with 5, 6 or 7 atoms, at least one of which is a heteroatom. Preferred heteroatoms are sulfur, oxygen and nitrogen. "Heterocycle" may be condensed political, such as benzimidazole, benzoxazole, benzthiazole, quinoline, or some of denserank, for example, as bipyridyl.

"Azaheterocycle" means a heterocycle comprising at least one nitrogen atom, such as benzimidazole, benzoxazole, benzthiazole, quinoline.

"Substituted heterocycle" means a heterocycle having one or more "not interfering" deputies.

"Condensed system" means a system of condensed cycles, such as benzimidazole, acridine or tetraline.

"Annelirovannymi cycle" or "condensed cycle" means a bi - or polycyclic system, where the "condensed" cycle and (poly)cycle, with whom he "annylirovan have at least two common atom.

"Heterogeneously cycle" means a cycle, which is attached ("Anneliese" or "condensed") to the other (poly)cycle and contains at least one heteroatom.

"Parallel synthesis" means a method for chemical synthesis of combinatorial libraries of individual connections.

The aim of the present invention are new azaheterocycle, including 3-(piperidine-2-yl)-pyridine fragment.

This goal is achieved azaheterocycle, including 3-(piperidine-2-yl)-pyridine fragment of General formula 1

in the form of the individual enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, oxides or igrati, in which R1represents a hydrogen atom, an inert Deputy or NH-protective Deputy, and W represents an optionally substituted azaheterocyclic, such as: pyridine-3-yl, pyrazolo[1,5-a]pyridine-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-9-yl, imidazo[1,2-a]pyrimidine-6-yl, imidazo[1,2-a]pyrimidine-8-Il or [1,8]naphthiridine-3-yl, except 5-bromo-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, 5-(4-forfinal)-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, and compounds in which W represents an unsubstituted pyridin-3-yl, unsubstituted pyridin-3-yl 1-oxide, alkyl substituted pyridine-3-yl, halogen-substituted pyridin-3-yl, 2-methylpyridin-3-yl, 2-carboxymethylamino-3-yl, optionally substituted on the nitrogen atom of the amino group of 2-aminopyridine-3-yl, 3-herperidin-5-yl, 5-(4-forfinal)-pyridine-3-yl, 3-ethoxycarbonylpyrimidine-5-yl, 3-piperidine-2-yl-pyridine-5-yl, 2-chloropyridin-5-yl, 2-methylpyridin-5-yl, 2-methoxypyridine-5-yl, [2,3']bipyridine-5-yl, optionally substituted on the nitrogen atom of the amino group of 2-aminopyridine-5-yl, 2-amino-3-nitropyridine-5-yl, 1-amino-pyridine-3-Ilium, 1-methyl-2-oxo-1H-pyridine-5-yl, 5-bromo-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, 5-(4-forfinal)-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, 7-(1-methylpiperidin-2-yl)-pyrido[1,2-a]pyrimidine-2,4-dione, 9-(1-methylpiperidin-2-yl)-pyrido[1,2-a]pyrim the Dean-2,4-dione.

Among the compounds of General formula 1, comprising one of the objects of the present invention, preferred are 1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl General formula 1.1 or 1.2

in the form of the individual enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, oxides or hydrates, in which R1has the above meaning, R2represents a hydrogen atom, halogen atom, optionally substituted will hydroximino group, optionally substituted mercapto group or an optionally substituted an amino group, and R3represents a halogen atom, formyl group, carboxyl group, optionally substituted allyloxycarbonyl group, optionally substituted aminocarbonyl group, optionally substituted by an aminomethyl group optionally substituted phenyl, optionally substituted aryl or optionally substituted heterocyclyl.

Among the compounds of General formula 1, comprising one of the objects of the present invention, preferred are 1,2,3,4,5,6-1 N-hexahydro-[2,3'] bipyridinyl General formula 1.3 and 1.4

in the form of the individual enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, oxides or igrati, in which R1and R3have the above value, a R4represents a hydrogen atom, an inert Deputy or electrophilic Deputy.

Among the compounds of General formula 1, comprising one of the objects of the present invention, are preferred piperidine-2-yl-pyrazolo[1,5-a]pyridine General formula 1.5 and 1.6

in the form of the individual enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, oxides or hydrates, in which R1and R3have the above significance, and R5and R6independently of one another represent optionally substituted hydroxyl group, optionally substituted by an amino group, or R5and R6together with the carbonyl group to which they are attached, and together with the carbon atoms to which is attached a carbonyl group, form an optionally substituted on the nitrogen atom of pyrrolidine-2,5-dione.

Among the compounds of General formula 1, comprising one of the objects of the present invention, are preferred piperidine-2-yl-pyrido[1,2-a]pyrimidines of General formula 1.7 and 1.8

in the form of the individual enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, oxides or g shall include, in which R1, R3and R5have the above value.

Among the compounds of General formula 1, comprising one of the objects of the present invention, preferred are 3-piperidine-2-yl-[1,8]naphthirydines General formula 1.9

in the form of the individual enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, oxides or hydrates, in which R1have the above significance, and R7and R8together with the carbon atoms to which they are attached, form an optionally substituted heterocyclic or aromatic cycle.

Among the compounds of General formula 1, comprising one of the objects of the present invention, are preferred piperidine-2-yl-imidazo[1,2-a]pyridine General formula 1.10 and 1.11

in the form of the individual enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, oxides or hydrates, in which R1and R3have the above significance, and R9and R10independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted carboxyl group, optionally substituted carbamoyl is the group or optionally substituted by an amino group.

The aim of the present invention are focused library to search for biologically active compounds leaders.

This goal is achieved by the focused library that includes at least one azaheterocycle General formula 1 or pharmaceutically acceptable salt, N-oxide or hydrate, except 5-bromo-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, 5-(4-forfinal)-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine and compounds in which W represents an unsubstituted pyridin-3-yl, unsubstituted pyridin-3-yl 1-oxide, alkyl substituted pyridine-3-yl, halogen substituted pyridine-3-yl, 2-methylpyridin-3-yl, 2-carboxymethylamino-3-yl, optionally substituted on the nitrogen atom of the amino group of 2-aminopyridine-3-yl, 3-herperidin-5-yl, 5-(4-forfinal)-pyridine-3-yl, 3-ethoxycarbonylpyrimidine-5-yl, 3-piperidine-2-yl-pyridine-5-yl, 2-chloropyridin-5-yl, 2-methylpyridin-5-yl, 2-methoxypyridine-5-yl, [2,3']bipyridine-5-yl, optionally substituted on the nitrogen atom of the amino group of 2-aminopyridine-5-yl, 2-amino-3-nitropyridine-5-yl, 1-amino-pyridine-3-Ilium, 1-methyl-2-oxo-1H-pyridine-5-yl, 5-bromo-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, 5-(4-forfinal)-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, 7-(1-methylpiperidin-2-yl)-pyrido [1,2-a]pyrimidine-2,4-dione, 9-(1-methylpiperidin-2-yl)-pyrido[1,2-a]pyrimidine-2,4-dione.

The aim of the present invention are but the traveler pharmaceutical composition in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing.

This goal is achieved by a pharmaceutical composition having activity against the action of nicotinic receptor comprising at least one azaheterocycle General formula 1 or pharmaceutically acceptable salt, N-oxide or hydrate, except 5-bromo-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, 5-(4-forfinal)-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine and compounds in which W represents an unsubstituted pyridin-3-yl, unsubstituted pyridin-3-yl 1-oxide, alkyl substituted pyridine-3-yl, halogen substituted pyridine-3-yl, 2-methylpyridin-3-yl, 2-carboxymethylamino-3-yl, optionally substituted on the nitrogen atom of the amino group of 2-aminopyridine-3-yl, 3-herperidin-5-yl, 5-(4-forfinal)-pyridine-3-yl, 3-ethoxycarbonylpyrimidine-5-yl, 3-piperidine-2-yl-pyridine-5-yl, 2-chloropyridin-5-yl, 2-methylpyridin-5-yl, 2-methoxypyridine-5-yl, [2,3']bipyridine-5-yl, optionally substituted on the nitrogen atom of the amino group of 2-aminopyridine-5-yl, 2-amino-3-nitropyridine-5-yl, 1-amino-pyridine-3-Ilium, 1-methyl-2-oxo-1H-pyridine-5-yl, 5-bromo-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, 5-(4-forfinal)-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, 7-(1-methylpiperidin-2-yl)-pyrido[1,2-a]pyrimidine-2,4-dione, 9-(1-methylpiperidin-2-yl)-pyrido[1,2-a]pyrimidine-2,4-dione.

Biological activity is the efficiency of the synthesized compounds was determined on cells rhabdomyosarcoma, in which nicotinic receptor controls the sodium permeability and, as a result, the cellular transmembrane electrical potential, which, in turn, was measured using a pair of anionic fluorescent probes (DiBAC4(5) and DiBAC4(3)by changing FRET during cell depolarization as described in [I. Okun, A. Okun, G. Kaler Pat. US 6287758, 2001]. Measuring FRET was performed using fluorescent parallel reader VICTOR2V (PerkinElmer, USA) by excitation of the fluorescent donor (DiBAC4(3)) light with a wavelength of 485 nm and measuring the fluorescence intensity of the acceptor (DiBAC4(5)) at a wavelength of 615 nm. When depolarization of the cell membrane as a result of activation of nicotinic receptor efficiency FRET increases, resulting in increase of the fluorescence intensity of the acceptor.

Below the invention is described using the examples of the preparation of specific compounds and focused libraries. The structure of the obtained compounds was confirmed by chromatographic and spectral data analysis.

The following examples illustrate but do not limit the invention.

1-Methyl-1,2,3,4,5,6-hexahydro[2,3']bipyridinyl-6'-ylamine 2.1: white crystals with TPL 96-97°;1H NMR (DMSO-D6): 1.25 (m, 1H), 1.45 (d, 1H), 1.53 (m, 1H), 1.63 (m, 1H), 1.7 (m, 1H), 1.78 (m, 1H), 1.97 (s, 3H), 2.0 (m, 1H), 2.82 (d, 1H), 2.95 (d, 1H), 6.15 (ush is p, 2H), 6.45 (DD, 1H), 7.23 (d, 1H), 7.8 (d, 1H) and 1-methyl-1,2,3,4,5,6-hexahydro[2,3']bipyridinyl-2'-ylamine 2.2: white crystals, TPL 92-94°;1H NMR (DMSO-D6): 1.25-1.75 (m, 6N), 1.85 (s, 3H), 2.0 (TD, 1H), 2.57 (DD, 1H), 2.9 (d, 1H), 5.7 (user s, 2H), 6.4 (d, 1H), 7.27 (DD, 1H), 7.75 (d, 1H) obtained as described in [Sadykov, A. s.. Chemistry of alkaloids Anabasis Aphylla. Academy of Sciences of Uzbekistan, Tashkent -1956, 94-95].

Example 1. 5'-Bromo-1-methyl-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-6'-ylamine 1.1.1(1). Dissolve 5 mmol of 1-methyl-1,2,3,4,5,6-hexahydro[2,3']bipyridinyl-6'-ylamine 2. in 10 ml of 10% H2SO4and 0.5 ml of concentrated HCl. To this solution slowly with stirring was added 5 mmol of bromine. After you have added half bromine, began precipitation, which is slowly dissolved by heating to 50°C. the resulting solution was stirred at 50°1 hour, cooled and maintained at 0°With 24 hours. Then the reaction was poured into an aqueous solution of NaOH. The precipitate was separated and recrystallized from acetonitrile. Get 1.1.1(1), with a yield of 75%,1H NMR (DMSO-d6): 1.25 (m, 1H), 1.33 (m, 1H), 1.5-1.65 (m, 3H), 1.72 (d, 1H), 1.9 (s, 3H), 2.0 (t, 1H), 2.65 (d, 1H), 2.92 (d, 1H), 6.0 (s, 2H), 7.6 (s, 1H), 7.8 (s, 1H). MS (70eV): M+269, 271.

Example 2. 5'-Bromo-1-methyl-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-2' -ylamine 1.2.1(1). To a solution of 5 mmol of 1-methyl-1,2,3,4,5,6-hexahydro[2,3']bipyridinyl-2'-ylamine 2.2 in 15 ml of acetic acid was slowly added bromine (5.2 mmol) at room the Oh temperature. Then the red solution is heated to 50°C and stirred until a yellow color (about 1 hour). The reaction was poured into an aqueous solution of NaOH, precipitated precipitate is filtered off and recrystallized from acetonitrile. Receive 1.2.1(1), yield 70%,1H NMR (DMSO-d6): 1.25 (m, 1H), 1.5-1.75 (m, 5H), 2.0 (m+s, 4H), 2.8-3.0 (m, 2H), 6.5 (s, 2H), 7.4 (s, 1H), 7.9 (s, 1H). MS (70eV): M+269, 271.

Example 3. 5'-Bromo-2-chloro-1-methyl-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl 1.2.2(1). To a solution of 1 mmol of 5'-bromo-1-methyl-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-6'-ylamine 1.1.1(1) in 10 ml of HCl, cooled to -5°C, was added dropwise a solution of NaNO2(1.2 mmol) in 0.5 ml of water. Then stirred at -5°With (1.5 hours), pour the reaction mixture into an aqueous solution of Na2CO3, extracted with ethyl acetate, the extract is dried over Na2SO4and concentrate. The residue is extracted with hot hexane. Hexane extract concentrate, get 1.2.2(1), with a yield of 90%,1H NMR (DMSO-d6): 1.3 (m, 2H), 1.5-1.75 (m, 4H), 2.0 (s, 3H), 2.1 (t, 1H), 3.0 (d, 1H), 3.25 (d, 1H), 8.1 (s, 1H), 8.45 (s, 1H).

Example 4. 5'-Bromo-2-fluoro-1-methyl-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl 1.2.3(1). To a solution of 10 mmol of 5'-bromo-1-methyl-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-6'-ylamine 1.1.1(1) in 20 ml of 65% HF in pyridine at -10°slowly add solid NaNO2(15 mmol) for 1 hour. After stirring for 3 hours at -10°the reaction was poured into cold 20% of odny solution of KOH (300 ml), extracted with ethyl acetate, the extract is dried over Na2SO4and evaporated. The product is subjected to flash chromatography. Get 1.2.3(1), with a yield of 75%,1H NMR (DMSO-d6): 1.3 (m, 2H), 1.4 (m, 1H), 1.5-1.75 (m, 4H), 2.0 (s, 3H), 2.1 (t, 1H), 2.95 (d, 1H), 3.07 (d, 1H), 8.1 (d, 1H), 8.27 (s, 1H).19F NMR (CFCl3): -77.62 (s).

Example 5. 1-Methyl-5'-(2-thienyl)-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-2'-ylamine 1.1.4(1). Added 1 mmol of 5'-Bromo-1-methyl-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-2'-ylamine 1.2.1(1) in 2 ml of THF to a mixture of 1.5 mmol thiophene-2-Bronevoy acid 3.3(1) 3 mmol Na2CO3and 50 mg PdCl2(PPh3)2in 2 ml of water. The resulting mixture was heated 10 min at 130°in a microwave oven. After the alkali treatment and extraction of the solid product was then purified flash chromatography. Get 1.1.4(1) with yields of 80%.1H NMR(DMSO-d6): 1.35 (m, 1H), 1.5-1.6 (m, 2H), 1.67 (m, 1H), 1.8 (m, 2H), 2.05 (m+s, 4H), 2.95 (m, 2H) 6.4 (user s, 2H), 7.1 (t, 1H), 7.25 (d, 1H), 7.4 (d,1H), 7.5 (s, 1H), 8.15 (s, 1H).

Example 6. 1-Methyl-5'-formyl-2-fluoro-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl 1.1.5(1). To a solution of 5 mmol of 5'-bromo-2-fluoro-1-methyl-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl 1.2.3(1) in absolute THF (50 ml) pin at -80°With under argon 6 mmol utility (1.6 M in hexane). The reaction mass was stirred at -80°30 min, and then immediately poured 20 mmol of DMF. The reaction mixture is allowed to warm to room temperature, then poured 50 ml of water, the organic layer Department of the Ute, and the aqueous layer was extracted with ethyl acetate. The organic extracts are combined, dried over Na2SO4, concentrated and the product purified column chromatography. Get 1.1.5(1), exit 85%,1H NMR (DMSO-d6): 1.3-1.45 (m, 2H), 1.5-1.8 (m, 4H), 1.95 (s, 3H), 2.1 (t, 1H), 2.95 (d, 1H), 3.15 (d, 1H), 8.4 (d, 1H), 8.7 (s, 1H), 10.1 (s, 1H).

Example 7. 1-Methyl-5'-(3-phenylpropylamine)methyl-2-fluoro-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl 1.1.7(1). Stirred for 12 hours 1 mmol of 1-methyl-5'-formyl-2-fluoro -1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl 1.1.5(1), 3 mmol of 3-phenylpropylamine and 3 mmol of sodium borohydride in 20 ml of methanol. Then add 20 ml of 10% HCl, the mixture is stirred for 10 min, alkalinized Na2CO3and extracted with ethyl acetate. The product was then purified column chromatography. Get 1.1.7(1), with an output of 60%,1H NMR (DMSO-d6): 1.3 (m, 2H), 1.4 (m, 1H), 1.5-1.75 (m, 4H), 2.0 (s, 3H), 2.1 (t, 1H), 2.45-2.6 (m, 6N), 2.95 (d, 1H), 3.07 (d, 1H), 7.1-7.25 (m, 5H), 7.9 (d, 1H), 8.0 (s, 1H).

Example 8. 1-(1-Methyl-2-fluoro-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-5'-ylmethyl)-3-(4-forfinal)-1-(3-phenylpropyl)-urea 1.1.7(2). Heated in a microwave oven at 160°10 min 0.3 mmol of 1-methyl-5'-(3-phenylpropylamine) methyl-2-fluoro-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl 1.1.7(1) and 0.4 mmol of 4-perteneciente in 3 ml of absolute ethanol. The reaction mass is evaporated and get quantitatively 1.1.7(2), LC-MS: 479 (M+1).

Example 9. 5'-Bromo-1-methyl-1,2,3,4,5,6-hexahydro-1'H-[2,3']bipyridinyl-2'-he 1.4.1(1). RA is Toru 1 mmol of 5'-bromo-1-methyl-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-6'-ylamine 1.1.1(1) in 10 ml of 10% H 2SO4cooled to -5°C, was added dropwise a solution of NaNO2(1.2 mmol) in 0.5 ml of water. Then stirred at -5°With (1.5 hours), pour the reaction mixture into an aqueous solution of Na2CO3, precipitated crystalline product is filtered off. Get 1.4.1(1), exit 65%,1H NMR (DMSO-d6): 1.1-1.3 (m, 2H), 1.5-1.75 (m, 4H), 2.0 (s, 3H), 2.1 (t, 1H), 2.9 (d, 1H), 3.2 (d, 1H), 7.4 (s, 1H), 7.55 (s, 1H), MS (70eV): M+270, 272.

Example 10. 6-(1-Benzoylpiperidine-2-yl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester 1.5.1(1). Dissolved in 20 ml of water, 10 mmol, 97% of hydroxylamine-O-sulfonic acids, 10 mmol of 1-benzoyl-1,2,3,4,5,6-hexahydro-1'H-[2,3']bipyridinyl and 10 mmol of NaOH. The resulting mixture was stirred for 1 hour at 70 to 90°C, cooled to room temperature, add 10 mmol NaHCO3and extracted with ethyl acetate (3×10 ml). Then the aqueous phase is saturated with Na2SO4and again extracted with ethyl acetate. The aqueous phase is evaporated in vacuum at 30°C. To the residue was added 6 ml of absolute ethanol, inorganic precipitate is filtered off, the filtrate is cooled to -20°and added 47% HI (0.72 ml, 4 mmol). The resulting mixture was stirred at -20°30 min, the precipitate is filtered off and washed with 2 ml of cold absolute ethanol. Get 1'-amino-1-benzoyl-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-1'-FMD iodide 2.3(1), with a yield of 40%, LC-MS 282 (M-128). Product is stored at low temperature. To with whom spencie of 10 mmol of compound 2.3(1) and 15 mmol K 2CO3in 50 ml of dry DMF is slowly added 11 mmol ethylpropyl 4.1, the mixture is stirred for 3 hours at room temperature by passing air. The reaction was poured into 200 ml of water, was extracted with ethyl acetate (3×50 ml), the volatiles removed in vacuum and the oily brown residue is purified column chromatography. Get 1.5.1(1), yield 25%,1H NMR (DMSO-d6): 1.35 (t, 3H), 1.55 (m, 3H), 1.7 (m, 1H), 1.95 (m, 1H), 2.5 (m, 1H), 2.85 (m, 1H), 3.5-3.9 (user s, 1H), 4.3 (K, 2H), 5.5-5.9 (broadened, 1H), 7.45 (m, 5H), 7.6 (d, 1H), 8.1 (d, 1H), 8.45 (, 1H), 8.75 (s, 1H).

Example 11. 6-(1-Benzoylpiperidine-2-yl)-pyrazolo[1,5-a]pyridine-2,3-dicarboxylic acid dimethyl ester 1.6.1(1). To a suspension of 10 mmol of compound (2.3) and 15 mmol K2CO3in 50 ml of dry DMF is slowly added 11 mmol of diethylazodicarboxylate 4.2. The mixture is stirred for 7 hours at room temperature before the termination of the allocation of air bubbles. Then it was poured into 200 ml of water, extracted with ethyl acetate (3×50 ml), volatile products are removed under vacuum and the oily brown residue is purified column chromatography. Get 1.6.1(1), yield 25%,1H NMR (DMSO-d6): 1.55 (m, 3H), 1.7 (m, 1H), 1.95 (m, 1H), 2.5 (m, 1H), 2.85 (m, 1H), 3.5-3.9 (user s, 1H), 3.85 (s, 3H), 3.95 (s, 3H), 5.6-5.9 (user s, 1H), 7.45 (m, 5H), 7.65 (d, 1H), 8.1 (d, 1H), 8.75 (s, 1H).

Example 12. 6-Methyl-2-oxo-8-(1-methyl-2-piperidinyl)pyrido[1,2-a]pyrimidine-6-carboxylic sour is and 1.7(1). To a solution of 2 mmol of compound 1.1 (R1=CH3, R2=H) in dry ethyl acetate is slowly added dropwise 2.5 mmol Tarakanova anhydride 4.3 for 2 hours at room temperature. The reaction mass is red and appears dark resinous precipitate. The reaction mass is stirred at room temperature for 48 hours, then concentrated in vacuo and separated on preparative chromatograph (H2O-MeOH-AcOH), there are two diastereomers faction connection 1.7(1) in a 1:1 ratio (total yield 40%) with almost identical NMR spectra.1H NMR (DMSO-d6): 1.3-1.6 (m, 5H), 1.4 (s, 3H), 1.8 (d, 1H), 1.9 (s, 3H), 2.1 (t, 1H), 2.75 (d, 1H). 2.8 (d, 1H), 2.9 (d, 1H), 3.15 (d, 1H), 7.0 (d, 1H), 7.75 (d, 1H), 8.2 (s, 1H).

Example 13. 2-(1-Methyl-piperidine-2-yl)-benzo[C]-[1,8]naphthiridine 1.9(1). To a solution of 3 mmol of Na2CO3and 50 mg PdCl2(PPh3)2in 2 ml of water was added 1.5 mmol of 2-formylphenylboronic acid 4.4(1), and then added 1 mmol of 5'-bromo-1-methyl-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-6'-ylamine 1.1.1(1) in 2 ml of THF. The reaction mass is heated for 10 minutes under stirring in a microwave oven at 130°C. the Solution was poured into an aqueous solution of Na2CO3, extracted with ethyl acetate and subjected to flash chromatography. Get 1.9(1):1H NMR (DMSO-d6): 1.4 (m, 1H), 1.5-1.9 (m, 5H), 2.0 (s, 3H), 2.0 (t, 1H), 3.0 (d, 1H), 3.2 (d, 1H), 7.85 (t, 1H), 8.0 (t, 1H), 8.3 (d, 1H), 8.9 (d, 1H), 9.0 (s, 1H), 9.1 (s, 1H), 9.5 (s, 1H). LCMS: 278 (M+1).

Example 14. 4-(4-shall Romper)-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine 1.10.1(1). To a solution of 1 mmole of compound 1.1 (R1=CH3, R2=H) in 10 ml of absolute ethanol was added 1.1 mmole 4-brompheniramine 4.5(1) and boil the mixture under stirring for 1 hour. After cooling the reaction was poured into an aqueous solution of NaHCO3(100 ml) and extracted with twice 30 ml of ethyl acetate. The extract is dried over Na2SO4and evaporated. The residue is recrystallized from ethyl acetate. Get 1.10.1(1), yield 80%,1H NMR (DMSO-d6): 1.3 (m, 1H), 1.5-1.7 (m, 4H), 1.75 (d, 1H), 1.97 (s, 3H), 2.1 (t, 1H), 2.82 (d, 1H), 2.95 (d, 1H), 7.25 (d, 1H), 7.5 (d, 1H), 7.6 (d, 2H), 7.9 (d, 2H), 8.33 (s, 1H), 8.4 (s, 1H). MS (70 eV) M+369, 371.

Example 15. 7-(1-Methyl-2-piperidinyl)imidazo[1,2-a]pyridine-4-carboxylic acid hydrobromide 1.10.1(2). To a solution of 10 mmol of compound 1.1 (R1=CH3, R2=H) in 100 ml of absolute ethanol was added 11 mmol bronirovochnoy acid 4.5(2) and the resulting mixture is boiled for 3 hours. After cooling, the precipitate is filtered and washed with ethanol. Get 1.10.1(2), yield 70%,1H NMR(D2O): 1.9 (m, 1H), 2.15 (K, 1H), 2.25 (m, 2H), 2.4 (m, 2H), 2.85 (s, 3H), 3.45 (t, 1H), 3.9 (d, 1H), 4.6 (d, 1H), 8.15 (AB, 2H), 8.5 (s, 1H), 9.0 (s, 1H).

Example 16. A General method of obtaining the amides of 7-(1-methyl-2-piperidinyl) imidazo[1,2-a]pyridine-4-carboxylic acid 1.10.1(3-5). Dissolve 1 mmol of hydrogen bromide 7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine-4-carboxylic acid 1.10.1(2), 1.1 mmol POCl3The 1.5 mmol of the corresponding amine 3.8 in 2 ml of dry pridine and heat the mixture for 15 min in a microwave oven at 160° C. the Reaction mass is then cooled, poured into a solution of NaHCO3, extracted with ethyl acetate or methylene chloride, dry the extract over Na2SO4and, if necessary, subjected to flash chromatography or recrystallized from a suitable solvent. Get 1.10.1(3-5), the output of 30-80%, N-propyl-7-(1-methyl-2-piperidinyl)-imidazo[1,2-a]pyridine-4-carboxamide 1.10.1(3):1H NMR (DMSO-d6): 0.9 (t, 3H), 1.35 (m, 1H), 1.45-1.65 (m, 6N), 1.75 (d, 1H), 1.95 (s, 3H), 2.07 (t, 1H), 2.8 (d, 1H), 3.0 (d, 1H), 3.25 (K, 2H), 7.3 (d, 1H), 7.55 (d, 1H), 8.2 (user s, 1H), 8.27 (s, 1H), 8.5 (s, 1H); N-(4-bromophenyl)-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine-4-carboxamide 1.10.1(4):1H NMR (DMSO-d6): 1.35 (m, 1H), 1.45-1.65 (m, 6N), 1.75 (d, 1H), 1.95 (s, MN), 2.07 (t, 1H), 2.8 (d, 1H), 3.0 (d, 1H), 7.3 (d, 1H), 7.5 (d, 2H), 7.6 (d, 1H), 7.9 (d, 2H), 8.45 (s, 1H), 8.55 (s, 1H), 10.3 (user s, 1H); N-(4-methoxybenzyl)-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine-4-carboxamide 1.10.1(5):1H NMR (DMSO-d6): 1.35 (m, 1H), 1.45-1.65 (m, 6N), 1.75 (d, 1H), 1.95 (s, 3H), 2.07 (t, 1H), 2.8 (d, 1H), 2.95 (d, 1H), 3.22 (s, 3H), 4.4 (d, 2H), 6.85 (d, 2H), 7.25 (d, 2H), 7.3 (d, 1H), 7.5 (d, 1H), 8.3 (s, 1H), 8.5 (s, 1H), 8.7 (user s, 1H).

Example 17. A common way to obtain 6-(1-methylpiperidin-2-yl)-imidazo[1,2-a]pyridine-3-ylamino 1.10.2(1-13). Mix 1 mmol of compound 2.1, 1.1 mmol aldehyde 3.9 and 1.1 mmol of isonitrile 3.10 in 5-10 ml of methanol. To the reaction mixture was added 4 mmol of acetic acid and incubated at room temperature for 72 hours. The reaction mixture was poured into an aqueous solution of NaHCO the product is filtered off or extracted with ethyl acetate, and then recrystallized from a mixture of hexane/ethyl acetate, or ethanol. In some cases, use flash chromatography. Get 1.10.2(1-13): 4-(3,4,5-trimethoxyphenyl)-5-cyclooctylamino-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine 1.10.2(1):1H NMR (DMSO-d6): 1.25-1.7 (m, N), 1.8 (d, 1H), 1.95 (s, 3H), 2.1 (t, 1H), 2.85 (d, 1H), 3.0 (d, 1H), 3.7 (s, 3H), 3.85 (s, 6N), 4.65 (s, 1H), 7.15 (d, 1H), 7.4 (d, 1H), 7.5 (s, 2H), 8.4 (s, 1H); 4-(4-methoxycarbonylbenzyl)-5-(1-adamantylamine)-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine 1.10.2(2):1H NMR (DMSO-d6): 1.3-1.75 (m, N), 1.87 (s, 3H), 1.95 (s, 3H), 2.1 (t, 1H), 2.85 (d, 1H), 2.95 (d, 1H), 3.7 (s, 3H), 4.4 (s, 1H), 7.2 (d, 1H), 7.4 (d, 1H), 7.95 (d, 2H), 8.3 (s, 1H), 8.4 (d, 2H); 4-(4-acetamidophenyl)-5-cyclooctylamino-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine 1.10.2(3):1H NMR (DMSO-d6): 1.2-1.7 (m, 20N), 1.77 in (d, 1H), 1.95 (s, 3H), 2.05 (s+m, 4H), 2.8 (d, 1H), 2.95 (d, 1H), 3.15 (m, 1H), 4.6 (s, 1H), 7.15 (d, 1H), 7.4 (d, 1H), 7.6 (d, 2H), 8.05 (d, 2H), 8.15 (s, 1H), 9.9 (s, 1H); 4-(4-hydroxy-3,5-di-tert-butylphenyl)-5-cyclooctylamino-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine 1.10.2(4):1H NMR (DMSO-d6): 1.2-1.7 (m, N), 1.77 in (d, 1H), 1.95 (s, 3H), 2.05 (m, 1H), 2.8 (d, 1H), 2.95 (d, 1H), 3.15 (m, 1H), 4.4 (s, 1H), 6.85 (s, 1H), 7.1 (d, 1H), 7.4 (d, 1H), 7.9 (s, 2H), 8.15 (s, 1H). MS (70eV) M+544; 4-(4-hydroxyphenyl)-5-cyclooctylamino-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine 1.10.2(5):1H NMR (DMSO-d6): 1.2-1.7 (m, N), 1.77 in (d, 1H), 1.95 (s, 3H), 2.1 (t, 1H), 2.8 (d, 1H), 2.95 (d, 1H), 3.15 (m, 1H), 4.5 (s, 1H), 6.8 (d, 2H), 7.1 (d, 1H), 7.35(d, 1H), 7.95 (d, 2H), 8.1 (s, 1H), 9.3 (s, 1H). MS (70eV) M+432; 4-(3,4-dihydroxyphenyl)-5-cyclooctylamino-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine 1.10.2(6):1H NMR (DMSO-d6): 1.2-1.7 (m, N), a 1.75 (d, 1H), 1.95 (s, 3H), 2.1 (t, 1H), 2.8 (d, 1H), 2.95 (d, 1H), 3.15 (m, 1H), 4.4 (s, 1H), 6.5 (d, 1H), 7.1 (d, 1H), 7.35 (d, 1H), 7.45 (d, 1H), 7.6 (s, 1H), 8.1 (s, 1H), 8.7 (broadened s, 2H). MS (70eV) M+448; 4-(4-hydroxy-3,5-di-trnt-butylphenyl)-5-(1-adamantylamine)-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine 1.10.2(7);1H NMR (DMSO-d6): 1.2-1.7 (m, N), 1.77 in (d, 1H), 1.8 (s, 3H), 1.95 (s, 3H), 2.05 (m, 1H), 2.8 (d, 1H), 2.95 (d, 1H), 4.3 (s, 1H), 6.8 (s, 1H), 7.1 (d, 1H), 7.4 (d, 1H), 8.1 (s, 2H), 8.25 (s, 1H). MS (70eV) M+568; 4-(4-hydroxyphenyl)-5-(1-adamantylamine)-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine 1.10.2(8):1NAMR (DMSO-d6): 1.2-1.7 (m, 17H), 1.77 in (d, 1H), 1.85 (s, 3H), 1.95 (s, 3H), 2.08 (t, 1H), 2.82 (d, 1H), 2.95 (d, 1H), 4.4 (s, 1H), 6.75 (d, 2H), 7.1 (d, 1H), 7.32 (d, 1H), 8.0 (d, 2H), 8.25 (s, 1H), 9.3 (s, 1H). MS (70eV) M+456; 4-(3,4-dihydroxyphenyl)-5-(1-adamantylamine)-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine 1.10.2(9):1H NMR (DMSO-d6): 1.2-1.7 (m, 17H), 1.77 in (d, 1H), 1.9 (s, 3H), 1.98 (s, 3H), 2.08 (t, 1H), 2.82 (d, 1H), 2.95 (D. 1H), 4.3 (s, 1H), 6.7 (d, 1H), 7.1 (d, 1H), 7.35 (d, 1H), 7.45 (d, 1H), 7.6 (s, 1H), 8.25 (s, 1H), 8.7 (broadened s, 2H). MS (70eV) M+472; 4-(N-ethylcarbazole-3)-5-cyclooctylamino-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine 1.10.2(10):1H NMR (DMSO-d6): 1.2-1.7 (m, 22N), 1.77 in (d, 1H), 1.95 (s, 3H), 2.1 (t, 1H), 2.8 (d, 1H), 2.95 (d, 1H), 3.2 (m, 1H), 4.45 (K, 2H), 4.6 (d, 1H), 7.15 (d, 1H), 7.2 (t, 1H), 7.45 (m, 2H), 7.6 (m, 2H), 8.15 (d, 1H), 8.2 (s, 1H), 8.33 (d, 1H), 8. (s, 1H). MS (70eV) M+533; 4-(4-cyanophenyl)-5-propylamino-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine 1.10.2(11):1H NMR (DMSO-d6): 0.9 (t, 3H), 1.3 (m, 1H), 1.5-1.7 (m, 6N), 1.77 in (d, 1H), 1.95 (s, 3H), 2.1 (t, 1H), 2.8-3.0 (m, 4H), 4.95 (t, 1H), 7.2 (d, 1H), 7.45 (d, 1H), 7.85 (d, 2H), 8.2 (s, 1H), 8.3 (d, 2H); 4-isopropyl-5-propylamino-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine 1.10.2(12):1H NMR (DMSO-d6): 0.9 (t, 3H), 1.2 (d, 6N), 1.3-1.7 (m, 7H), 1.77 in (d, 1H), 1.95 (s, 3H), 2.1 (t, 1H), 2.8-3.0 (m, 4H), 3.15 (m, 1H), 4.45 (t, 1H), 7.05 (d, 1H), 7.3 (d, 1H), 8.0 (s, 1H); 4-(4-tolyl)-5-propylamino-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine 1.10.2(13):1H NMR (DMSO-d6): 0.9 (t, 3H), 1.3 (m, 1H), 1.5-1.7 (m, 6N), a 1.75 (d, 1H), 1.95 (s, 3H), 2.1 (t, 1H), 2.32 (s, 3H), 2.8-2.9 (m, 3H), 2.96 (d, 1H), 4.7 (t, 1H), 7.15 (d, 1H), 7.25 (d, 2H), 7.4 (d, 1H), 8.0 (d, 2H), 8.15 (s, 1H).

Example 18. A common way to obtain N-[6-(1-methylpiperidin-2-yl)-imidazo [1,2-a]pyridine-3-yl]-acetamide and their analogues 1.10.2(14-18). Heat 0.5 mmol amine 1.10.2(1-13) and 1 mmol of the appropriate acid chloride, anhydride, isocyanate or isothiocyanate in 2.5 ml of dry dioxane or THF for 10 min in a microwave oven at 170°C. the Reaction was poured into an aqueous solution of NaHCO3, extracted several times with ethyl acetate and subjected to flash chromatography. Get 1.10.2(14-18), with a yield of 60-80%: N-TRIFLUOROACETYL-N-propyl-4-(4-tolyl)-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine-5-amine 1.10.2(14):1H NMR (DMSO-d6): 0.9 (t, 3H), 1.3-1.7 (m, 7H), of 1.75 (d, 1H), 1.95 (2s, 3H), 2.1 (m, 1H), 2.32 (s, 3H), 3.0 (m, 2H), 3.6 (m,1H), 3.9 (m, 1H), 7.25 (d, 2H), .4 (d, 1H), 7.6 (d, 1H), 7.75 (d, 2H), 8.4 (s, 1H); N-acetyl-N-propyl-4-(4-tolyl)-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine-5-amine 1.10.2(15);1H NMR (DMSO-d6): 0.9 (t, 3H), 1.3-1.7 (m, 11N), 1.95 (2s, 3H), 2.1 (t, 1H), 2.32 (s, 3H), 3.0 (m, 2H), 3.4 (m, 1H), 3.75 (m, 1H), 7.25 (d, 2H), 7.4 (d, 1H), 7.6 (d, 1H), 7.75 (d, 2H), 8.1 (s, 1H); N-(4-tortenelmebol)-N-propyl-4-(4-tolyl)-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine-5-amine 1.10.2(16):1H NMR (DMSO-d6): 0.9 (t, 3H), 1.3-1.7 (m, 7H), 1.78 (d, 1H), 1.95 (s, 3H), 2.05 (m, 1H), 2.32 (s, 3H), 2.9 (m, 2H), 3.4 (m,1H), 3.7 (m, 1H), 7.0 (t, 2H), 7.25 (d, 2H), 7.35 (m, 3H), 7.6 (d, 1H), 7.75 (m, 2H), 7.95 (d, 1H), 8.6 (s, 1H); N-benzoyl-N-propyl-4-(4-tolyl)-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine-5-amine 1.10.2(17):1H NMR (DMSO-d6): 0.9 (t, 3H), 1.3-1.7 (m, 7H), 1.75 (d, 1H), 1.85 and 1.95 (2s, 3H), 2.05 (m, 1H), 2.3 (s, 3H), 3.0 (m, 2H), 3.5 (m, 1H), 4.1 (m, 1H), 6.95 (m, 2H), 7.15 (m, 3H), 7.25 (t, 1H), 7.3 (m, 2H), 7.4 (m, 1H), 7.8 (m, 2H), 8.1 (s, 1H). MS (70 eV) M+466; N-(4-tortenelmebol)-N-propyl-4-isopropyl-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine-5-amine 1.10.2(18): 0.9 (t, 3H), 1.2-1.75 (m, 11N), 1.95 (2s, 3H), 2.1 (t, 1H), 2.8-3.0 (m, 3H), 3.4 (m,1H), 3.6 (m, 1H), 7.0 (t, 2H), 7.25 (d, 1H), 7.35 (m, 2H), 7.5 (d, 1H), 7.9 (d, 1H), 8.25 (s, 1H).

Example 19. 7-(1-Methyl-2-piperidinyl)imidazo [1,2-a]pyridine-5-carboxylic acid hydrobromide 1.11.1(1). To a solution of 10 mmol of compound (1.2: R1=CH3, R2=H) in 100 ml of absolute ethanol was added 11 mmol bronirovochnoy acid 4.5(2), boiled for 3 hours, cooled and evaporated, then the residue is again dissolved in 25 ml of MeCN/MeOH 1:1 and incubated obtained the solution for 12 hours at 0° C. the Precipitate is filtered and washed with ethyl acetate. Get 1.11.1(1), exit 77%,1H NMR (DMSO-d6): 1.7 (m, 1H), 1.95-2.0 (m, 5H), 2.15 (m, 1H), 2.3 (s, 3H), 3.6 (d, 1H), 4.9 (d, 1H), 7.1 (DD, 1H), 7.7 (d, 1H), 8.6 (s, 1H), 8.63 (d, 1H), 9.6 (user s, 1H), 12.8 (user s, 1H).

Example 20. A common way to obtain amides of 7-(1-methyl-2-piperidinyl) imidazo[1,2-a]pyridine-5-carboxylic acid 1.11.1(2-3). Dissolve 1 mmol of compound 1.11.1(1), 1.1 mmol POCl3and 1.5 mmol of the corresponding amine 3-8 in 2 ml of dry pyridine and heated the mixture for 15 min in a microwave oven at 160°C. the Reaction mass is then cooled, poured into an aqueous solution of NaHCO3, extracted with ethyl acetate or methylene chloride, dried over Na2SO4and subjected to flash chromatography. Get 1.11.1(2-3), with the release of 30-80%: N-propyl-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine-5-carboxamide 1.11.1(2):1H NMR (DMSO-d6): 0.9 (t, 3H), 1.35-1.85 (m, 8H), 2.0 (s, 3H), 2.2 (t, 1H), 3.0 (d, 1H), 3.25 (K, 2H), 3.7 (d, 1H), 6.95 (DD, 1H), 7.3 (d, 1H), 8.2 (user s, 1H), 8.27 (s, 1H), 8.4 (d, 1H); N-phenethyl-7-(1-methyl-2-piperidinyl)imidazo[1,2-a]pyridine-5-carboxamide 1.11.1(3):1H NMR (DMSO-d6): 1.3-1.5 (m, 2H). 1.6-1.85 (m, 4H), 2.0 (s, 3H), 2.15 (t, 1H), 2.9 (t, 2H), 3.0 (d, 1H), 3.5 (K, 2H), 3.7 (d, 1H), 6.95 (DD, 1H), 7.2-7.35 (m, 6N), 8.2 (user t, 1H), 8.37 (s, 1H), 8.45 (d, 1H)

Example 21. In accordance with this invention is a method of obtaining 5'-bromo-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-6'-ylamino or mixtures thereof of the General formula 1.1.1 and 5'-bromo-1,2,3,4,5,6-hexahydro-[2,3']piperidin the l-2'-ylamino or mixtures thereof of the General formula 1.2.1 is the action of bromine (3.1 respectively 1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-6'-aluminum 2.1 or 1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-2'-aluminum 2.2 scheme 1

in which R1has the above value.

In accordance with this invention is a method of obtaining 5'-bromo-6'-chloro-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl General formula 1.1.2 and enantiomeric 5'-bromo-2'-chloro-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl or mixtures thereof of the General formula 1.2.2 is the action of sodium nitrite 3.2 in the presence of hydrochloric acid, respectively, 5'-bromo-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-6'-Illuminati 1.1.1 or 5'-bromo-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-2'-Illuminati 1.2.1 scheme 2

in which R1has the above value.

In accordance with this invention is a method of obtaining 5'-bromo-6'-fluoro-1,2,3,4,5,b-hexahydro-[2,3']bipyridinyl or General formula 1.1.3 and enantiomeric 5'-bromo-2'-fluoro-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl or mixtures thereof of the General formula 1.2.3 is the action of sodium nitrite 3.2 in the presence of HF at respectively 5'-bromo-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-6'-Illuminati 1.1.1 or 5'-bromo-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-2'-Illuminati 1.2.1 scheme 3

in which R1has the above value.

In accordance with this invention is a method of obtaining substituted 1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl General formula 1.1.4 lies in the interaction in the presence of the palladium is on catalyst corresponding bromo-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl 1.1.2, 1.1.3, 1.2.2 or 1.2.3 with boric acid 3.3 or [1,3,2]dioxaborolane 3.4 scheme 4

in which: R1and R2have the above value, a R3arepresents optionally substituted phenyl, optionally substituted aryl or optionally substituted heterocyclyl.

In accordance with this invention is a method of obtaining 5'-formyl-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl General formula 1.1.5 is consistent effect on the corresponding bromo-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl 1.1.2, 1.1.3, 1.2.2 or 1.2.3 butyllithium 3.5, and then dimethylformamide 3.6 scheme 5

in which: R1and R2have the above value.

In accordance with this invention is a method of obtaining 1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-5'-carboxylic acids of General formula 1.1.6 is consistent effect on the corresponding bromo-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl 1.1.2, 1.1.3, 1.2.2 or 1.2.3 butyllithium 3.5, and then CO23.7 according to the scheme 6

in which: R1and R2have the above value.

In accordance with this invention is a method of obtaining 5'-aminomethyl-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl General formula 1.1.7 is a sequential interaction of amines with 3.8 5'-formyl-1,2,3,4,5,6-hexahydro-[,3']bipyridinyl 1.1.5 and recovering the formed products of the reaction according to scheme 7

in which: R1and R2have the above significance, and R11and R12independently from each other represent a hydrogen atom or an inert Deputy.

In accordance with this invention is a method of obtaining substituted 1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl General formula 1.1.8 is the acylation of amines 3.8 derivatives of 1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-5'-carboxylic acid 1.1.6.1 scheme 8

in which: R1, R2, R11and R12have the above significance, and R13represents a chlorine atom, imidazol-1-yl or the remainder of the mixed anhydride.

In accordance with this invention is a method of obtaining 5'-bromo-1,2,3,4,5,6-1'H-hexahydro-[2,3']bipyridinyl General formula 1.3.1, 1.3.2, 1.4.1 and 1.4.2 is the action of sodium nitrite 3.2 in the presence of sulfuric acid at the 5'-bromo-1,2,3,4,5,6-hexahydro-[2,3']piperidinylidene 1.1.1 or 1.2.1 and subsequent alkylation of the resulting enantiomeric 5'-bromo-1,2,3,4,5,6-1'H-hexahydro-[2,3']bipyridinyl or mixtures thereof of the General formula 1.3.1 and 1.4.1 alkylating reagents 3.9 scheme 9

in which: R1, R3and R4have the above value.

In accordance with this invention a method for production of piperidine-2-yl-pyrazolo[1,5-a]pyridines of General Faure the uly 1.5.1, 1.5.2 or 1.5.3 lies in the interaction of salts of 1'-amino-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-1'-s 2.3 with ethyl ether acetylanthranilic acid 4.1, followed by hydrolysis of the resulting esters 1.5.1 to acids 1.5.2 and acylation of amines 3.8 derivatives of the acid a to amides 1.5.3 scheme 10

in which: R1, R11and R12have the above meaning and X represents a chlorine atom, imidazol-yl or the remainder of the mixed anhydride.

In accordance with this invention a method for production of piperidine-2-yl-pyrazolo[1,5-a]pyridines of General formula 1.6 is in the interaction of salts of 1'-amino-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-1'-s 2-3 with diethyl ether acetylenedicarbonic acid 4.2, formed by hydrolysis of the diesters 1.6.1 to digisat 1.6.2, dehydration in the last anhydrides 1.6.3 and transformation in the last amides 1.6.4 and 1.6.5 or imides 1.6.6 interaction with amines 3.8 or 3.10 chart 11

in which: R1, R11and R12have the above value, a R13represents a hydrogen atom or a residue of the primary amine.

In accordance with this invention a method for production of piperidine-2-yl-pyrido[1,2-a]pyrimidines of General formula 1.7 and 1.8 is in the interaction between the amino-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl 1.1 (R4=NH2) or 1.2 ( 4=NH2c maleic anhydrides 4.3 scheme 12

in which: R1and R3have the above significance, and R14represents a hydrogen atom, an inert Deputy, optionally substituted carboxymethyl or optionally substituted aminocarbonylmethyl.

In accordance with this invention is a method of obtaining 3-piperidine-2-yl-[1,8]naphthirydines General formula 1.9 lies in the interaction between the 5'-bromo-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl-6'-ylamino 1.1.1 α-formylamino acids 4.4 scheme 13

in which R1, R7and R8have the above value.

In accordance with this invention a method for production of piperidine-2-yl-imidazo[1,2-a]pyridines of General formula 1.10.1 1.11.1 and lies in the interaction of amino-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl 1.1 α-halogenocarboxylic connections 4.5 scheme 14

in which R1and R3have the above value, a R9aand R10aindependently from each other represent a hydrogen atom, an inert Deputy, optionally substituted carboxyl group or optionally substituted carbamino group.

In accordance with this invention a method for production of piperidine-2-yl-imidazo[1,2-a]pyridines of General formula is 1.10.2 and 1.11.2 lies in the interaction of amino-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl 1.1 with aldehydes 3.9 and isocyanide 3.10 scheme 15

in which R1and R3have the above significance, and R9brepresents optionally substituted phenyl, optionally substituted aryl or optionally substituted heterocyclyl, and R10bis replaced by the amino group.

Example 22. Focused library of new (piperidine-2-yl)-pyridines of General formula 1. Focused library consists of 35 compounds, the synthesis of which is described in examples 1-20, and determine their activity at the nicotinic receptor on the cells of rhabdomyosarcoma. As standard use gramicidin. Cells rhabdomyosarcoma grow in an environment of Dulbecco at 37°C in a humid atmosphere with CO25% to about 100% of confluently in the wells of 96 well plates. The medium is removed from the wells and replaced with fresh medium (250 μL)containing a mixture of dyes in a ratio of 1:1 at a final concentration of 1 μm for each dye. Cells are incubated for 30 minutes in order for the concentration of the dyes was balanced between intra-and extracellular environments in accordance with the cellular transmembrane potential. After 30 min equilibration dyes produce a first measurement of the fluorescence of the cells in a quiescent state (Io), after which the studied 3-pyridylmethylamine General formula (1) or (2)dissolved in dimetilan is oxide, add to each well. The concentration was adjusted to 30 μM and measure the fluorescence at zero time (°Ii). Cells are incubated for 10 minutes with 3-pyridylmethylamine General formula (1) or (2), after which produce a re-measurement of fluorescence (10Ii). Increase intensity (ΔIi=10Ii-0Ii) characterizes the depolarization of the cells, which is expressed relative to the depolarization induced by gramicidin D (ΔIGID=10IGID-0IGID):ΔIi/ΔIGID×100%. The effect of each compound was measured in four repetitions and the reliability of the effect estimate for the coefficient of Student with confidence interval of 95%. The results of the screening of biological activity at the nicotinic receptor was changed from a few units % of RDTs to several tens% of the GID and demonstrated the promise of the new compounds of General formula 1.

1. Azaheterocycle, including the fragment piperidine-2-yl-, General formula 1

in the form of the individual enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, oxides or hydrates, in which

R1represents a hydrogen atom, an inert Deputy or NH-protective Deputy;

W represents an optionally substituted azaheterocyclic, such as pyridine-3-yl, pyrazolo[1,5-a]pyridine-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-9-yl, imidazo[1,2-a]pyrimidine-6-yl, imidazo[1,2-a]pyrimidine-8-yl or [1,8]naphthiridine-3-yl, excluding compounds of General formula 1, in which W represents an unsubstituted pyridin-3-yl, unsubstituted pyridin-3-yl 1-oxide, alkyl substituted pyridine-3-yl, halogen-substituted pyridin-3-yl, 2-carboxymethylamino-3-yl, optionally substituted on the nitrogen atom of the amino group of 2-aminopyridine-3-yl, 3-herperidin-5-yl, 5-(4-forfinal)pyridine-3-yl, 3-ethoxycarbonylmethyl-5-yl, 3-piperidine-2-yl-pyridine-5-yl, 2-chloropyridin-5-yl, 2-methylpyridin-5-yl, 2-methoxypyridine-5-yl, [2,3']bipyridine-5-yl, optionally substituted on the nitrogen atom of the amino group of 2-aminopyridine-5-yl, 2-amino-3-nitropyridine-5-yl, 1-amino-pyridine-3-Ilium or 1-methyl-2-oxo-1H-pyridine-5-yl, 5-bromo-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, 5-(4-forfinal)-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, 7-(1-methylpiperidin-2-yl)pyrido[1,2-a]pyrimidine-2,4-dione, 9-(1-methylpiperidin-2-yl)pyrido[1,2-a]pyrimidine-2,4-dione.

2. Compounds according to claim 1, which represents 1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl General formula 1.1 and 1.2

in the form of individual enantiomers is whether mixtures of enantiomers or its pharmaceutically acceptable salt, oxides or hydrates, in which

R1has the above meaning;

R2represents a hydrogen atom, halogen atom, optionally substituted hydroxyl group, optionally substituted by mercaptopropyl or optionally substituted by an amino group; R3represents a halogen atom, formyl group, carboxyl group, optionally substituted allyloxycarbonyl group, optionally substituted aminocarbonyl group, optionally substituted by an aminomethyl group optionally substituted phenyl, optionally substituted aryl or optionally substituted heterocyclyl.

3. Compounds according to claim 1, represents 1,2,3,4,5,6-1'H-hexahydro-[2,3']bipyridinyl General formula 1.3 and 1.4

in the form of the individual enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, oxides or hydrates, in which R1and R3have the above significance, and R4represents a hydrogen atom, an inert Deputy or electrophilic Deputy.

4. Compounds according to claim 1, which represents piperidine-2-yl-pyrazolo[1,5-a]pyridine General formula 1.5 and 1.6:

in the form of the individual enantiomers or mixtures of enantiomers Il is their pharmaceutically acceptable salts, oxides or hydrates, in which

R1and R3have the above meaning;

R5and R6independently of one another represent optionally substituted hydroxyl group, optionally substituted by an amino group, or R5and R6together with the carbonyl group to which they are attached, and together with the carbon atoms to which is attached a carbonyl group, form an optionally substituted on the nitrogen atom of pyrrolidine-2,5-dione.

5. Compounds according to claim 1, which represents piperidine-2-yl-pyrido[1,2-a]pyrimidines of General formula 1.7 and 1.8

in the form of the individual enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, oxides or hydrates, in which R1, R3and R5have the above value.

6. Compounds according to claim 1, which represents a 3-piperidine-2-yl-[1,8]naphthirydines General formula 1.9

in the form of the individual enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, oxides or hydrates, in which R1have the above significance, and R7and R8together with the carbon atoms to which they are attached, form an optionally substituted heterocyclic or aromatic cycle.

7. Conn is the link according to claim 1, represent piperidine-2-yl-imidazo[1,2-a]pyridine General formula 1.10 and 1.11

in the form of the individual enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, oxides or hydrates, in which

R1and R3have the above meaning; and

R9and R10independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted carboxyl group, optionally substituted karbamoilnuyu group or optionally substituted by an amino group.

8. Focused library to search for biologically active compounds comprising at least one 2-azaheterocycle General formula 1 or pharmaceutically acceptable salt, N-oxide or hydrate according to claim 1, except 5-bromo-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, 5-(4-forfinal)-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, and compounds in which W represents an unsubstituted pyridin-3-yl, unsubstituted pyridin-3-yl 1-oxide, alkyl substituted pyridine-3-yl, halogen-substituted pyridin-3-yl, 2-carboxymethylamino-3-yl, optionally substituted on the nitrogen atom of the amino group of 2-aminopyridine-3-yl, 3-herperidin-5-yl 5-(4-forfinal)pyridine-3-yl, 3-ethoxycarbonylmethyl-5-yl, 3-piperidine-2-yl-pyridine-5-yl, 2-chloropyridin-5-yl, 2-methylpyridin-5-yl, 2-methoxypyridine-5-yl, [2,3']bipyridine-5-yl, optionally substituted on the nitrogen atom of the amino group of 2-aminopyridine-5-yl, 2-amino-3-nitropyridine-5-yl, 1-amino-pyridine-3-Ilium or 1-methyl-2-oxo-1H-pyridine-5-yl, 7-(1-methylpiperidin-2-yl)pyrido[1,2-a]pyrimidine-2,4-dione, 9-(1-methylpiperidin-2-yl)pyrido[1,2-a]pyrimidine-2,4-dione.

9. Pharmaceutical composition having activity against the action of nicotinic receptor comprising at least one azaheterocycle General formula 1 or pharmaceutically acceptable salt, N-oxide or hydrate according to claim 1, except 5-bromo-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, 5-(4-forfinal)-3-(2-N-tert.-butoxycarbonyl-piperidinyl)pyridine, and compounds in which W represents an unsubstituted pyridin-3-yl, unsubstituted pyridin-3-yl 1-oxide, alkyl substituted pyridine-3-yl, halogen-substituted pyridin-3-yl, 2-carboxymethylamino-3-yl, optionally substituted on the nitrogen atom of the amino group of 2-aminopyridine-3-yl, 3-herperidin-5-yl, 5-(4-forfinal)pyridine-3-yl, 3-ethoxycarbonylmethyl-5-yl, 3-piperidine-2-yl-pyridine-5-yl, 2-chloropyridin-5-yl, 2-methylpyridin-5-yl, 2-methoxypyridine-5-yl, [2,3']bipyridine-5-yl, optionally substituted on the nitrogen atom of the amino group of 2-aminopyridine-5-yl, 2-amino-3-nitropyridine-5-yl, 1-amino-pyridine-3-Ilium and the 1-methyl-2-oxo-1H-pyridine-5-yl, 7-(1-methylpiperidin-2-yl)pyrido[1,2-a]pyrimidine-2,4-dione, 9-(1-methylpiperidin-2-yl) pyrido[1,2-a]pyrimidine-2,4-dione.



 

Same patents:

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

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

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

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

EFFECT: valuable medicinal properties of compound.

25 cl, 1 tbl, 11 ex

FIELD: organic chemistry, pharmaceutical composition.

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

EFFECT: pharmaceutically applicable compounds and compositions.

7 cl, 16 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to improved synthesis method of pyrlindone hydrochloride having formula (I) 1. Method features intramolecular cyclization of 6-methyl-1-(2-chloroethyl-imino)-1,2,3,4-tetrahydrocarbazole hydrochloride of formula IV 2 at 80°-140°C with alkali agent in presence of phase transfer catalyst to provide 1,2,5,6-tetrahydro-8-methyl-pyrazine[3,2,1-j,k]-4H-carbazole of formula VI 3 followed by reduction at 80°-120°C. Method of present invention makes in possible to produce compound of formula I with yield nearly 70 % and purity more than 99 %.

EFFECT: method of high yield with reduced amount of alkali agent and phase transfer catalyst.

7 cl, 2 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

The invention relates to imidazole derivative of the formula (I)

or its pharmaceutically acceptable salt

The invention relates to organic chemistry and can find application in medicine

The invention relates to a method for producing calcium folinata

The invention relates to new stable crystalline calcium or magnesium salts of (6R,S),(6S) - or (6R)-tetrahydrofolate acid, method for their production and pharmaceutical compositions based on them

The invention relates to crystalline forms of 6(R) or 6(S)-tetrahydrofolate acid, method for their production and pharmaceutical compositions

FIELD: organic chemistry, medicine, psychiatry, pharmacy.

SUBSTANCE: invention relates to medicinal agents used for prophylaxis and treatment of schizophrenia by inhibition or suppression of neurodegenerative disease caused by hypofunction of glutamic acid receptors. As an active component agents comprise derivative of 5-substituted 3-oxadiazolyl-1,6-naphthiridine-2(1H)-one of the formula (I):

wherein Het represents oxadiazolyl group; R1 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, trifluoromethyl group, lower alkenyl group, lower alkynyl group, lower alkoxyl group, lower alkoxy-(lower)-alkyl group, lower hydroxyalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; R2 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, lower cycloalkylmethyl group, lower alkenyl group, lower cycloalkenyl group, lower alkynyl group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group wherein indicated groups represent phenyl or naphthyl and indicated heteroaryl groups represents furyl, thienyl or pyridyl, or their physiologically acceptable acid-additive salts.

EFFECT: valuable medicinal properties of agents.

10 cl, 1 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines of the general formula (1)

that are effective inhibitors if caspase-3 that can be used for preparing medicinal agents and for experimental (in vitro, in vivo) investigation of apoptosis processes as "pharmacological tools". Also, invention proposes pharmaceutical composition and a method for their preparing and applying. In the general formula (1) radicals R1, R2, R3 and R8 represent independently of one another hydrogen atom, halogen atom, CF3, CN, inert substitute, optionally substituted hydroxyl group, optionally substituted carboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group; R4 represents hydrogen atom, halogen atom, inert substitute, optionally substituted amino-group, substituted hydroxyl group; R5 represents hydrogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; R6 and R7 represent independently of one another hydrogen atom, inert substitute, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; or R6 and R7 in common with nitrogen atom to which they are bound represent optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur, 3-10-membered cycle; or R6 and R7 in common with nitrogen atom to which they are bound represent condensed heterocycle being optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur.

EFFECT: improved preparing method and treatment.

9 cl, 19 sch, 7 tbl, 25 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

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

SUBSTANCE: invention relates to a new improved method for preparing 6-methyl-2-(4-methylphenyl)-imidazolo[1,2-a]pyridine-3-(N,N-dimethylacetamide) of the formula (I) or its pharmaceutically acceptable acid additive salts. Method involves interaction of ester of the general formula (II) (wherein R is a lower alkyl or phenyl-lower alkyl) with dimethylamine in polar aproton solvent and if necessary conversion of synthesized compound of the formula (I) to pharmaceutically acceptable acid additive salt. Compound of the formula (I) is the known effective sedative agent used in therapy. Also, invention relates to intermediate compounds of the general formula (II) wherein R is a lower alkyl or phenyl-lower alkyl using in this method. Method provides preparing highly pure product for a single stage being without applying harmful and toxic reagents.

EFFECT: improved method for preparing.

16 cl, 15 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compound of the formula (I): wherein cycle A represents imidazo[1,2-a]pyrid-3-yl or pyrazole[2,3-a]pyrid-3-yl; R2 is joined to cyclic carbon atom and taken among halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkyl-S(O)a wherein a = 0, phenyl, phenylthio- or (heterocyclic group)-thio-group wherein any (C1-C6)-alkyl, phenyl or heterocyclic group can be substituted optionally by carbon atom with one or some G wherein heterocyclic group represents saturated, partially saturate or unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least atom is taken among nitrogen, sulfur or oxygen atom that can be bound if another variants are not specified with unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least one atom is taken among nitrogen, sulfur or oxygen atoms that can be bound if another variants are not specified with carbon or nitrogen atom wherein group -CH2- can be substituted optionally with -C(O)- and cyclic atom can carry optionally (C1-C6)-alkyl group and to form quaternary compound, or cyclic atom of nitrogen and/or sulfur can be oxidized to form N-oxide and/or S-oxides; m = 0-2 and R2 values can be similar or different; R1 means halogen atom, (C1-C3)-alkyl-S(O)a wherein a = 0 wherein any (C1-C3)-alkyl can be substituted optionally by carbon atom with one or some J; n = 0-1; cycle B represents phenyl or phenyl condensed with (C5-C7)-cycloalkyl cycle; R3 means halogen atom or sulfamoyl; p = 0-2 and R3 values can be similar or different; R4 means group A-E- wherein A is taken among (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heterocyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl wherein (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heteroccyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl can be substituted optionally by carbon atom with one or some D and wherein above mentioned heterocyclic group comprises fragment -NH- then nitrogen atom can be substituted optionally with group taken among R; E means a simple bond or -O-, -C(O)-, -N(Ra)C(O)- or -N(Ra)SO2-, -S(O)r wherein Ra means hydrogen atom or (C1-C6)-alkyl and r = 0-2; D is taken independently among hydroxy-, amino- (C1-C6)-alkoxy-, N-(C1-C6-alkyl)-amino-, N,N-(C1-C6-alkyl)-amino-, (C1-C6)-alkoxycarbonylamino- and benzyloxycarbonylamino-group wherein any (C1-C6)-alkyl or phenyl can be substituted optionally by carbon atom with one or some K; q = 0-1; G, J and K are taken independently among hydroxy-, dimethylamino-, diethylamino-group; R is taken among (C1-C4)-alkyl; or its pharmaceutically acceptable salt. Invention proposes applying pyrimidine compounds for inhibition of activity of kinases CDK2, CDK4 and CDK6 in cellular cycle eliciting anti-proliferative properties. Indicated properties have value in treatment of cancer diseases (solid tumors and leukemia), fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, osseous and ophthalmic diseases with proliferation of cellular tissue in vessels.

EFFECT: valuable medicinal properties of compounds.

22 cl, 99 ex

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