Bicyclic n-acylated imidazo-3-amine or imidazo-5-amine salts, method for their preparing and pharmaceutical composition based on thereof

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

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

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

12 cl, 2 dwg, 32 ex

 

The present invention relates to salts of bicyclic N-acylated, imidazo-3-amines and imidazo-5-amine, method of production thereof, their use for obtaining the appropriate drugs and medicines containing these compounds.

It is known that some compounds from the class reallymoving bicyclic, imidazo-3-amines and imidazo-5-amines that form the basis of the compounds according to the invention possess important pharmacological properties. Thus, in particular, in a number of publications describe certain imidazo[1,2-a]pyridine as active substances that lower blood pressure (see GB-B 1135893), as an antihelminthic funds and antifungal agents (see Journ Med. Chem. 15, pp. 982-985 (1972)) and as antisecretory active substances used for the treatment of inflammatory diseases (see EP-A 0068378). Some imidazopyridines against inflammatory diseases, particularly diseases of the stomach, also described in EP-A 0266890 and Journ Med. Chem. 30 p. 2031-2046 (1987). Among others described in the publications of the pharmacological properties possessed by some members of the class reallymoving imidazo-3-amines and imidazo-5-amines, should call their antibacterial and antiviral properties (see, respectively, Chem. Pharm. Bull. 40, page 1170 (1992), and Journ. Med. Chem. 41 p. 5108-5112 (1998)); also described agastia as an antagonist of the benzodiazepine receptor (see Journ Heterocyclic Chem. 35, pp. 1205-1217 (1998)).

Increased interest class reallymoving bicyclic, imidazo-3-amines and imidazo-5-amines caused even for the reason that for their synthesis have been developed multicomponent reactions, suitable for use in automated combinatorial chemistry. If the appropriate response in the normal sequence of isolated intermediate product reacts further at a later stage, when the implementation of multicomponent reactions in contrast, is an equilibrium reaction between eductae and various intermediate products formed as a result of a stable product. Multicomponent reaction is effective especially in cases where the desired product in equilibrium far exceeds the quantity of other components, or even when it is given the irreversible reaction is removed from equilibrium. In the ideal case, in addition, multicomponent reactions, carried out with the possibility of application in combinatorial chemistry, would be required to create conditions for use maximum many different and produced simple by doctow.

So, S. Blackburn, and others described in Tetrahedron Lett. 39 p. 3635-3638 (1998), three-component condensation reaction used in the synthesis of the bicyclic imidazo-3-AMI is s, imidazo-5-amine. Similar to the synthesis in this reaction, the synthesis described K. Groebke and others in Synlett, pp. 661-663 (1998). Multicomponent reaction, carried out with the combinatorial synthesis of bicyclic imidazo-amines and allows you to get together and separate imidazo-5-amines described also N. Bienayme and K. Bouzid in Angew. Chem. 110 (16), pp. 2349-2352 (1998).

Information about N-acylated, bicyclic, imidazo-3-amines have had known to date only from the publication Chayer, etc. in Tetrahedron Lett. 39 p. 9685-9688 (1998), which describes salts of N-acylated, but not substituted in position 3 imidazo[1,2-a]pyridines as intermediates in obtaining the appropriate S-acylated at position 3 connections.

In addition, some obtained by solid-phase synthesis of the bicyclic imidazo-3-amines only known N-acylation at the amine nitrogen, Blackburn described in Tetrahedron Lett. 39 p. 5469-5472 (1998).

With regard to the foregoing, the present invention was used the first task to get salt bicyclic, N-acylated at the imidazole nitrogen of imidazo-3-amines and imidazo-5-amine.

This problem was solved according to the invention by producing the salts of bicyclic N-acylated, imidazo-3-amines and imidazo-5-amines of General formula I

in which R1represents tert-butyl, 1,1,3,3-TETRAMETHYLBUTYL, (C 2)nCN, where n is 4, 5 or 6, optionally substituted phenyl,4-C8cycloalkyl, CH2CH2R (R denotes 4-morpholino) or CH2Rawhere Rarepresents hydrogen, C1-C8alkyl straight or branched chain, optionally substituted phenyl, CO(OR') (where R' represents a C1-C8alkyl straight or branched chain), PO(OR')2(where R represents a C1-C4alkyl straight or branched chain) or Si(RxRyRz)(Rx, Ryand Rzeach independently from each other represents remotemachine or branched C1-C4alkyl, C4-C8cycloalkyl or phenyl),

R2denotes hydrogen, CORbwhere Rbrepresents a C1-C8alkyl straight or branched chain, With1-C8alkoxygroup straight or branched chain, With3-C8cycloalkyl, CH2CH2CO(OR') (where R' represents a C1-C4alkyl straight or branched chain, substituted, optionally substituted phenyl, benzyloxy, optionally substituted 1-naphthyl or 2-naphthyl or optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl or furyl, CH2Rcwhere Rcrepresents hydrogen, C1- 8alkyl straight or branched chain, or optionally substituted phenyl, CH2CH2Rdwhere Rdrepresents optionally substituted phenyl, or CONHRewhere Rerepresents a branched or remotemachine1-C8alkyl, aryl, heteroaryl,3-C8cycloalkyl or associated through With1-C3alkylenes aryl group, heteroaryl or3-C8cycloalkyl or primarily phenyl,

R3means remotemachine or branched C1-C8alkyl, C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted 1-naphthyl, 2-naphthyl, quinoline, anthracene, phenanthrene, benzothiophen, benzofuranyl, optionally substituted pyrrole, 2-, 3 - or 4-pyridyl, optionally substituted furfuryl or optionally substituted thiophene,

And indicates the three-tier ring fragment, selected from the group of the formula

or four fragment ring one of the following formulas:

where R4, R5, R6and R7each independently of one another denotes hydrogen, C1-C8alkyl straight or branched chain, fluorine, chlorine, bromine, CF3, CN, NO2, Otherfwhere Rfrepresents hydrogen, C1-C alkyl straight or branched chain, or COR"' (where R"' represents a C1-C4alkyl straight or branched chain, or optionally substituted phenyl), SRgwhere Rgrepresents hydrogen, C1-C4alkyl straight or branched chain, optionally substituted phenyl, optionally substituted pyridine, optionally substituted benzyl or optionally substituted fluorenyl, ORhwhere Rhrepresents hydrogen, C1-C8alkyl straight or branched chain, COR"' (R"' represents a C1-C4alkyl straight or branched chain, or

optionally substituted phenyl) or CO(OR') (R' represents a C1-C8alkyl straight or branched chain), CO(ORior CH2CO(ORi), where Rirepresents respectively With1-C8alkyl branched or straight-chain or optionally substituted phenyl, or R6and R7together represent a fragment of the rings-CRi=CRj-CH=CH-, where Riand Rjrepresent hydrogen, or one of both residues Rior Rjhas a meaning different from hydrogen, and denotes F, Cl, Br, I or C1-C8alkyl straight or branched chain, and R4and R5regardless of this, have the meanings specified above,

R8 denotes a branched or remotemachine1-C8alkyl, aryl, heteroaryl,3-C8cycloalkyl or associated through With1-C3alkylenes aryl group, heteroaryl or3-C8cycloalkyl and

X denotes the anion of an inorganic or organic acid.

The dashed line in the formula

indicates that between one of the nitrogen atoms and related R6With the atom there is a double bond, and the other nitrogen atom of the free space link is saturated by a hydrogen atom.

Preferred according to the invention are salts of bicyclic N-acylated, imidazo-3-amines and imidazo-5-amines of formula I in which R2denotes hydrogen, R1selected from the group comprising (CH2)6CN, cyclohexyl, CH2WITH(Said;"), 2,6-dimetilfenil, tert-butyl or CH2CH2R (R denotes 4-morpholino), and R3selected from the group comprising 4-acetamidophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-bromo-2-forfinal, 5-bromo-2-forfinal, 3-bromo-4-forfinal, 4-tert-butylphenyl, 2-chloro-4-forfinal, 2-chloro-6-forfinal, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-cyanophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,3-acid, 3,4-acid, 2,4-dimetilfenil, 2,5-dimetilfenil, 2-forfinal, 3-forfinal, 4-forfinal, 4-hexylphenyl is, 3-hydroxyphenyl, 2-methoxyphenyl, 2-were, 3-were, 4-were, 4-nitrophenyl, 3-phenoxyphenyl, 4-(1-pyrrolidino)phenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 3,4,5-trimethoxyphenyl, 3-(4-chlorophenoxy)phenyl, 4-acetoxy-3-methoxyphenyl, 4-dimethylaminoethyl, 2-ethoxyethyl, 4-methoxyethyl, 2-(1-(phenylsulfonyl)pyrrole), 2-(N-methylpyrrole), 2-(N-(3,5-dichlorophenyl)pyrrole), 2-(1-(4-chlorophenyl)pyrrole), 2-(5-acetoxymethyl), 2-(5-methylfentanyl), 2-(5-nitrofurfural), 2-[5-(3-nitrophenyl)furfural], 2-[5-(2-nitrophenyl)furfural], 2-(5-bromofuran), 2-[5-(4-chlorophenyl)furfuryl], 2-(4,5-dimethylphenyl), 2-[5-(2-chlorophenyl]furfuryl], 2-(5-ethylfuran), 2-[5-(1,3-DIOXOLANYL], 2-(5-chlorothiophene), 2-(5-methylthiophenyl), 2-(5-ethylthiophene), 2-(3-methylthiophenyl), 2-(4-bromothiophene), 2-(5-nitrothiophene), 5-(2 thiophenyl-carboxylic acid, 2-[4-(phenylethyl)thiophenyl], 2-[5-(methylthio)thiophenyl], 2-(3-bromothiophene), 2-(3-phenoxytoluene) and 2-(5-bromothiophene) or primarily methyl, cyclohexyl, phenyl, furan-2-yl, 2-pyridyl and 2-thiophenyl.

To a preferred further include such salts bicyclic, N-acylated, imidazo-3-amines and imidazo-5-amines, in which a denotes a three-tier fragment of a ring of the formula

or four fragment ring one of the following formulas:

In addition, the salt b is a cyclic N-acylated, imidazo-3-amines and imidazo-5-amines of the formula I according to the invention, the substituents R 4, R5, R6and R7independently of one another have the meanings preferably selected from the group comprising hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, fluorine, bromine, CF3, CN, NO2, Otherfwhere Rfrepresents hydrogen, methyl, ethyl, n-propyl, n-butyl, C(O)methyl, or C(O)phenyl, SRgwhere Rgrepresents hydrogen, methyl, ethyl, n-propyl, n-butyl or phenyl, ORhwhere Rhrepresents hydrogen, methyl, ethyl, n-propyl, n-butyl, phenyl, C(O)methyl, C(O)phenyl, WITH(Said;") or(Outil), CO(ORior CH2CO(ORi), where Rirepresents respectively methyl, ethyl, n-propyl, n-butyl or phenyl, the preferred values of R4, R5R6and R7are hydrogen, methyl, chlorine, NH2and NOz.

R8the salts of bicyclic N-acylated, imidazo-3-amines and imidazo-5-amines of the formula I according to the invention preferably denotes methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, unsubstituted, one-deputizing in position 4, or disubstituted in position 2 and 6 of the phenyl, cyclohexyl or 2-naphthyl, particularly preferred at this methyl, n-hexyl, 2,6-dichlorophenyl, 4-methoxyphenyl, cyclohexyl or 2-naphthyl.

Under the anion X is an inorganic or organic acid is meant according to the invention predpochtitel what about the anion Hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid or primarily of hydrochloric acid.

As salts of the formula I contain at least one basic nitrogen atom, with acids, preferably with physiologically acceptable acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonate acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid can normally translate into the corresponding additive products. To obtain the HCl-additive product is suitable, in addition, trimethylchlorosilane in aqueous solution. These additive products are also the object of the present invention.

The most preferred are proposed in the invention bicyclic salts of N-acylated, imidazo-3-amines and imidazo-5-amines and their additive products with acids selected from the group including

1-acetyl-3-tert-butylamino-2-phenylimidazo[1,2-a]pyridine-1-ihlo the ID,

1-acetyl-3-tert-butylamino-2-phenylimidazo[1,2-a]pyrazin-1-ichorid,

1-acetyl-3-tert-butylamino-2-phenylimidazo[1,2-a]pyrimidine-1-ichorid,

7-acetyl-5-tert-butylamino-6-phenylimidazo[2,1-b]thiazole-7-ichorid,

3-acetyl-1-cyclohexylamino-2-phenylimidazo[1,2-a]quinoline-3-ichorid,

1-acetyl-3-cyclohexylamino-2-phenylimidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-8-benzyloxy-3-cyclohexylamino-2-methylimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-8-benzyloxy-3-tert-butylamino-2-methylimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-8-benzyloxy-2-methyl-3-(1,1,3,3-tetramethylbutylamine)imidazo[1,2-a]pyridine-1-ichorid,

3-(tert-butylcyclohexanecarboxylic)-1-cyclohexanecarbonyl-2-phenylimidazo[1,2-a]pyridine-1-ichorid,

3-(tert-butylpiperazine)-1-heptanoyl-2-phenylimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-6-nitro-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-5-methyl-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-pyridine-2-ilinizas is[1,2-a]pyrazin-1-ichorid,

1-acetyl-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-cyclohexylamino-5,7-dimethyl-2-pyridin-2-elimidate[1,2-a]pyrimidine-1-ichorid,

7-acetyl-5-cyclohexylamino-6-pyridine-2-elimidate[2,1-b]thiazole-7-ichorid,

1-acetyl-2-cyclohexyl-3-cyclohexylmaleimide[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-methylimidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-methylimidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-thiophene-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-2-furan-2-yl-3-(methoxycarbonylmethylene)imidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-2-cyclohexyl-3-(methoxycarbonylmethylene)imidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-2-cyclohexyl-3-(methoxycarbonylmethylene)imidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-(2,6-dimethylphenylimino)-2-methyl-6-nitroimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-(2,6-dimethylphenylimino)-2-thiophene-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyridine-1-ichorid, hydrochloride.

As proposed in the invention bicyclic salts of N-acylated, imidazo-3-amines and imidazo-5-amines may include the step of optically active carbon atoms, the enantiomers of these compounds, as well as mixtures thereof, are also the object of the present invention.

Under the aryl radical is meant preferably optionally one or mnogozalny phenyl or nattily radical.

Under heteroaryl radical refers to aromatic radicals containing at least one heteroatom, preferably nitrogen, oxygen and/or sulfur, particularly preferably nitrogen and/or oxygen.

Unexpectedly, in addition, it was found that salts of bicyclic N-acylated, imidazo-3-amines and imidazo-5-amines according to the invention associated with opiate μ-receptor and can therefore also be used as pharmaceutical active substances.

The object of the invention in accordance with this are also medicinal products containing as active substance at least one salt of the corresponding bicyclic, N-acylated, imidazo-3-amine or imidazo-5-amine of General formula I, in which R1-R8and a have the above meanings and X represents a pharmaceutically acceptable anion of an inorganic or organic acid, preferably Hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond is islote, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid and/or its additive product with a physiologically acceptable acid, preferably hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid.

Preferably with the invention, the drug contains as active substance at least one salt of the corresponding bicyclic, N-acylated, imidazo-3-amine or imidazo-5-amine or its acid-additive product selected from the group including

1-acetyl-3-tert-butylamino-2-phenylimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-3-tert-butylamino-2-phenylimidazo[1,2-a]pyrazin-1-ichorid,

1-acetyl-3-tert-butylamino-2-phenylimidazo[1,2-a]pyrimidine-1-ichorid,

7-acetyl-5-tert-butylamino-6-phenylimidazo[2,1-b]thiazole-7-ichorid,

3-acetyl-1-cyclohexylamino-2-phenylimidazo[1,2-a]quinoline-3-ichorid,

1-acetyl-3-cyclohexylamino-2-phenylimidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-8-benzyloxy-3-cyclohexylamino-2-methylimidazo[1,2-a]pyrid the n-1-ichorid,

1-acetyl-8-benzyloxy-3-tert-butylamino-2-methylimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-8-benzyloxy-2-methyl-3-(1,1,3,3-tetramethylbutylamine)imidazo[1,2-a]pyridine-1-ichorid,

3-(tert-butylcyclohexanecarboxylic)-1-cyclohexanecarbonyl-2-phenylimidazo[1,2-a]pyridine-1-ichorid,

3-(tert-butylpiperazine)-1-heptanoyl-2-phenylimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-6-nitro-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-5-methyl-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyrazin-1-ichorid,

1-acetyl-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-cyclohexylamino-5,7-dimethyl-2-pyridin-2-elimidate[1,2-a]pyrimidine-1-ichorid,

7-acetyl-5-cyclohexylamino-6-pyridine-2-elimidate[2,1-b]thiazole-7-ichorid,

1-acetyl-2-cyclohexyl-3-cyclohexylmaleimide[1,2-a]pyridine-1-ihlo the ID,

1-acetyl-3-cyclohexylamino-2-methylimidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-methylimidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-thiophene-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-2-furan-2-yl-3-(methoxycarbonylmethylene)imidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-2-cyclohexyl-3-(methoxycarbonylmethylene)imidazo [1,2-a]pyridine-1-ichorid,

1-acetyl-2-cyclohexyl-3-(methoxycarbonylmethylene)imidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-(2,6-dimethylphenylimino)-2-methyl-6-nitroimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-(2,6-dimethylphenylimino)-2-thiophene-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyridine-1-ichorid as hydrochloride.

Salts according to the invention are primarily analgesic action. According to one particularly preferred embodiment of the invention in accordance with this is the use of salts of at least one bicyclic, N-acylated, imidazo-3-amine or imidazo-5-amine of General formula I, in which R1-R8And X have the above meanings, and/or additive products with corresponding physiologically acceptable acid to obtain the medicinal product is intended is about to treat the pain.

In addition, these active substances are especially suitable for the treatment of drug addiction and/or alcoholism, diarrhea, gastritis, ulcers, urinary incontinence, depression, narcolepsy, obesity, asthma, glaucoma, tinnitus, itching and/or hyperkinetic syndrome. In addition, they are suitable for the treatment/prevention of epilepsy and schizophrenia and/or for anxiolysis and/or anesthesia.

Medicinal product according to the invention, primarily pain relievers (analgesics), along with at least one salt of the formula I or its additive product with a corresponding physiologically acceptable acid contain carriers, fillers, solvents, diluents, dyes and/or binders. The choice of auxiliary substances and their quantities used by prominent specialists manner, and the choice depends on whether this drug for oral, intravenous, intraperitoneal, intradermal, intramuscular, nasal, buccal or topical application, such as skin infections, infections of the mucous membranes and eye infections. For oral administration suitable compositions in the form of tablets, pills, capsules, granules, drops, tinctures and syrups; for parenteral, local, and inhalation use can naznachatb the solutions suspension, easily recoverable dry formulations and sprays. The proposed salt of formula I or their additive products with physiologically acceptable acids, designed for percutaneous introduction, can be represented in depot form, in dissolved form or embedded in a plaster, optionally with the addition of tools to facilitate penetration.

Used for oral or percutaneous injection dosage form can release proposed in the invention salts of the formula I or their additive products with physiologically acceptable acids gradually slowed down, i.e. to have a prolonged action.

Assigned patients, the amount of the active substance varies depending on the weight of the patient, method of administration, indications for use and the severity of the corresponding disease. Usually salt bicyclic, N-acylated, imidazo-3-amines and imidazo-5-amines of formula I or their additive products with physiologically acceptable acids administered in a dosage of from 2 to 500 mg/kg

Another object of the invention are methods of obtaining salts of bicyclic N-acylated, imidazo-3-amines and imidazo-5-amines of formula I and their acid-additive products. These methods include the following stages:

a) obtaining imidazo-3-amine, respectively imidazo-5-amines three is komponentai reaction of amidine, aldehyde and isonitrile in a solvent, preferably dichloromethane, in the presence of acid, preferably perchloric acid, while the parent compound is added in the following sequence: first, amicin, then aldehyde and at the end of isonitrile;

b) if necessary to obtain compounds in which R2has a meaning different from hydrogen, the interaction generated at the stage a) products with a connection R2Hal (Hal denotes bromine, iodine or primarily chlorine) or with isocyanate;

C) interaction of the reaction product from stage a), respectively b) with the acid chloride of the acid R8C(O)Cl, preferably used with at least a fourfold molar excess;

g) removing from the reaction mixture upon completion of the reaction indicated the excess carboxylic acid;

d) if necessary, the replacement of the known acid chloride by any other acid residue, preferably on the balance of Hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid;

e) if necessary, obtaining the proposed acid-additive products, site is preferably with a physiologically acceptable acid.

Stage a) of the method preferably be carried out as follows: amidine General formula II, primarily derivatives of 3-aminopyrazole, 3-amino-1,2,4-triazole, 2-amino-1,3,4-thiadiazole, 2-aminothiazole, 2-aminopyridine, 2-aminopyrimidine and 2-aminopyrazine, which is commercially available products of such companies as Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma or TCI-Jp, interaction with a variety of aldehydes of the formula III and isonitrile formula IV in the presence of 20%-Noah perchloric acid turn on three-component reaction of compounds of formula V, where R1and R3and a have the values specified above for compounds of formula I.

The reaction in stage a) is carried out in a solvent, preferably in dichloromethane (DHM), at temperatures from -20 to +100°C, preferably from 0 to 40°and most preferably from 10 to 20°C.

To obtain the compounds according to the invention, in which R2has a meaning different from hydrogen, formed respectively at the stage of (a) compounds of formula V is dissolved in a solvent, preferably THF or DHM, and depending on the desired final product by interaction with connection R2Hal, where Hal represents bromine, iodine or primarily chlorine, for example, optionally substituted Alky the-, aryl - or acid chloride acid, or,

if R2denotes, as above, CONHR8interacting with isocyanate in the presence of inorganic or organic bases, preferably in the presence of morpholinos resin (for example, politicalmoneyline company Argonaut), in a solvent, preferably in dichloromethane, for 2-24 h at temperatures in the range from -20 to +100°C, preferably from 10 to 40°turn in the compounds of formula VI, in which R2matter other than hydrogen

Then, in stage C) of the reaction product V from stage a) or the product VI from stage b), where R2has a meaning different from hydrogen, the interaction with the acid chloride of the acid R8C(O)Cl, used in excess, preferably at least four and above all in excess of 4 - to 10-fold, turn in the following salt of the formula Ia according to the invention, with R8has the values specified above for formula I. This stage reaction is carried out in a solvent, preferably in a simple ether or halogenated hydrocarbon, particularly preferably THF or DHM, at a temperature in the range from -20 to +100°C, preferably from 0 to 60°C.

If the product of formula V from stage a) subjecting the reaction according to this technique, and at this stage it is possible p is to receive the offer in the invention, the product of formula I, in which R2is not a hydrogen atom, and the acid residue CORbwhere Rbidentical to R8. Depending on the reaction conditions this product may be a side or main product, respectively the only reaction product. For purpose of receiving this product, it is preferable to work with very large, especially at least ten-fold, excess carboxylic acid and/or at high temperature and/or when significant time duration of the reaction. When possible obtain mixtures of products such mixtures can be separated according to known methods, for example by chromatography or preferably in stage (e) deposition of the additive product with the appropriate acid of the solvent or solvent mixture.

Preferably through 2-12 h after adding the carboxylic acid stage) this excess acid chloride in stage g) from the reaction mixture removed. This operation can in principle be implemented by methods known in the art, for example under vacuum or with inorganic or organic bases. According to the invention, however, this separation is preferably carried out in heterogeneous phase, primarily due to the addition of resin-absorbent. As such resin-absorber preferably apply Tris(2-amino-ethyl)unpolitical. Examples of the most preferred option for implementation C) and d) are presented on the following scheme:

To obtain the proposed invention salts of the formula I, in which X denotes not the acid chloride of the acid and any acid residue, optionally, in stage d) in a known manner are replacing the acid chloride on the balance of another organic or inorganic acid, preferably Hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid. It is preferable to use properly prepared basic ion exchangers.

Proposed in the invention method is primarily suitable for implementation in automated systems for synthesis.

For purpose of producing compounds of the formula I according to the invention from the products of formula V from stage a), i.e. compounds in which R2denotes a hydrogen atom, optionally, the use of protective groups (see P.J. Kocienski, Protecting Groups, published by Thieme Verlag (1994); T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, published by John Wiley & Sons, 3rd edition (1999)). With ethically preferably the group R 2N transferred to the carbamate, particularly preferably benzyl or tert-BUTYLCARBAMATE or amide or R2transferred to silyl group, preferably tert-butyldimethylsilyl or trimethylsilyl, and if necessary, these protective groups interaction with the acid chloride of the acid R8C(O)Cl can in a known manner to remove.

Stage e) of the method preferably takes place by the interaction of the product from stage d), respectively d) with physiologically acceptable acids, preferably hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid, in a solvent or solvent mixture, preferably in diethyl ether, diisopropyl ether, Akilova ether acetic acid, acetone and/or 2-butanone, while the resulting additive product precipitated, optionally after removal of part of the solvent or after adding another non-polar solvent, such as hydrocarbon or simple aliphatic ether. Particularly preferably in this case, to obtain the HCl-additive product to carry out cooperation is s with an aqueous solution of trimethylchlorosilane. According to the invention stage (e) of the method preferably also for the purification of salts of General formula I. In this case, the salt after the above deposition in the usual manner again release of the additive product.

If the salt of formula I get when using stage g) method and use for cleaning stage (e), this last can be alternatively stage d) or as an addition to it.

Examples

Below the invention is explained in more detail by examples, which do not limit its scope.

General methods of synthesis of imidazoles of formula V (stage a) of the method)

Synthesis of imidazoles of the formula V is carried out using the automated installation company Zymark presented in figure 1 and 2.

Figure 1 shows the capping position (position 1), the reaction tubes, the robot 1 (item 2) and robot 2 (position 3), the first of which (the robot 1 moves the reaction tube, respectively racks with tubes, and the second (robot 2) pipethread reagents in the reaction tube, and is shown mounted on the work in the given temperature of the reactor module (item 4), the mixing modules (item 5) and the position of the filter (item 6), where the reaction solution is filtered.

Figure 2 also shows the robot 1 (position 1) and robot 2 (position 2), moving the glass tube with productlicense at different positions, where is their further processing. In this position 3 marked cyclonic mixing module for mixing samples and dosed add solutions or solvents; position 4 is marked centrifugal reactor module, designed for mixing samples, position 5 marked phase a module designed to determine the phase boundaries and phase separation, and position 6 designated module, designed for drying products of the synthesis of the above salt replaceable cartridges.

The synthesis was carried out according to the following General method. Round bottom threaded tube of glass (diameter of 16 mm and a length of 125 mm) manually equipped with a stirrer and a capping position was closed with a screw cap with a membranous lining. This tube with the help of a robot 1 was placed in the set to work in the temperature range 15°reactor module. Robot 2 has consistently epatiroval the following reagents:

1) 1 ml of 0.1-molar solution of amidine and 20%HClO4in dichloromethane,

2) 0.5 ml of 0.3 molar solution of aldehyde in dichloromethane and

3) 0,575 ml 0.2-molar solution of isonitrile in dichloromethane.

The reaction mixture was stirred at 15°in one of the reactor modules within 660 min, after which the reaction solution was filtered to position the filter. When this Tr is BKU twice washed with 1 ml dichloromethane and 200 μl of water, respectively. Then the tripod with tubes manually placed into the processing shown in figure 2, where the reaction mixture using a cyclone mixer was mixed with 3 ml of 10%NaCl solution and 1.5 ml of dichloromethane. Next, in a centrifugal reactor module for 10 min, thoroughly mixed, and due to the slow decrease of the speed of rotation formed a clear phase boundary. This phase boundary was determined by optical and the organic phase was removed with a pipette. At the next stage to the reaction mixture was re-mixed into 1.5 ml of dichloromethane, after which the solution was shaken, centrifuged and the organic phase was removed with a pipette. The combined organic phases were dried over 2.4 g MgSO4(granular) and finally the solvent was removed in a vacuum centrifuge.

A General method of implementation stages C) and d) method

In the following examples, the synthesis proposed in the invention salts of the formula I is carried out on the basis of the imidazoles of the formula V (stages C) and d) of the method) using a special robot company MultiSyntech. This robot has a heated and cooled reactor module with 40 positions stirring tripod for reagents with 32 positions, seven larger containers for reagents and two manipulator arms for pipetting of solvents and reagents. Salts of the formula I according to the invention p the were given by the following General method.

In a glass tube pre-installed manually in the reactor module, pietravalle 0.1 mmole of imidazole. After adding 2 ml of THF and approximately a 10-minute stirring was added 0.4 mmole of carboxylic acid. Then the reaction mixture was stirred for 6 h at room temperature. Then manually added 0.5 mmole resin-absorber (Tris(2-amino-ethyl)unpolitical, 2,43 mmole/g). After 2 hours stirring the reaction solution by filtration was separated from the resin washed three times with dichloromethane portions in 1.5 ml and concentrated in a vacuum centrifuge.

If the description of the method not stated otherwise, chemicals and solvents used commercially available products of the traditional manufacturers (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI-Jp and Novabiochem). Characteristics of the obtained products were determined by NMR or MC(ESI) [mass spectrometry with ionization by beam electrons].

Example 1

1-Acetyl-3-tert-butylamino-2-phenylimidazo[1,2-a]pyridine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyridine (a 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution of tert-utilityfree (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole solution of benzaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M=308,41 detected mass M+=308,1.

Example 2

1-Acetyl-3-tert-butylamino-2-phenylimidazo[1,2-a]pyrazin-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyrazine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution of tert-utilityfree (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of benzaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated for M=309,35 detected mass M+=309,2.

Example 3

1-Acetyl-3-tert-butylamino-2-phenylimidazo[1,2-a]pyrimidine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyrimidine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution of tert-utilityfree (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of benzaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) how obtained product is t were subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M=309,35 detected mass M+=309,2.

Example 4

7-Acetyl-5-tert-butylamino-6-phenylimidazo[2,1-b]thiazole-7-ignored

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminothiazole of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution of tert-utilityfree (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of benzaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M=314,39 detected mass M+=314,1.

Example 5

3-Acetyl-1-cyclohexylamino-2-phenylimidazo[1,2-a]quinoline-3-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminoquinoline of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of benzaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) how the product p which has Dorgali interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M=419,96 detected weight M-H=418,5.

Example 6

1-Acetyl-3-cyclohexylamino-2-phenylimidazo[1,2-a]pyrimidine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyrimidine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of benzaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M=335,39 detected mass M+=335,3.

Example 7

1-Acetyl-8-benzyloxy-3-cyclohexylamino-2-methylimidazo[1,2-a]pyridine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-amino-3-benzyloxypyridine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of acetaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d)of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M=378,5 detected mass M+-acetyl=336,4.

Example 8

1-Acetyl-8-benzyloxy-3-tert-butylamino-2-methylimidazo[1,2-a]pyridine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-amino-3-benzyloxypyridine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution of tert-utilityfree (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of acetaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M=352,46 detected mass M+-acetyl=310,3.

Example 9

1-Acetyl-8-benzyloxy-2-methyl-3-(1,1,3,3-tetramethylbutylamine)imidazo[1,2-a]pyridine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-amino-3-benzyloxypyridine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution of 1,1,3,3-tetramethylbutylamine (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of acetaldehyde (from 0.3 molar solution in DHM) is 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M=408,57 detected mass M+-acetyl=366,0.

Example 10

3-(tert-Butylcyclohexanecarboxylic)-1-cyclohexanecarbonyl-2-phenylimidazo[1,2-a]pyridine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyridine (a 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution of tert-utilityfree (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of benzaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages b) - d) method, the obtained product was subjected to interaction with 0.4 mmole of acid chloride cyclohexylcarbamate acid.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=486,68 detected mass M+=486,3.

Example 11

3-(tert-Butylpiperazine)-1-heptanoyl-2-phenylimidazo[1,2-a]pyridine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyridine (a 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution of tert-utilityfree (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of benzaldehyde (from 0.3 molar R is the target in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages b) - g) method, the obtained product was subjected to interaction with 0.4 mmole of acid chloride heptacosanoic acid.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=490,72 detected mass M+=490,3.

Example 12

1-Acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyridine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyridine (a 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) solution of furfural (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=324,41 detected mass M+=324,3.

Example 13

1-Acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyrimidine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyrimidine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.1 mmole) solution of furfural (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=325,39 detected mass M+=325,3.

Example 14

1-Acetyl-5-amino-chlor-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyrimidine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2,6-diamino-4-chloropyrimidine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) solution of furfural (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=374,85 detected mass M+=374,5.

Example 15

1-Acetyl-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyridine (a 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of pyridine-2-carbaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric what Islami (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=335,42 detected mass M+=335,4.

Example 16

1-Acetyl-3-cyclohexylamino-6-nitro-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-amino-5-nitropyridine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of pyridine-2-carbaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=380,43 detected mass M+=380,3.

Example 17

1-Acetyl-3-cyclohexylamino-5-methyl-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-amino-6-methylpyridine (of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of pyridine-2-carbaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=349,46 detected mass M+=349,4.

Example 18

1-Acetyl-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyrazin-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyrazine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of pyridine-2-carbaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=336,42 detected mass M+=336,3.

Example 19

1-Acetyl-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyrimidine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyrimidine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of pyridine-2-carbaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid is more than 20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=336,42 detected mass M+=336,3.

Example 20

1-Acetyl-5-amino-7-chloro-3-cyclohexylamino-2-pyridine-2-elimidate [1,2-a]pyrimidine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2,6-diamino-4-chloropyrimidine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of pyridine-2-carbaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=336,42 detected mass M+=336,3.

Example 21

1-Acetyl-3-cyclohexylamino-5,7-dimethyl-2-pyridin-2-elimidate[1,2-a]pyrimidine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-amino-4,6-dimethylpyrimidine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of pyridine-2-carbaldehyde (0.3 to Alamy solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=364,47 detected mass M+=364,4.

Example 22

7-Acetyl-5-cyclohexylamino-6-pyridine-2-elimidate[2,1-b]thiazole-7-ignored

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminothiazole of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of pyridine-2-carbaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=341,46 detected mass M+=341,2.

Example 23

1-Acetyl-2-cyclohexyl-3-cyclohexylmaleimide[1,2-a]pyridine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyridine (a 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) solution cyclohexanecarboxaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 is AC.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=340,49 detected mass M+=340,5.

Example 24

1-Acetyl-3-cyclohexylamino-2-methylimidazo[1,2-a]pyrimidine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyrimidine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of acetaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=273,63 detected mass M+=272,3.

Example 25

1-Acetyl-5-amino-7-chloro-3-cyclohexylamino-2-methylimidazo[1,2-a]pyrimidine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2,6-diamino-4-chloropyrimidine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of acetaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 is AC.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=322,82 detected mass M+=it was 322.3.

Example 26

1-Acetyl-5-amino-7-chloro-3-cyclohexylamino-2-thiophene-2-elimidate[1,2-a]pyrimidine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2,6-diamino-4-chloropyrimidine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution cyclohexylaniline (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of thiophene-2-carbaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=322,82 detected mass M+=it was 322.3.

Example 27

1-Acetyl-5-amino-7-chloro-2-furan-2-yl-3-(methoxycarbonylmethylene)imidazo[1,2-a]pyrimidine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2,6-diamino-4-chloropyrimidine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution of methyl ester isocyanurates acid (0,2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution is uhuras (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=364,77 detected mass M+=364,5.

Example 28

1-Acetyl-2-cyclohexyl-3-(methoxycarbonylmethylene)imidazo[1,2-a]pyridine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyridine (a 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution of methyl ester isocyanurates acid (0,2-molar solution in DHM), 0,500 ml (0.15 mmole) solution cyclohexylcarbodiimide (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=330,41 detected mass M+=330,4.

Example 29

1-Acetyl-2-cyclohexyl-3-(methoxycarbonylmethylene)imidazo[1,2-a]pyrimidine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-aminopyrimidine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution of methyl ester isocyanurates acid (0,2-molar solution in DHM), 0,500 ml (0.15 mmole) of a mixture of cyclohex is carbaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=331,40 detected mass M+=331,3.

Example 30

1-Acetyl-3-(2,6-dimethylphenylimino)-2-methyl-6-nitroimidazo[1,2-a]pyridine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2-amino-5-nitropyridine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution of 2,6-dimethylphenylsilane (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of acetaldehyde (from 0.3 molar solution in DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=339,38 detected mass M+=339,0.

Example 31

1-Acetyl-5-amino-7-chloro-3-(2,6-dimethylphenylimino)-2-thiophene-2-elimidate[1,2-a]pyrimidine-1-ichorid

Specified in the title compound was synthesized as used in stage a) of the method the General method from 1.0 ml (0.1 mmole) of 2,6-diamino-4-chloropyridine of 0.1-molar solution in DHM), 0,575 ml (0,115 mmole) solution of 2,6-dimethylphenylsilane (of 0.2-molar solution in DHM), 0,500 ml (0.15 mmole) of a solution of thiophene-2-carbaldehyde (from 0.3 molar of rastvorov DHM) and 10 μl perchloric acid (20 wt.%-Noah and stages C) and d) of the method, the obtained product was subjected to interaction with 0.4 mmole of acetylchloride.

Characteristics of the compounds were determined by the method of MC(ESI)mass calculated M-Cl-=412,92 detected mass M+=412,2.

Example 32

1-Acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyridine-1-ichorid, hydrochloride

655 mg (6.1 mmole) of 5-methyl-2-aminopyridine was previously placed in 12 ml of methanol, and then added 874 mg (0.75 ml; 9.1 mmole) furan-2-carbaldehyde, 768 mg (0,86 ml; 7.0 mmol) of cyclohexylaniline and 0.59 ml of aqueous perchloric acid (20 wt.%-Noah) and for 22 h and was stirred at room temperature. For further processing was added 50 ml of water and 40 ml DHM, was stirred for 10 minutes and then the phases were separated. The aqueous phase was extracted three more times with dichloromethane (DHM) 20 ml, after which the combined organic phases over a short period of time was shaken with 50 ml saturated sodium chloride solution, separated, dried over magnesium sulfate, filtered and concentrated under vacuum. The obtained intermediate product (1,83 g, 6.2 mmole) was dissolved in 10 ml DHM and with stirring was added dropwise at 20°With four equivalent acetylchloride (24.8 mmole; 1.8 ml) and continued to stir for 4 h Then the reaction mixture was concentrated under vacuum and dried under vacuum created by the oil pump. The crude product (PR is approximately 2 g) was dissolved 15.5 ml of 2-butanone, to the solution was added 51 μl water and 0.72 of trimethylchlorosilane and was stirred overnight. Fallen in sediment HCl-adduct of 1-acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyridine-1-iflorida was separated by vacuum filtration and dried under vacuum. The result was 776 mg of 1-acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyridine-1-iflorida as hydrochloride.

Characteristics of the compounds were determined by the method1H-NMR spectroscopy at 300 MHz (impurities were below the detection limit).

Pharmacological studies

Studies of the binding of opiate μ-receptor

Research to identify affinity proposed in the invention compounds of formula I to opiate μ-receptor were performed on membrane homogenates of rat brain (brain homogenate of male Wistar rats without cerebellum, Pons and medulla oblongata). To this end svezhepriobretenny in each case the brain of rats homogenized under ice cooling in 50 mmol/l Tris-HCl (pH 7.4) and for 10 min, centrifuged at 5000 g and 4°C. After desantirovaniya and discarding the supernatant and re-dissolution and homogenization of the membrane sediment in 50 mmol/l Tris-HCl (pH 7.4) and the homogenate for 20 min, centrifuged at 20000 g and 4°C. This washing was repeated once more. After tohospital decantation, and membrane sediment homogenized in 50 mmol/l of cold Tris-HCl, 20%glycerol (wt./vol.), 0,01%bacitracine (wt./about.) (pH 7.4) and aliquot number of homogenizate was frozen before testing. To study the receptor binding aliquots were thawed and diluted in the ratio 1:10 used in the experiments the buffer.

In studies on the binding as buffer used 50 mmol/l Tris-HCl, 5 mmol/l MgCl (pH 7.4), and as a radioactive ligand 1 nmol/l of labeled naloxone.

The connection according to the inventionAffinity μ-receptor, % suppression at 10 µm
Example 490
Example 579
Example 653
Example 791
Example 898

1. Salt bicyclic, N-acylated, imidazo-3-amines or imidazo-5-amines of General formula I

in which R1represents tert-butyl, 1,1,3,3-TETRAMETHYLBUTYL,4-C8cycloalkyl, disubstituted With1-C4the alkyl phenyl, CH2Rawhere Ramean group CO(OR')where R' represents a C1-C8alkyl straight or branched chain;

R2 denotes hydrogen, CORbwhere Rbrepresents a C1-C8alkyl straight or branched chain or3-C8cycloalkyl;

R3means remotemachine or branched C1-C8alkyl, C3-C8cycloalkyl, unsubstituted phenyl, unsubstituted pyridyl, unsubstituted furfural or an unsubstituted thiophenyl;

And indicates three fragment rings

where R6and R7denotes hydrogen,

or four fragment of a ring of the formula

where R4'denotes hydrogen or benzyloxy,

R5'denotes hydrogen,

R6'denotes hydrogen, C1-C8alkyl straight or branched chain or NO2,

R7'denotes hydrogen, C1-C8alkyl straight or branched chain

or R6'and R7'together represent a fragment of the rings-CRi=CRj-CH=CH-,

where Riand Rjrepresent hydrogen;

where R5"denotes hydrogen, chlorine or1-C8alkyl straight or branched chain,

R6"denotes hydrogen,

R7"denotes hydrogen, NH2what if C 1-C8alkyl straight or branched chain;

where R4"', R6"'and R7"'represent hydrogen;

R8denotes a branched or remotemachine1-C8alkyl or C3-C8cycloalkyl;

X denotes the anion of an inorganic or organic acid,

or their acid-additive products.

2. Salt bicyclic, N-acylated, imidazo-3-amines or imidazo-5-amine according to claim 1, wherein R4'and R5'denote hydrogen, R6'denotes hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl or NO2, R7'denotes hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, or R6'and R7'together represent a fragment of the rings-CRi=CRj-CH=CH-, where Riand Rjdenote hydrogen; R5"and R6"denote hydrogen, R7"denotes hydrogen, NH2, methyl, ethyl, isopropyl, n-propyl, n-butyl.

3. Salt bicyclic, N-acylated, imidazo-3-amines or imidazo-5-amine according to claim 1 or 2, wherein R8denotes methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, cyclohexyl.

4. Salt bicyclic, N-acylated, imidazo-3-amines or imidazo-5-amine according to any one of claims 1 to 3, characterized in that X represents an anion Hydrobromic key is lots sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond glutamic acid or aspartic acid or primarily of hydrochloric acid.

5. Salt bicyclic, N-acylated, imidazo-3-amines or imidazo-5-amine according to any one of claims 1 to 4 in the form of their acid-additive products preferably with physiologically acceptable acids.

6. Salt bicyclic, N-acylated, imidazo-3-amines or imidazo-5-amine according to any one of claims 1 to 4 or acid-additive products according to claim 5, characterized in that they are selected from a group including

1-acetyl-3-tert-butylamino-2-phenylimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-3-tert-butylamino-2-phenylimidazo[1,2-a]pyrazin-1-ichorid,

1-acetyl-3-tert-butylamino-2-phenylimidazo[1,2-a]pyrimidine-1-ichorid,

7-acetyl-5-tert-butylamino-6-phenylimidazo[2,1-b]thiazole-7-ichorid,

3-acetyl-1-cyclohexylamino-2-phenylimidazo[1,2-a]quinoline-3-ichorid,

1-acetyl-3-cyclohexylamino-2-phenylimidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-8-benzyloxy-3-cyclohexylamino-2-methylimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-8-benzyloxy-3-tert-butylamino-2-methylimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-8-benzyloxy-2-methyl-3-(1,1,3,3-tetramethylbutylamine)imidazo[1,2A]pyridine-1-ichorid,

3-(tert-butylcyclohexanecarboxylic)-1-cyclohexanecarbonyl-2-phenylimidazo[1,2-a]pyridine-1-ichorid,

3-(tert-butylpiperazine)-1-heptanoyl-2-phenylimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-6-nitro-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-5-methyl-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyrazin-1-ichorid,

1-acetyl-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-cyclohexylamino-5,7-dimethyl-2-pyridin-2-elimidate[1,2-a]pyrimidine-1-ichorid,

7-acetyl-5-cyclohexylamino-6-pyridine-2-elimidate[2,1-b]thiazole-7-ichorid,

7-acetyl-5-cyclohexylamino-6-pyridine-2-elimidate[2,1-b]thiazole-7-ichorid,

1-acetyl-2-cyclohexyl-3-cyclohexylmaleimide[1,2-a]pyridine-1-ichorid,

1-a is ethyl-3-cyclohexylamino-2-methylimidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-methylimidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-thiophenyl-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-2-furan-2-yl-3-(methoxycarbonylmethylene)imidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-2-cyclohexyl-3-(methoxycarbonylmethylene)imidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-2-cyclohexyl-3-(methoxycarbonylmethylene)imidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-(2,6-dimethylphenylimino)-2-methyl-6-nitroimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-(2,6-dimethylphenylimino)-2-thiophenyl-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyridine-1-ichorid, hydrochloride.

7. The method of obtaining salts of bicyclic N-acylated, imidazo-3-amines or imidazo-5-amines of General formula I or their acid-additive product according to any one of claims 1 to 6, namely, that amidin General formula II, where a has the values specified in claim 1, successively subjected to interaction with the aldehyde of General formula III

where R3matter specified in claim 1,

and then isonitriles General formula IV

where R1matter of the decree is given in claim 1,

in a solvent, preferably dichloromethane, in the presence of acid, preferably perchloric acid, to obtain the compounds of General formula V

where R1, R3and a have the above meanings;

R2means hydrogen,

which if necessary is subjected to interaction with the compound of General formula

R2Hal,

where R2matter specified in claim 1, except hydrogen;

Hal means chlorine, bromine or iodine,

or with the isocyanate to obtain compounds of General formula VI

where R1, R3and a have the above meanings;

R2matter specified in claim 1, except for hydrogen, which is the same as the compound of formula V is subjected to interaction with the acid chloride of the acid R8C(O)Cl, where R8matter specified in claim 1, used preferably in at least a fourfold molar excess, with subsequent removal of excess from the reaction mixture and, if necessary, by moving the target product in acid-additive products are preferably physiologically acceptable acid.

8. The method according to claim 7, characterized in that the interaction of the compounds of formulas II, III and IV of the implementation is given in a simple ether or halogenated hydrocarbon, preferably THF or DHM as solvent, at temperatures from 0 to 60°C.

9. The method according to claim 7 or 8, characterized in that the removal of excess quantities of acid chloride of exercise after 2-12 h after its addition at the previous stage.

10. The method according to any of claims 7 to 9, characterized in that the excess acid chloride of the acid is removed by means of the resin-absorbent, preferably using Tris(2-amino-ethyl)aminoplasmal.

11. Pharmaceutical composition having affinity for opiate μ-receptor, containing as active substance at least one salt of a bicyclic, N-acylated, imidazo-3-amine or imidazo-5-amine of General formula I according to claim 1 and/or at least one additive product with a physiologically acceptable acid according to claim 5, where R1-R8And X have the meanings indicated in claim 1.

12. The pharmaceutical composition according to claim 11, characterized in that the active substance it contains at least one salt of a bicyclic, N-acylated, imidazo-3-amine or imidazo-5-amine or its acid-additive product selected from the group including

1-acetyl-3-tert-butylamino-2-phenylimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-3-tert-butylamino-2-phenylimidazo[1,2-a]pyrazin-1-ichorid,

1-acetyl-3-tert-BU is ylamino-2-phenylimidazo[1,2-a]pyrimidine-1-ichorid,

7-acetyl-5-tert-butylamino-6-phenylimidazo[2,1-b]thiazole-7-ichorid,

3-acetyl-1-cyclohexylamino-2-phenylimidazo[1,2-a]quinoline-3-ichorid,

1-acetyl-3-cyclohexylamino-2-phenylimidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-8-benzyloxy-3-cyclohexylamino-2-methylimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-8-benzyloxy-3-tert-butylamino-2-methylimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-8-benzyloxy-2-methyl-3-(1,1,3,3-tetramethylbutylamine)imidazo[1,2-a]pyridine-1-ichorid,

3-(tert-butylcyclohexanecarboxylic)-1-cyclohexanecarbonyl-2-phenylimidazo[1,2-a]pyridine-1-ichorid,

3-(tert-butylpiperazine)-1-heptanoyl-2-phenylimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-6-nitro-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-5-methyl-2-pyridine-2-elimidate[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyrazin-1-ichorid,

1-acetyl-3-cyclohexyl the Mino-2-pyridine-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-pyridine-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-cyclohexylamino-5,7-dimethyl-2-pyridin-2-elimidate[1,2-a]pyrimidine-1-ichorid,

7-acetyl-5-cyclohexylamino-6-pyridine-2-elimidate[2,1-b]thiazole-7-ichorid,

1-acetyl-2-cyclohexyl-3-cyclohexylmaleimide[1,2-a]pyridine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-methylimidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-methylimidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-cyclohexylamino-2-thiophenyl-2-elimidate[1,2-a]pyrimidine-1-ichorid,

1-acetyl-5-amino-7-chloro-2-furan-2-yl-3-(methoxycarbonylmethylene)imidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-2-cyclohexyl-3-(methoxycarbonylmethylene)imidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-2-cyclohexyl-3-(methoxycarbonylmethylene)imidazo[1,2-a]pyrimidine-1-ichorid,

1-acetyl-3-(2,6-dimethylphenylimino)-2-methyl-6-nitroimidazo[1,2-a]pyridine-1-ichorid,

1-acetyl-5-amino-7-chloro-3-(2,6-dimethylphenylimino)-2-thiophenyl-2-elimidate[1,2-a] pyrimidine-1-ichorid,

1-acetyl-3-cyclohexylamino-2-furan-2-elimidate[1,2-a]pyridine-1-ichorid, hydrochloride.



 

Same patents:

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

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

SUBSTANCE: invention relates to novel heterocyclic compounds comprising 2-aminopyridin-3-sulfonic fragment of the general formula (1) or their pharmaceutically acceptable salts, N-oxides or hydrates possessing properties of antagonists of glutamate-induced calcium ions transport, in particular, neuroprotective effect. Also, invention relates to the focused library for the search of biologically active leader-compounds comprising at least one heterocyclic compound of the general formula (1) and to pharmaceutical composition if form of tablets, capsules or injections placed into pharmaceutically acceptable package containing compounds of invention as an active substance. In compound of the general formula (1) R1 represents hydrogen atom; R2 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; or R1 and R2 in common with nitrogen and sulfur atoms to which they are bound form optionally substituted and optionally condensed with other cycles 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine or optionally substituted and optionally condensed with other cycles 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triazabenzocyclohepten-8-one. Also, invention discloses methods for preparing different compounds of the general formula (1).

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

10 cl, 4 sch, 4 tbl, 9 ex

FIELD: pharmaceutical chemistry, medicine.

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

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

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

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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

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

and (1.2):

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

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

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

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to methods for treatment of diseases or syndromes associated with metabolism of fatty acids and glucose and to new compounds and their pharmaceutically acceptable salts. Invention relates to applying new compounds and pharmaceutical compositions for treatment of cardiovascular diseases, diabetes mellitus, cancer diseases, acidosis and obesity by inhibition of activity of enzyme malonyl-CoA-decarboxylase. Indicated compounds correspond to formulae (I) and (II) wherein Y, C, R1, R2, R6 and R7 have values given in the invention claim.

EFFECT: valuable medicinal and biochemical properties of azoles.

27 cl, 8 tbl

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 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, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

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

The invention relates to the field of production of new heterocyclic o-dicarbonitriles

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new anellated carbamoyl azaheterocycles of the general formula (1)

or (2) possessing the inhibitory effect on protein kinase activity, a focused library comprising these compounds, and pharmaceutical composition based on thereof. In the general formula (1) or (2) R1 represents hydrogen atom or optionally substituted (C1-C6)-alkyl; R2 and R3 represent independently of one another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R4 represents optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; A and B in common with carbon and nitrogen atoms joined to the form an optionally substituted and optionally condensed azaheterocycle; D and F in common with carbon atoms joined form an optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle. K and L in common with carbon and nitrogen atoms joined to them form an optionally substituted azaheterocycle. Also, invention related to methods for preparing compounds of the general formulae (1) or (2).

EFFECT: improved preparing methods.

10 cl, 2 sch, 25 tbl, 7 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to a heteroarylamino-substituted derivative of dihydropyrimido[4,5-d]pyrimidinone taken among of compounds order corresponding to the formula (I): wherein a subscript symbol n mans a whole number 1; R1 means (C1-C6)-alkyl (substituted with one or two substitutes taken among group involving hydroxy group, (C1-C6)-alkoxy group and others), piperidinyl-(C0-C4)-alkyl [wherein piperidinyl fragment is monosubstituted optionally with benzyl, carbamoyl, (C1-C4)-alkane sulfonyl, (C1-C6)-alkyl and so on], morpholinyl-(C0-C4)-alkyl, tetrahydropyranyl-(C0-C4)-alkyl, 2-oxoimidazolidinyl-(C0-C4)-alkyl, 2-oxopyrrolidinyl-(C0-C4)-alkyl or 1,1-dioxotetrahydrothienyl-(C0-C4)-alkyl, (C3-C6)-cycloalkyl (monosubstituted with monohydroxy group, (C1-C6)-alkoxy group and so on), 1,4-dioxaspiro[4,5]decane-8-yl, 2,4-dione-1,3-diazaspiro[4,5]decane-8-yl or (3-hydroxymethyl-3-methyl)-1,5-dioxaspiro[5,5]undecane-9-yl; R2 means (C1-C4)-alkyl, halogen atom; R3 means hydrogen atom, (C1-C6)-alkyl (optionally substituted with one or two substitutes taken among group involving (C1-C4)-alkoxy group, pyrrolidinyl, di-(C1-C4-alkyl)-amino-group and so on), phenyl, benzyl or piperidinyl (N-substituted optionally with (C1-C4)-alkyl); R4 means hydrogen atom, and also its individual isomers, racemic and nonracemic mixtures of isomers, prodrugs and its pharmaceutically acceptable salts. Also, invention proposes a pharmaceutical composition possessing inhibitory activity with respect to activity of p38 MAP kinase. The composition comprises a heteroalkylamino-derivative of dihydropyrimido[4,5-d]pyrimidinone of the formula (I), isomer, racemic or nonracemic mixture of isomers or its pharmaceutically acceptable salt in mixture with at least one pharmaceutically acceptable vehicle. Invention provides representing a heteroalkylamino-substituted derivative of dihydropyrimido[4,5-d]pyrimidinone possessing inhibitory activity with respect to activity of p38 MAP kinase.

EFFECT: valuable biochemical properties of compounds and composition.

14 cl, 4 tbl, 90 ex

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

SUBSTANCE: invention describes alkylamino-substituted bicyclic nitrogen-containing heterocycles of the general formula (I):

wherein n = 1; R1 means (C1-C6)-alkyl; R2 means halogen atom; R3 means (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkylsulfonyl-(C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, dihydroxy-(C1-C6)-alkyl, N-heterocyclyl-(C1-C6)-alkyl or (C1-C6-alkylene)-C(O)R31 wherein R31 means hydroxy- or (C1-C6)-alkoxy-group, and its pharmaceutically acceptable salts. New compounds are inhibitors of protein kinase p38 and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

8 cl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

EFFECT: valuable medicinal properties of compounds and compositions.

40 cl, 1 tbl, 4 ex

FIELD: organic chemistry, chemical technology, pharmacy.

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

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

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

7 cl, 2 tbl, 33 ex

FIELD: organic chemistry, chemical technology, medicine.

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

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

15 cl, 1 tbl, 250 ex

FIELD: organic chemistry, medicine, hormones.

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

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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

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

10 cl, 6 tbl, 337 ex

FIELD: pharmaceutical chemistry, medicine.

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

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

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

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes new 7-azaindoles of the general formula (I): wherein n = 1 or 2; R1 means mono- or multi-unsaturated, linear or branched (C2-C10)-alkenyl, linear or branched, unsubstituted (C1-C10)-alkyl that can be monosubstituted with (C1-C6)-alkoxy-group, naphthyl, pyridinyl, (C3-C6)-cycloalkyl, phenyl that, in turn, can be substituted with (C1-C6)-alkyl, halogen atom, (C1-C6)-alkoxy-group or hydroxy-group, or radical of the formula: ; R2 and R3 are similar or different being only one of them can mean hydrogen atom and mean (C1-C5)-alkyl possibly substituted with -O-(C1-C6)-alkyl or pyridyl, phenyl possibly substituted twice with -F, -Cl, -Br, -O-(C1-C3)-alkyl or monosubstituted with -COOH or -COO-(C1-C3)-alkyl, pyridyl possibly twice substituted with -Cl, -Br, or group of formulae: or , or R2 and R3 in common with N-atom mean: or under condition that if n = 1 then they don't mean simultaneously: R1 - (C1-C6)-alkyl; R2 - hydrogen atom (H) or (C1-C6)-alkyl, and R3 or wherein R and R' mean independently -Cl or -Br. These compounds possess inhibitory activity with respect to activity of phosphodiesterase 4. Also, invention relates to a medicinal agent comprising these compounds, methods for its preparing and using these compounds for preparing medicinal agents.

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

17 cl, 6 tbl, 40 ex

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