Derivatives of pyridine and pyrimidine, methods for their preparing (variants), pharmaceutical composition and using

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

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing inhibitory effect on activity of dipeptidyl peptidase IV (DPP IV) that can be used, for example, in treatment of diabetes mellitus type 2. In compounds of the formula (I) X means nitrogen atom (N) or -C-R5; R1 and R2 mean independently hydrogen atom, (C1-C6)-alkyl; R3 means saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, or perfluoro-(C1-C6)-alkyl; R4 means (lower)-alkyl, (lower)-alkoxy-, (lower)-alkylthio-group, saturated or aromatic 7-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-, amino-group or perfluoro-(C1-C6)-alkyl, 4-fluorophenyloxy-(C1-C6)-alkyl or (C3-C6)-cycloalkyl; R5 means hydrogen atom or (C1-C6)-alkyl. Also, invention relates to methods for synthesis of compounds of the formula (I), pharmaceutical compositions and their using for preparing medicaments used in treatment and/or prophylaxis of DPP IV-mediated diseases.

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

21 cl, 93 ex

 

The present invention relates to a derivative of pyridine, and pyrimidine, to receive them and their use as medicines. The invention primarily relates to compounds of formula (I)

where

X is N or C-R5,

R1and R2independently mean hydrogen or (ness.)alkyl,

R3means heterocyclyl, heterocyclyl, independently mono - or tizamidine (ness.)the alkyl, PERFLUORO(ness.)the alkyl, amino, (ness.)alkoxy or halogen, aryl or aryl independently mono-, di - or tizamidine halogen, (ness.)the alkyl, amino, (ness.)alkoxy or PERFLUORO(ness.)the alkyl,

R4means (ness.)alkyl, (ness.)alkoxy, (ness.)alkylthio, heterocyclyl, heterocyclyl, independently mono-, di - or tizamidine (ness.)the alkyl, (ness.)alkoxy, PERFLUORO(ness.)the alkyl, amino or halogen, aryl or aryl independently mono-, di - or tizamidine (ness.)the alkyl, (ness.)alkoxy, halogen, amino or PERFLUORO(ness.)by alkyl; aryloxy(ness.)alkyl or cycloalkyl,

R5means hydrogen or (ness.)alkyl,

and their pharmaceutically acceptable salts.

The enzyme dipeptidyl peptidase IV (EC, abbreviated as DPP-IV) participates in the regulation of activity of some hormones. DPP-IV primarily effectively and rapidly hydrolyzes glucagon-like peptide 1 (GLP-1), which is considered one of the most active promoters of production and secretion of insulin. When the inhibition of DPP-IV is stimulating action of endogenous GLP-1 and increasing concentrations of insulin in plasma (blood). In patients with impaired glucose tolerance and diabetes mellitus type 2 with increasing concentrations of insulin in plasma decreases the intensity of hyperglycemia and, accordingly, reduces the risk of tissue damage. Therefore, inhibitors of DPP-IV are proposed as a promising drug for the treatment of impaired glucose tolerance and diabetes mellitus type 2 (for example, Vilhauer, WO 98/19998). Other documents relating to the prior art, include WO 99/38501, DE 19616486, DE 19834591, WO 01/40180, WO 01/55105, US 6110949, WO 00/34241 and US 6011155.

We have developed new inhibitors of DPP-IV, which are extremely effective in reducing the level of glucose in plasma (blood). Therefore, the compounds of the present invention can be used for the treatment and/or prevention of diabetes, especially insulin-independent diabetes mellitus and/or impaired glucose tolerance, as well as other States in which therapeutic effect is due to enhanced activity of the peptide, usually inactivating the enzyme DPP-IV. Unexpectedly found that compounds of the present invention can also be used for the treatment and/or prevention of diseases of the digestive tract, ulcerative number is the Crohn's disease and/or metabolic syndrome. In addition, the compounds of the present invention can be used as diuretic agents and for the treatment and/or prophylaxis of hypertension. It was unexpectedly found that the compounds of the present invention exhibit improved therapeutic and pharmacological properties compared with other known inhibitors of DPP-IV, known in the art, for example, in the context of pharmacokinetic properties and bioavailability.

Unless otherwise stated, terms used in the description have the following meanings.

The term "nits.", used in the description, means a group containing from one to six, preferably one to four, carbon atoms.

The term "halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, bromine or chlorine, most preferably chlorine.

The term "alkyl", used alone or in combination with other groups, means a branched or straight monovalent saturated aliphatic hydrocarbon radical containing from 1 to 20, preferably from 1 to 16, carbon atoms, more preferably from 1 to 10 carbon atoms.

The term "(ness.)alkyl", used alone or in combination with other groups, means a branched or straight monovalent alkyl radical containing from 1 to 6 atoms ug is erode, preferably from 1 to 4 carbon atoms. Examples (ness.)alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl etc. Preferred methyl and ethyl, most preferred methyl.

The term "PERFLUORO(ness.)alkyl" means a group (ness.)alkyl, in which all hydrogen atoms are replaced by fluorine. Preferred PERFLUORO(ness.)alkyl groups are trifluoromethyl, pentafluoroethyl and heptafluoropropyl preferred trifluoromethyl.

The term "alkoxy" means the group R'-O-, where R' is alkyl. The term "(ness.)alkoxy" means the group R'-O-, where R' means (ness.)alkyl. Examples (ness.)alkoxygroup are, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, hexyloxy, preferably methoxy.

The term "(ness.)alkylthio" means the group R'-S-, where R' means (ness.)alkyl as indicated above.

The term "cycloalkyl" means a monovalent carbocyclic radical containing from 3 to 6, preferably from 3 to 5, carbon atoms. Examples cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, preferably cyclopropyl.

The term "heterocyclyl" means a saturated, unsaturated or aromatic monovalent 5-7-membered monocyclic, 9-membered bicicletas is s or 13-membered tricyclic radical, containing at least one heteroatom selected from nitrogen atoms, sulfur and oxygen, or a combination of both. Examples heterocyclyl residues include pyridyl, pyrimidinyl, furyl, thienyl, indolyl, benzo[1,3]dioxole, benzofuranyl, benzothiophene, dibenzofuran, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxadiazolyl, tetrazolyl, pyridil, pyrimidinyl, pyrazinyl, pyrrolidinyl, azepane, morpholine. These heterocyclyl residues independently mono-, di - or tizamidine group halogen, amino, and PERFLUORO(ness.)alkyl, (ness.)alkyl or (ness.)alkoxy, preferably (ness.)alkyl or (ness.)alkoxy.

The term "aryl" means an aromatic monovalent mono - or polycarbocyclic radical, such as phenyl and naphthyl, preferably phenyl, optionally independently mono-, di - or tizamidine groups (ness.)alkyl, (ness.)alkoxy, halogen, amino or PERFLUORO(ness.)alkyl, preferably (ness.)alkyl, (ness.)alkoxy and halogen.

The term "aryloxy(ness.)alkyl" means an aryl residue, as stated above, attached to (ness.)alkalinous group via hydroxy radical, i.e. aryl-O-R, where R means (ness.)alkylen.

The term "pharmaceutically acceptable salt" includes salts of compounds of formula (I) and an inorganic or organic acids, t is such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonate acid, salicylic acid, paratoluenesulfonyl acid and the like, which are non-toxic in the body of the patient. The preferred salts are the formate, maleate, citrates, hydrochloride, hydrobromide, methanesulfonate, the most preferred hydrochloride.

In one embodiment of the present invention R1means (ness.)alkyl, preferably methyl and isopropyl. In a preferred embodiment, R1means hydrogen.

In another embodiment of the present invention R2means (ness.)alkyl, preferably methyl. In a preferred embodiment, R2means hydrogen.

In yet another embodiment of the present invention X is N, in another embodiment, X is C-R5preferably X is N.

In one embodiment, R3means heterocyclyl, such as pyridyl, pyrimidinyl, furyl, thienyl, indolyl, benzo[1,3]dioxole, benzofuranyl, benzothiophene, dibenzofuran, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxadiazolyl, tetrazolyl, pyridil, pyrazinyl, pyrrolidinyl, is tepanil, morpholino, and heterocyclyl remains optional and independently mono-, di - or tizamidine group (ness.)alkyl, (ness.)alkoxy, PERFLUORO(ness.)alkyl, amino or halogen, preferably (ness.)alkyl, (ness.)alkoxy or halogen. Preferred heterocyclyl residues R are the unsubstituted thienyl and unsubstituted benzo[1,3]dioxole. In a preferred embodiment, R is aryl, preferably phenyl, optionally and independently ortho-, meta - and/or para-, preferably ortho - and para-substituted by a group (ness.)alkyl, (ness.)alkoxy, halogen, amino or PERFLUORO(ness.)alkyl, preferably groups of halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy. The most preferred residue R3is 2,4-dichlorophenyl.

In another embodiment, R4means aryl, such as phenyl or naphthyl, preferably phenyl. Phenyl residue R4optionally and independently ortho-, meta - and/or parzanese group halogen, amino, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy, preferably halogen, such as fluorine, (ness.)alkyl, such as methyl, or (ness.)alkoxy, such as methoxy. Nattily the remainder R4preferably unsubstituted or monogamist group (ness.)alkoxy, such as methoxy. In another embodiment, R4means (ness.)alkoxy, preferably methoxy. In another embodiment, R4OZNA the AET (ness.)alkyl, preferably methyl and isopropyl. In another embodiment, R4means cycloalkyl, preferably cyclopropyl. In another embodiment, R4means (ness.)alkylthio, preferably methylthio. In another embodiment, R4means heterocyclyl. Preferred heterocyclyl residues R4are pyridyl, pyrimidinyl, furyl, thienyl, indolyl, benzo[1,3]dioxole, benzofuranyl, benzothiophene, dibenzofuran, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxadiazolyl, tetrazolyl, pyridil, pyrimidinyl, pyrazinyl, pyrrolidinyl, azepane, morpholine. More preferred pyridyl, thienyl, indolyl, benzo[1,3]dioxole, benzofuranyl, benzothiophene, dibenzofuran, pyrrolidinyl, azepane, morpholine. These heterocyclyl residues optionally mono-, di - or tizamidine, preferably and independently mono - or tizamidine halogen, amino, and PERFLUORO(ness.)the alkyl, (ness.)the alkyl or (ness.)alkoxy, preferably (ness.)alkyl or (ness.)alkoxy. In another embodiment, R4means aryloxy(ness.)alkyl, preferably of phenoxy(ness.)alkyl, where the phenyl group is substituted with halogen, most preferably 4-forfinancial.

In another embodiment of the present invention R5means (ness.)alkyl, prepact the tion methyl. In another embodiment, R5means hydrogen.

Preferred compounds of the present invention are the compounds of formula I where X is N, R1and R2mean hydrogen, R3means aryl, as stated above, preferably phenyl, independently ortho - and para-substituted by a group (ness.)alkyl, (ness.)alkoxy, halogen, amino or PERFLUORO(ness.)alkyl, most predpodtitelno 2,4-dichlorophenyl and R4means alkoxy, preferably methoxy, alkylthio, preferably methylthio, aryl, preferably phenyl, optionally and independently ortho-, meta - and/or para-substituted, as described above, preferably by halogen, such as fluorine, (ness.)the alkyl, such as methyl, or (ness.)alkoxy, such as methoxy, or heterocyclyl, as indicated above, preferably pyrrolidinyl or azepane. The preferred option of the present invention are the compounds of formula (I), and pharmaceutically acceptable salts of compounds of formula (I).

Preferred compounds of General formula (I) are compounds selected from the group including

5-aminomethyl-4-(2,4-dichlorophenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2-phenyl-6-para-tolylboronic-4-ylamine,

5-aminomethyl-4-(2,4-dichlorophenyl)-2-(3-methoxyphenyl)pyrimidine-4-ylamine,

5-aminomethyl-2-phenyl-6-ortho-tolylboronic-4-ylamine,

5-aminomethyl-6-(2,differenl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-meta-tolylboronic-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3,4,5-trimethoxyphenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dimetilfenil)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3,5-acid)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3-forfinal)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(4-forfinal)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(4-methoxy-1-methyl-1H-indol-6-yl)pyrimidine-4-ylamine,

5-aminomethyl-2-benzofuran-2-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(1H-indol-2-yl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-meta-tolylboronic-4-ylamine,

2-(4-amino-3-methoxyphenyl)-5-aminomethyl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-2-azepin-1-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3,4-differenl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-pyrrolidin-1-Yeremey-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-methylsulfonylamino-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3,4-acid)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-thiophene-2-Yeremey-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(2-forfinal)pyrimidine-4-ylamine,

5-aminomethyl-2-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-a is isomethyl-6-(2,4-dichlorophenyl)-2-methoxypyridine-4-ylamine,

5-aminomethyl-2-cyclopropyl-6-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-pair-tolylboronic-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(4-methoxyphenyl)pyrimidine-4-ylamine,

5-aminomethyl-2-benzo[1,3]dioxol-5-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3-triptoreline)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-morpholine-4-Yeremey-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(4-triptoreline)pyrimidine-4-ylamine,

5-aminomethyl-2-(3-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-methylpyrimidin-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-naphthalene-2-Yeremey-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-naphthalene-1-Yeremey-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3-methoxyphenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3,5-differenl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(2-methoxyphenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(4-ethylphenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-isopropylpyrimidine-4-ylamine,

5-aminomethyl-2-(2-chloro-4-forfinal)-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-2-benzo[b]thiophene-2-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(6-methoxynaphthalene-2-yl)pyrimidine-4-ylamine,

5-aminomethyl-2-phenyl-6-the ETA-tolylboronic-4-ylamine,

5-aminomethyl-6-(4-chlorophenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2-phenyl-6-(4-triptoreline)pyrimidine-4-ylamine,

5-aminomethyl-6-(2-methoxyphenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-ortho-tolylboronic-4-ylamine,

5-aminomethyl-2-(3,5-bis-triptoreline)-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(4-forfinancial)pyrimidine-4-ylamine,

5-aminomethyl-6-(2-chlorophenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2-bromophenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2-dibenzofuran-2-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-bis-triptoreline)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2-fluoro-4-methoxyphenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-acid)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2-(1H-indol-2-yl)-6-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-benzo[1,3]dioxol-5-yl-2-cyclopropylamino-4-ylamine,

5-aminomethyl-6-(2-forfinal)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2-phenyl-6-(2-triptoreline)pyrimidine-4-ylamine,

5-aminomethyl-2-benzofuran-2-yl-6-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(4-forfinal)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2-(3,4-acid)-6-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-phenyl-2-pyridine-4-Yeremey-4-ylamine,

5-aminomethyl-6-(3-chlorophenyl)-2-phenylpyrimidine-4-and the amine,

5-aminomethyl-6-phenyl-2-thiophene-2-Yeremey-4-ylamine,

5-aminomethyl-6-(3-forfinal)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2,6-diphenylpyridine-4-ylamine,

5-aminomethyl-6-(4-methoxyphenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2-phenyl-6-thiophene-3-Yeremey-4-ylamine,

5-aminomethyl-6-(3-methoxyphenyl)-2-phenylpyrimidine-4-ylamine,

6-(2,4-dichlorophenyl)-5-methylaminomethyl-2-phenylpyrimidine-4-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-6-phenylpyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-5-methyl-6-phenylpyridine-2-ylamine,

[5-aminomethyl-6-(4-chlorophenyl)-2-pyridin-3-Yeremey-4-yl]-methylamine,

5-aminomethyl-6-benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-benzo[1,3]dioxol-5-yl-2-phenylpyrimidine-4-ylamine,

[5-aminomethyl-6-(4-chlorophenyl)-2-pyridin-3-Yeremey-4-yl]-Isopropylamine,

(5-aminomethyl-2,6-diphenylpyridine-4-yl)-methylamine,

3-aminomethyl-4-(4-chlorophenyl)-5-methyl-6-phenylpyridine-2-ylamine, 3-aminomethyl-4-(4-chlorophenyl)-6-phenylpyridine-2-ylamine,

3-aminomethyl-4,6-bis-(4-forfinal)-pyridine-2-ylamine, and

3-aminomethyl-4-benzo[1,3]dioxol-5-yl-6-vinylpyridin-2-ylamine,

and pharmaceutically acceptable salts of such compounds.

The compounds of formula (I)in which X is C-R5, R5means (ness.)alkyl, and R3means ortho-substituted phenyl, can be in the form of optically pure is s enantiomers or racemates. The invention includes all such forms.

It is assumed that compounds of General formula (I) according to the present invention can be modified by functional groups with the formation of derivatives, which can turn into the parent compound in vivo.

Compounds of the present invention are given as shown below in schemes I and II.

Scheme I

Scheme II

The present invention also relates to a method for producing compounds of formula I. this method comprises the reconstruction of the NITRILES of the formula IV, IVa, IX and IXa with the formation of amines of the formula Ia and Ic, respectively. The restoration carried out by the known methods. For example, recovery can be a metal hydride, such as sociallyengaged, in an inert solvent.

The NITRILES of the formula IV and IVa are known compounds or can be obtained from arylidenaminoimidazo formula V and amidino formula VII with known methods. For example, the reaction can be carried out in the presence of a base such as potassium carbonate in an inert solvent, such as methanol.

The NITRILES of the formula IX and IXa are known compounds or can be obtained by known methods. One of such ways is the interaction of arylidenaminoimidazo formula V with ketones of the formula X. E.g. the measures the reaction can be conducted by heating in a mixture with ammonium acetate in an inert solvent, such as methanol.

Areliterally formula V are known compounds or can be obtained by known methods, for example, by the reaction of aromatic aldehydes VI with malononitrile in the presence of a base such as piperidine.

Amidine formula VII are known soedinenii or they can be obtained by known methods. For example, amidine formula VII is obtained from the NITRILES of formula VIII by the way, is known as the Pinner reaction.

Compounds of formula Ib and Id can be obtained from corresponding compounds of formula Ia and Ic, respectively, the known method of alkylation (for example, see Bar-Haim G., Kol M., Tetrahedron Lett., 39, 2663 (1998)).

In addition, the invention relates to compounds of formula (I)above, obtained by the method described above.

As indicated above, the compounds of formula (I) according to the present invention can be used as medicines for the treatment and/or prevention of diseases associated with DPP IV, such as diabetes, especially insulin-independent diabetes mellitus, impaired glucose tolerance, disease of the digestive tract, ulcerative colitis, Crohn's disease, obesity and/or metabolic syndrome, preferably insulin-neshaminy sugar Diab is t and/or impaired glucose tolerance. In addition, the compounds of the present invention can be used as diuretic agents or for the treatment and/or prophylaxis of hypertension.

The invention also relates to pharmaceutical compositions comprising a compound as defined above, and a pharmaceutically acceptable carrier and/or adjuvant.

In addition, the invention relates to the above compounds for use as therapeutically active substances, especially as therapeutically active substances for the treatment and/or prevention of diseases associated with DPP IV, such as diabetes, especially insulin-independent diabetes mellitus, impaired glucose tolerance, disease of the digestive tract, ulcerative colitis, Crohn's disease, obesity and/or metabolic syndrome, preferably for use as therapeutically active substances for the treatment and/or prophylaxis of insulin-nezavisimogo diabetes mellitus and/or impaired glucose tolerance. In addition, the invention relates to the compounds mentioned above, for use as a diuretic agents or for use as therapeutically active substances for the treatment and/or prophylaxis of hypertension.

In another embodiment, the invention relates to a method of treatment and/or prevention of diseases associated with PP IV, such as diabetes, especially insulin-independent diabetes mellitus, impaired glucose tolerance, disease of the digestive tract, ulcerative colitis, Crohn's disease, obesity and/or metabolic syndrome, preferably for the treatment and/or prophylaxis of insulin-nezavisimogo diabetes mellitus and/or impaired glucose tolerance, and this method includes the introduction of compounds specified above, a person or an animal. In addition, the invention relates to a method of treatment and/or prophylaxis of the above, where the disease means hypertension or where a therapeutic effect is achieved through the use of a diuretic agent.

In addition, the invention relates to the use of the above compounds for the treatment and/or prevention of diseases associated with DPP IV, such as diabetes, especially insulin-independent diabetes mellitus, impaired glucose tolerance, disease of the digestive tract, ulcerative colitis, Crohn's disease, obesity and/or metabolic syndrome, preferably insulin-nezavimaya diabetes mellitus and/or impaired glucose tolerance. In addition, the invention relates to the use specified above, where the disease means hypertension, or for use as a diuretic agent.

In addition, the invention of what is worn to the application of the aforementioned compounds to obtain drugs, intended for treatment and/or prevention of diseases associated with DPP IV, such as diabetes, especially insulin-independent diabetes mellitus, impaired glucose tolerance, disease of the digestive tract, ulcerative colitis, Crohn's disease, obesity and/or metabolic syndrome, preferably for the treatment and/or prophylaxis of insulin-nezavisimogo sharego diabetes and/or impaired glucose tolerance. Such medicines include the connection specified above. In addition, the invention relates to the use specified above, where the disease means hypertension, or for use in receiving diuretic agents.

In connection with the above methods and applications preferred diseases are: diabetes, especially insulin-independent diabetes mellitus, impaired glucose tolerance, obesity and/or metabolic syndrome, preferably insulin-independent diabetes mellitus and/or impaired glucose tolerance.

The compounds of formula (I) are obtained by the following methods, according to the methods described in examples, or similar methods. Optimal conditions of individual stages of the reactions known to the person skilled in the art. The source materials are commercial products or get them in the same way as described below, Asano in the examples or known methods.

The activity of compounds of the formula (I) is determined by the following method.

The activity of inhibitors of DPP-IV define when using native DPP-IV human, isolated from plasma (blood) of a person, or recombinant DPP-IV man. Treated with citrate plasma (blood) of a person obtained from different donors are pooled, filtered through a membrane with a pore diameter of 0.2 μm in sterile conditions, aliquot parts by volume of 1 ml quickly frozen and stored at -120°until analysis. When the colorimetric analysis as the source of the enzyme DPP-IV use from 5 to 10 µl of plasma (blood) person, and when fluorimetric analysis of 1.0 µl of plasma (blood) of a person, the total volume of the mixture for analysis, 100 µl of cDNA encoding the amino acid sequence of DPP-IV (31-766), not containing N-terminal fragment and the transmembrane domain, clone in yeast (pichia pastoris). DPP-IV person Express and isolated from the culture medium by chromatography on a column, including gel permeation, anyone - and cation-exchange chromatography. The degree of purification of the obtained enzyme preparation according to the results of electrophoresis in DDS-page staining of Kumasi is >95%. When the colorimetric analysis of DPP-IV as the source of enzyme used 20 ng of recombinant DPP-IV man, and when fluo americas.com analysis 2 ng of recombinant DPP-IV person in a total volume of 100 μl.

When fluorophenol analysis as the substrate using H-Ala-Pro-7-amido-4-triptorelin (firm Calbiochem, cat. No. 125510). The original 20 mm substrate solution in 10% DMF/N2About stored at -20°C. When determining the IC50the final concentration of the substrate is 50 μm. When determining the kinetic parameters, such asmVmaxToithe concentration of the substrate is from 10 to 500 μm.

When the colorimetric analysis as the substrate using H-Ala-Pro-pNA·HCl (company Bachem L-1115). The original 10 mm substrate solution in 10% MeOH/H2O stored at -20°C. When determining the IC50the final concentration of the substrate is 200 μm. When determining the kinetic parameters, such as KmVmax, Kithe concentration of the substrate is from 100 to 2000 microns.

Fluorescence was measured on an LS 50B, Perkin Elmer) with the wave excitation at 400 nm and the wave emission 505 nm, and the measurement is carried out every 15 s for 10 to 30 minutes of Constant initial speed calculated by the method of optimal linear regression.

The uptake of pNA, visvideo of the colorimetric substrate, determined on the spectrophotometer SrectraCount (Packard company) at 405 nm, and the measurement is carried out every 2 min for 30 to 100 minutes of Constant initial speed is calculated by the method of optimal linear regression the AI.

The activity of DPP-IV is determined in 96-well tablets at 37°in the volume of the reaction mixture of 100 μl. Buffer solution for analysis includes 50 mm Tris/HCl, pH of 7.8, containing 0.1 mg/ml BSA and 100 mm NaCl. The analyzed compounds dissolved in 100% DMSO and diluted to the desired concentration in 10% DMSO/N2O. the Final concentration of DMSO in the reaction mixture is 1% (vol./vol.). At this concentration, inactivation of the enzyme under the action of DMSO is<5%. Compounds analyzed using pre-incubation with the enzyme (37°C, 10 min) and without pre-incubation. The reaction is initiated by adding the substrate, followed by stirring.

The value of the IC50the analyzed compounds calculated by the method of nonlinear regression based on the results of the inhibition of DPP-IV at least five different concentrations of the analyzed compounds. Kinetic parameters of the enzymatic reaction count at least five different concentrati substrate and at least five different concentrations of the analyzed compounds.

As shown in the table, the preferred compounds of the present invention are characterized by the values of the IC50from 1 nm to 10 μm, more preferably 1-100 nm.

Example No.IC50(MK is)
760,391
13is 0.0002
120,0001
230,013
200,003
430,389
110,172
160,0007
790,873

The compounds of formula (I) and/or their pharmaceutically acceptable salts can be used as medicines, for example in the form of pharmaceutical preparations for enteral, parenteral or local administration. Connections can be entered, for example, by oral way, for example, in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally way in the form of suppositories, by parenteral way, for example, in the form of injection solutions or solutions for injection, local way, for example, in the form of ointments, creams or oils. Practicalin oral method.

Pharmaceutical drugs get in a known manner, for example, the recycling of specified compounds of the formula I and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable compounds in a mixture with suitable, non-toxic, inert, therapeutically acceptable the mi solid or liquid carriers and, if necessary, pharmaceutical adjuvants, in the finished herbal form.

Suitable carriers include both inorganic and organic materials. So, for example, at reception of tablets, coated tablets, dragées and hard gelatin capsules as carriers are lactose, corn starch or its derivatives, talc, stearic acid or its salts. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid or liquid polyols (depending on the nature of the active compounds in the case of soft gelatin capsules usually do not require any media). Suitable carriers for the receiving of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and other Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carriers for drugs topical application are glycerides, semi-synthetic and synthetic glycerides, hydrogenomonas oils, liquid waxes, vaseline, liquid fatty alcohols, sterols, glycols and derivatives of cellulose.

As pharmaceutical adjuvants used various hundred is ilistory, preservatives, wetting and emulsifying agents, agents for improving the texture, flavors, salts for regulating osmotic pressure, buffering agents, solubilizing agents, colorants, masking agents and antioxidants.

Doses of the compounds of formula I can vary from curable diseases, the age and relative health of the patient, method of administration, and must meet the individual requirements in each particular case. For adult patients a daily dose of from approximately 1 to 1000 mg, preferably from about 1 to 100 mg depending on the severity of the disease and specific pharmacokinetic profile of the compound can be introduced in the form of one or more standard doses, for example from 1 to 3 standard drinks.

The pharmaceutical preparations normally contain about 1-500 mg, preferably 1-100 mg of the compounds of formula I.

The invention is illustrated by the following examples without limiting its scope.

Examples

Abbreviations:

MS mass spectrometry, CT room temperature, THF tetrahydrofuran, TFU of triperoxonane acid, NMR spectroscopy nuclear magnetic resonance, DMF is dimethylformamide, DMSO is dimethylsulfoxide, DHM dichloromethane.

Example 1

Synthesis of arylmethylidene.

(scheme I, im the 1)

2-(2,4-Dichlorobenzamide)malononitrile

2,4-Dichlorobenzaldehyde (30,00 g, 171 mmol) and malononitrile (13,59 g, 206 mmol) suspended in 1-butanol (350 ml) in an argon atmosphere and was stirred for 15 minutes Then at RT was added 8 drops of piperidine and stirred for another 3 h, after which was added diethyl ether. The precipitate was separated by filtration, washed with diethyl ether and hexane, to receive specified in the title compound as a colourless solid (35,34 g, 92%). MS: m/e 222,8 (M+).

1H NMR (300 MHz, DMSO-d6, 25°): δ was 7.45 (m, 1H), to 7.59 (m, 1H), 8,18 (m, 2H).

The following methodenlehre was obtained in the same way as described above:

2-(4-triphtalocyaninine)malononitrile was obtained from 4-triftormetilfullerenov in the form of a solid (1.35 g, 48%), MS: m/e 222,9 (M+),

2-(2-methylbenzylidene)malononitrile was obtained from ortho-tolylaldehyde in the form of solids (1,99 g, 73%), MS: m/e 168, 8mm (M+),

2-(3-methoxybenzylidene)malononitrile received from a meta-anisic aldehyde in the form of solids (1,71 g, 55%), MS: m/e 184,7 (M+),

2-(2,4-dimethoxybenzamide)malononitrile was obtained from 2,4-dimethoxybenzaldehyde in the form of solids (2,48 g, 96%), MS: m/e 214,8 (M+),

2-(2,4-dimethylbenzylidene)malononitrile was obtained from 2,4-dimethylbenzaldehyde in the form of a solid (1.75 g, 63%), MS: m/e 1828 (M +),

2-(2-fluoro-4-methoxybenzylidene)malononitrile was obtained from 2-fluoro-4-methoxybenzaldehyde in the form of a solid (1.56 g, 64%), MS: m/e 202,7 (M+),

2-(2,4-differenziale)malononitrile was obtained from 2,4-diferentialglea in the form of a solid (2.38 g, 96%), MS: m/e 190,7 (M+),

2-(4-formanilide)malononitrile was obtained from 4-forventelige in the form of solids (1,87 g, 84%), MS: m/e to 172.8 (M+),

2-(2-bromobenzylamine)malononitrile was obtained from 2-bromobenzaldehyde in the form of solids (1,59 g, 57%), MS: m/e 233,8 (M+),

2-(2,4-bis-triphtalocyaninine)malononitrile was obtained from 2,4-bis(trifluoromethyl)benzaldehyde in the form of a solid (1.10 g, 92%), MS: m/e 290,7 (M+),

2-(2-formanilide)malononitrile was obtained from 2-forventelige in the form of a solid (1.55 g, 75%), MS: m/e 172,9 (M+),

2-thiophene-3-eletromechanical was obtained from 3-thiophenecarbaldehyde in the form of a solid (0.4 g, 21%),

2-(3-formanilide)malononitrile was obtained from 3-forventelige in the form of solids (1,72 g, 83%), MS: m/e 160,8 (M+),

2-(3-methylbenzylidene)malononitrile received from a meta-tolylaldehyde in the form of a solid (0.74 g, 37%), MS: m/e 168,7 (M+),

2-(2-triphtalocyaninine)malononitrile was obtained from 2-triftormetilfullerenov in the form of a solid (2.20 g, 83%), MS: m/e 222,8 (M+),

2-benzo[1,3]diox is l-5-eletromechanical received from piperonal in the form of solids (19,4 g, 98%), MS: m/e 189,8 (M+),

2-(4-methylbenzylidene)malononitrile was obtained from 4-methylbenzaldehyde in the form of solid, MS: m/e 168,9 (M+),

2-(4-chlorobenzylidene)malononitrile was obtained from 4-chlorobenzaldehyde in the form of solid, MS: m/e amounts to 188.7 (M+),

2-(2-methoxybenzylidene)malononitrile was obtained from 2-methoxybenzaldehyde in the form of solid, MS: m/e 184,8 (M+),

2-(2-chlorobenzylidene)malononitrile was obtained from 2-chlorobenzaldehyde in the form of solid, MS: m/e 188,9 (M+),

2-(3-chlorobenzylidene)malononitrile was obtained from 3-chlorobenzaldehyde in the form of solid, MS: m/e 188,9 (M+),

2-(4-methoxybenzylidene)malononitrile was obtained from 4-methoxybenzaldehyde in the form of solid, MS: m/e 184,7 (M+),

2-thiophene-3-eletromechanical was obtained from 3-thiophenecarbaldehyde in the form of solid, MS: m/e 160,8 (M+),

2-(3-methoxybenzylidene)malononitrile was obtained from 3-methoxybenzaldehyde in the form of solid, MS: m/e 184,8 (M+).

Example 2

Synthesis of benzamidine (scheme I, method 2)

3,5-Dimethoxybenzamide

Through a cooled (-15° (C) a solution of 3,5-dimethoxybenzonitrile (1.50 g, 9,20 mmole) for 30 min was passed dry HCl, and then reactional the mixture was kept in the refrigerator over night. The solvent is evaporated, the residue in the form of a solid white color Rast rely in ethanol, added to 9.2 ml of 2 M solution of ammonia in methanol and the reaction mixture was stirred at room temperature overnight. The solvent is evaporated, the residue was purified by chromatography on silica gel (eluent: Meon, DHM), to receive specified in the header connection (1,21 g, 71%). MS: m/e 181,2 (M+N+).

1H NMR (300 MHz, DMSO-d6, 25°): δ of 3.80 (s, 6H), PC 6.82 (t, J 2 Hz, 1H), 7,05 (t, J 2 Hz, 2H), 9,35 (.b, 3H).

The following benzamidine was obtained in the same way as described above:

3-triftorperasin was obtained from 3-trifluoromethyl-benzonitrile in the form of solids (1,14 g, 69%), MS: m/e 189,2 (M+N+),

2-methoxybenzamide was obtained from 2-methoxybenzonitrile in the form of a solid (113 mg, 7%), MS: m/e 151,2 (M+N+),

3,4,5-trimethoxybenzamide were obtained from 3,4,5-trimethoxybenzaldehyde in the form of solid, MS: m/e 211,3 (M+N+),

3,4-dimethoxybenzamide was obtained from 3,4-dimethoxybenzaldehyde in the form of solid, MS: m/e 181,2 (M+N+),

thiophene-2-carboxamide were obtained from thiophene-3-carbonitrile in the form of solid, MS: m/e 127,1 (M+N+),

2-ferbenstein was obtained from 2-perbenzoate in the form of solid, MS: m/e 139,2 (M+N+),

4-chlorobenzamide was obtained from 4-chlorobenzonitrile in the form of solid, MS: m/e 154,2 (M+N+),

4-methylbenzamide was obtained from 4-methylbenzonitrile as the firmness of the Dogo substances, MS: m/e 135,1 (M+N+),

4-methoxybenzamide was obtained from 4-methoxybenzonitrile in the form of solid, MS: m/e 151, 3mm (M+N+),

benzo[1,3]dioxol-5-carboxamidine received from benzo[1,3]dioxol-5-carbonitrile in the form of solid, MS: m/e 165,2 (M+H+),

naphthalene-1-carboxamidine received from naphthalene-1-carbonitrile in the form of solid, MS: m/e 171,2 (M+N+),

3-methoxybenzamide was obtained from 3-methoxybenzonitrile in the form of solid, MS: m/e 151, 3mm (M+N+),

2-chloro-4-ferbenstein was obtained from 3-chloro-4-perbenzoate in the form of solid, MS: m/e 173,1 (M+N+),

2-methylbenzamide was obtained from 2-methylbenzonitrile in the form of solid, MS: m/e 134,1 (M+N+),

1H-indole-2-carboxamidine was obtained from 1H-indole-2-carbonitrile in the form of solid, MS: m/e 160,2 (M+N+),

benzofuran-2-carboxamidine received from benzofuran-2-carbonitrile in the form of solid, MS: m/e 161,3 (M+N+),

isonicotinamide was obtained from 4-cyanopyridine in the form of solid, MS: m/e 122,2 (M+N+).

Example 3 (scheme I), 3)

Synthesis of 4-aminopyrimidine-3-carbonitrile

4-Amino-6-(2,4-dichlobenil)-2-phenylpyrimidine-5-carbonitrile

To a suspension of 2-(2,4-dichlorobenzamide)malononitrile (4 g, 17.9 mmole) in methanol was added potassium carbonate (4,34 g of 31.4 mmole) and benzamidine (2,59 g, 21.5 mmole), the mixture was yellow what about the color was stirred at room temperature for 1 h, and then boiled under reflux for 2 hours Then the mixture was cooled, the solvent was removed under reduced pressure and the residue was transferred into ethyl acetate/ice. The organic phase was separated, washed with water and dried over sodium sulfate. The solvent is evaporated, the residue is orange tolerated in acetone, was added 1,91 g permanganate potassium and was stirred for 90 minutes the Reaction mixture was filtered through dekalim and evaporated. The residue was purified rapid chromatography on silica gel (eluent: EtOAc/hexane), was obtained is listed in the title compound as a solid (2,63 g, 43%). MS: m/e 340,8 (M+).

1H NMR (300 MHz, DMSO-d6, 25°): δ of 7.48-of 7.60 (m, 3H), 7,62-to 7.68 (m, 2H), to 7.77 (s, 1H), 8.30 to (.s, 2H), 8,60-to 8.70 (m, 2H).

The following 4-aminopyrimidine-5-carbonitrile was obtained in the same way as described above:

4-amino-6-benzo[1,3]dioxol-5-yl-2-phenylpyrimidine-5-carbonitrile was obtained from 2-benzo[1,3]dioxol-5-eletromechanical in the form of solids (629 mg, 23%), MS: m/e 315,9 (M+),

4-amino-6-benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)pyrimidine-5-carbonitrile was obtained from 2-benzo[1,3]dioxol-5-eletromechanical and a pair of methoxybenzamide in the form of a solid (78 mg, 26%), MS: m/e 346,2 (M+).

4-amino-2-phenyl-6-(4-triptoreline)pyrimidine-5-carbonitrile was obtained from 2-(4-triphtalocyaninine)malonamic the sludge in the form of a solid (312 mg, 20%), MS: m/e 340,1 (M+),

4-amino-2-phenyl-6-ortho-tolylboronic-5-carbonitrile was obtained from 2-(2-methylbenzylidene)malononitrile in the form of a solid (700 mg, 22%), MS: m/e 286,8 (M+N+),

4-amino-6-(3-methoxyphenyl)-2-phenylpyrimidine-5-carbonitrile was obtained from 2-(3-methoxybenzylidene)malononitrile in the form of a solid (391 mg, 15%), MS: m/e 301,8 (M+),

4-amino-2-phenyl-6-meta-tolylboronic-5-carbonitrile was obtained from 2-(3-methylbenzylidene)malononitrile in the form of a solid (515 mg, 28%), MS: m/e 286,1 (M+),

4-amino-2-phenyl-6-para-tolylboronic-5-carbonitrile was obtained from 2-(4-methylbenzylidene)malononitrile in the form of a solid (3.13 g, 37%), MS: m/e 286,0 (M+),

4-amino-6-(2,4-dichlorophenyl)-2-(3-methoxyphenyl)pyrimidine-5-carbonitrile was obtained from 2-(2,4-dichlorobenzamide)malononitrile and 3-methoxybenzamide in the form of a solid (17 mg, 32%), MS: m/e 371,2 (M+N+),

4-amino-6-(2,4-differenl)-2-phenylpyrimidine-5-carbonitrile was obtained from 2-(2,4-differenziale)malononitrile in the form of a solid (430 mg, 88%),

4-amino-6-(2,4-dichlorophenyl)-2-meta-tolylboronic-5-carbonitrile was obtained from 2-(2,4-dichlorobenzamide)malononitrile and 3-methylbenzamide in the form of a solid (150 mg, 87%), MS: m/e 308,1 (M+),

4-amino-6-(2,4-dichlorophenyl)-2-(3,4,5-trimethoxyphenyl)pyrimidine-5-carbonitrile was obtained from 2-(2,4-dichlorobenzamide)malononitrile and 3,4,5-three is ethoxybenzylidene in the form of a solid (1.4 g, 96%), MS: m/e 430,0 (M+).

Example 4 (scheme I, method 4)

Synthesis of 5-aminomethylpyrimidine-4-ylamino

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-phenylpyrimidine-4-ylamine

To a suspension of LiAlH4 in THF (3 ml) in an argon atmosphere was slowly added a solution of 4-amino-6-(2,4-dichlobenil)-2-phenylpyrimidine-5-carbonitrile (1,16 g 0,34 mmole) in THF (6 ml) and the reaction mixture was stirred at 40°C for 2 hours Then the mixture was cooled to -20°and added water (0.6 ml). After 15 min was added ethyl acetate and the mixture was filtered through dekalim. The organic phase was separated, washed with water and dried over sodium sulfate. The product was purified rapid chromatography on silica gel (eluent: methanol, diclomelan), to receive specified in the title compound in the form of solid light yellow (0,446 g, 40%). MS: m/e 344,2 (M+).

1H NMR (300 MHz, DMSO-d6, 25°): δ at 3.35 (d, J 11 Hz, 1H), 3,50 (d, J 11 Hz, 1H), 7,28 (.s, 2H), 7,38-7,46 (M, 3H), 7,50-7,58 (M, 2H), of 7.75 (s, 1H), 8,20-8,30 (M, 2H).

Example 5

5-Aminomethyl-2-phenyl-6-para-tolylboronic-4-ylamine

Specified in the title compound was obtained as a solid (190 mg, 37%) of 4-amino-2-phenyl-6-para-tolylboronic-5-carbonitrile similar to the method described in example 4. MS: m/e 289,9 (M+).

Example 6

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(3-methoxy who enyl)pyrimidine 4-ylamine

Specified in the title compound was obtained as a solid (1.5 mg, 9%) of 4-amino-6-(2,4-dichlorophenyl)-2-(3-methoxyphenyl)pyrimidine-5-carbonitrile similar to the method described in example 4. MS: m/e 374,9 (M+).

Example 7

5-Aminomethyl-2-phenyl-6-ortho-tolylboronic-4-ylamine

Specified in the title compound was obtained as a solid (62 mg, 31%) of 4-amino-2-phenyl-6-ortho-tolylboronic-5-carbonitrile similar to the method described in example 4. MS: m/e 290,8 (M+N+).

Example 8

5-Aminomethyl-6-(2,4-differenl)-2-phenylpyrimidine 4-ylamine

Specified in the title compound was obtained as a solid (21 mg, 10%) from 4-amino-2-phenyl-6-ortho-tolylboronic-5-carbonitrile similar to the method described in example 4. MS: m/e 312,1 (M+).

Example 9

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-meta-tolylboronic-4-ylamine

Specified in the title compound was obtained as a solid (1.4 mg, 92%) of 4-amino-6-(2,4-dichlorophenyl)-2-meta-tolylboronic-5-carbonitrile similar to the method described in example 4. MS: m/e 359,1 (M+N+).

Example 10

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(3,4,5-trimethoxyphenyl)pyrimidine-4-ylamine

Listed is in the title compound was obtained as a solid (164 mg, 12%) of 4-amino-6-(2,4-dichlorophenyl)-2-(3,4,5-trimethoxyphenyl)pyrimidine-5-carbonitrile similar to the method described in example 4. MS: m/e 434,9 (M+).

Example 11

Preparative synthesis of 5-aminomethylpyrimidine-4-ylamino from arylmethylidene (scheme I, method 5)

5-Aminomethyl-6-(2,4-dimetilfenil)-2-phenylpyrimidine-4-ylamine

Benzamide (48 mg, 0.4 mmole) and potassium carbonate (97 mg, 0.7 mmole) were placed in a reaction vessel and suspended in 2 ml of the Meon. Then added 2-(2,4-dimethylbenzylidene)malononitrile (87 mg, 0.48 mmol), the reaction vessel was sealed and shaken at RT for 30 min and then at 60°C for 3 hours the Mixture was cooled and filtered, the filtrate was evaporated in a vacuum centrifuge (45°). The residue was dissolved in 2 ml acetone, was added 63 mg (0.4 mmole) KMnO4and the mixture was shaken at RT for 2 h Then the mixture was filtered and the filtrate was evaporated in a vacuum centrifuge (45°). The residue was dissolved in 1 ml DMF and purified using the automated system for preparative GHUR (column YMC CombiPrep C18, 50×20 mm, eluent: gradient of CH3CN/water+0.1% of TFU, from 5% to 95%, the rate of elution of 40 ml/min, the time of 6.0 min, λ 230 nm). The obtained intermediate compound (22 mg) was dissolved in THF (1 ml) and cooled (0° (C) in argon atmosphere was added into the reaction vessel with suspensie is 100 mg of sociallyengaged in 1 ml THF. The reaction mixture was shaken at RT for 2 h and then at 40°C for 4 h, After cooling, to the mixture was carefully added water and the mixture was filtered. The filtrate was evaporated in a vacuum centrifuge (45°). The residue was dissolved in 1 ml DMF and purified using the system for preparative GHUR (column YMC CombiPrep C18, 50×20 mm, eluent: gradient of CH3CN/water +0.1% of TFU, from 5% to 95%, the rate of elution of 40 ml/min, the time of 6.0 min, λ 230 nm), while received 8 mg (7%) indicated in the title compounds as solids. MS: m/e 304,9 (M+).

Example 12

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(3,5-acid)pyrimidine-4-ylamine

Specified in the title compound was obtained as a solid substance from a 3.5-dimethoxybenzidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 405,4 (M+N+).

Example 13

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(3-forfinal)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 3-ferbenstein and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 362,9 (M+N+).

Example 14

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(4-forfinal)pyrimidine-4-ylamine

Specified in reception is e compound was obtained as solid from 4-ferbenstein and 2-(2,4-dichlorobenzamide)malononitrile same way, described in example 11. MS: m/e 362,9 (M+N+).

Example 15

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(4-methoxy-1-methyl-1H-indol-6-yl)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 4-methoxy-1-methyl-1H-indole-6-carboxamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 428,0 (M+N+).

Example 16

5-Aminomethyl-2-benzofuran-2-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine

Specified in the title compound was obtained in the form of solid substances from benzofuran-2-carboxamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 385,3 (M+N+).

Example 17

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(1H-indol-2-yl)pyrimidine-4-ylamine

Specified in the title compound was obtained as a solid substance from 1H-indole-2-carboxamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 383,9 (M+N+).

Example 18

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-meta-tolylboronic-4-ylamine

Specified in the title compound was obtained as solid from 3-methylbenzamide and 2-(2,4-dichlorobenzamide)malononitrile same way, describe the approach in example 11. MS: m/e 359,1 (M+N+).

Example 19

2-(4-Amino-3-methoxyphenyl)-5-aminomethyl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 4-amino-3-methoxybenzamide and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 389,9 (M+N+).

Example 20

5-Aminomethyl-2-azepin-1-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine

Specified in the title compound was obtained as a solid substance from azepin-1 carboxamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 366,0 (M+N+).

Example 21

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(3,4-differenl)pyrimidine-4-ylamine

Specified in the title compound was obtained as a solid substance of 3,4-diftorbenzofenon and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 381,3 (M+N+).

Example 22

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-pyrrolidin-1-yl-pyrimidine-4-ylamine

Specified in the title compound was obtained in the form of solid substances from pyrrolidin-1 carboxamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 337,8 (M+).

Example 23

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-methylsulfonylamino-4-ylamine

Specified in the title compound was obtained as solid from 2-methylisothiazoline and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 315,2 (M+).

Example 24

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(3,4-acid)pyrimidine-4-ylamine

Specified in the title compound was obtained as a solid substance of 3,4-dimethoxybenzamide and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 405,3 (M+N+).

Example 25

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-thiophene-2-Yeremey-4-ylamine

Specified in the title compound was obtained as a solid substance from thiophene-2-carboxamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 351,2 (M+N+).

Example 26

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(2-forfinal)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-ferbenstein and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 363,0 (M+N+).

Example 27

5-Aminomethyl-2-(4-chlorophenyl)-6(2,4-dichlorophenyl)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 4-chlorobenzamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 377,8 (M+).

Example 28

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-methoxy-pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-methylisoleucine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 337,8 (M+).

Example 29

5-Aminomethyl-2-cyclopropyl-6-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as a solid substance of cyclopropanecarboxamide and 2-benzylidenemalononitrile similar to the method described in example 11. MS: m/e 240,1 (M+).

Example 30

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-pair-tolylboronic-4-ylamine

Specified in the title compound was obtained as solid from 4-methylbenzamide and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 358,2 (M+).

Example 31

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(4-methoxyphenyl)pyrimidine-4-ylamine

Specified in the title compound was obtained is a solid 4-methoxybenzamide and 2-(2,4-dichlorobenzamide)malononitrile same way, described in example 11. MS: m/e 375,3 (M+N+).

Example 32

5-Aminomethyl-2-benzo[1,thioxo-5-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine

Specified in the title compound was obtained as a solid substance from benzo[1,3]dioxol-5-carboxamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 388,2 (M+).

Example 33

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(3-triptoreline)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 3-triftorperasin and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 412,9 (M+N+).

Example 34

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-morpholine-4-yl-pyrimidine-4-ylamine

Specified in the title compound was obtained as a solid substance from morpholine-4-carboxamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 353,9 (M+).

Example 35

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(4-triptoreline)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 4-triftorperasin and 2-(2,4-dichlorobenzamide)malononitrile similar to the way described is anomo in example 11. MS: m/e 412,9 (M+N+).

Example 36

5-Aminomethyl-2-(3-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 3-chlorobenzamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 378,8 (M+N+).

Example 37

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-methylpyrimidin-4-ylamine

Specified in the title compound was obtained as a solid substance of acetamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 282,9 (M+N+).

Example 38

5-Aminomethyl-6-(2.4-dichlorophenyl)-2-naphthalene-2-yl-pyrimidine-4-ylamine

Specified in the title compound was obtained as a solid substance from naphthalene-2-carboxamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 394,9 (M+N+).

Example 39

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-naphthalene-1-yl-pyrimidine-4-ylamine

Specified in the title compound was obtained as a solid substance from naphthalene-1-carboxamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 395,3 (M+N+).

Example 40

5-Aminomethyl-6-(2,4-Dich arvanil)-2-(3-methoxyphenyl)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 3-methoxybenzamide and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 374,8 (M+).

Example 41

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(3,5-differenl)pyrimidine-4-ylamine

Specified in the title compound was obtained as a solid substance from a 3.5-diftorbenzofenon and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 380,9 (M+N+).

Example 42

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(2-methoxyphenyl)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-methoxybenzamide and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 374,8 (M+N+).

Example 43

5-Aminomethyl-6-(4-ethylphenyl)-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(4-ethylbenzamide)malononitrile similar to the method described in example 11. MS: m/e 304,8 (M+N+).

Example 44

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-isopropylpyrimidine-4-ylamine

Specified in the title compound was obtained in VI is e solids of isobutyramide and 2-(2,4-dichlorobenzamide)malononitrile same way, described in example 11. MS: m/e 311,2 (M+N+).

Example 45

5-Aminomethyl-2-(2-chloro-4-forfinal)-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-chloro-4-ferbenstein and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 396,8 (M+).

Example 46

5-Aminomethyl-2-benzo[b]thiophene-2-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine

Specified in the title compound was obtained as a solid substance from benzo[b]thiophene-2-carboxamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 400,9 (M+N+).

Example 47

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(6-methoxy-naphthalene-2-yl)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 6-methoxynaphthalene-2-carboxamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 425,0 (M+N+).

Example 48

5-Aminomethyl-2-phenyl-6-meta-tolylboronic-4-ylamine

Specified in the title compound was obtained as solid from 4-amino-2-phenyl-6-meta-tolylboronic-5-carbonitrile similar to the method described in example 11. MS m/e 291,2 (M+N +).

Example 49

5-Aminomethyl-6-(4-chlorophenyl)-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(4-chlorobenzylidene)malononitrile similar to the method described in example 11. MS: m/e 311,0 (M+N+).

Example 50

5-Aminomethyl-2-phenyl-6-(4-triptoreline)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(4-triphtalocyaninine)malononitrile similar to the method described in example 11. MS: m/e 344,0 (M+).

Example 51

5-Aminomethyl-6-(2-methoxyphenyl)-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(2-methoxybenzylidene)malononitrile similar to the method described in example 11. MS: m/e 306,8 (M+).

Example 52

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-ortho-tolylboronic-4-ylamine

Specified in the title compound was obtained as solid from 2-methylbenzamide and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 358,9 (M+N+).

Example 53

5-Aminomethyl-2-(3,5-bis-triptoreline)-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine

The decree is Noah in the title compound was obtained as a solid substance from 3,5-bis-triftorperasin and 2-(2,4-dichlorobenzamide)malononitrile same way, described in example 11. MS: m/e 481,2 (M+N+).

Example 54

5-Aminomethyl-6-(2,4-dichlorophenyl)-2-(4-forfinancial)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(4-pertenece)acetamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 392,8 (M+N+).

Example 55

5-Aminomethyl-6-(2-chlorophenyl)-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(2-chloro-benzylidene)malononitrile similar to the method described in example 11. MS: m/e 311,0 (M+).

Example 56

5-Aminomethyl-6-(2-bromophenyl)-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(2-bromo-benzylidene)malononitrile similar to the method described in example 11. MS: m/e 354,8 (M+).

Example 57

5-Aminomethyl-2-dibenzofuran-2-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine

Specified in the title compound was obtained in the form of solid substances from dibenzofuran-2-carboxamidine and 2-(2,4-dichlorobenzamide)malononitrile similar to the method described in example 11. MS: m/e 434,9 (M+).

Example 58

5-Aminomethyl-6-(2,4-bis-triptoreline-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(2,4-bis-triphtalocyaninine)malononitrile similar to the method described in example 11. MS: m/e 413,0 (M+N+).

Example 59

5-Aminomethyl-6-(2-fluoro-4-methoxyphenyl)-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(2-fluoro-4-methoxybenzylidene)malononitrile similar to the method described in example 11. MS: m/e 324,8 (M+).

Example 60

5-Aminomethyl-6-(2,4-acid)-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(2,4-dimethoxybenzamide)malononitrile similar to the method described in example 11. MS: m/e 336,8 (M+).

Example 61

5-Aminomethyl-2-(1H-indol-2-yl)-6-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as a solid substance from 1H-indole-2-carboxamidine and 2-benzylidenemalononitrile similar to the method described in example 11. MS: m/e 315,8 (M+N+).

Example 62

5-Aminomethyl-6-benzo[1,3]dioxol-5-yl-2-cyclopropylamino-4-ylamine

Specified in the title compound was obtained in the form of solid substances from cyclopropyl is carboxamidine and 2-benzo[1,3]dioxol-5-eletromechanical same way, described in example 11. MS: m/e 284,7 (M+N+).

Example 63

5-Aminomethyl-6-(2-forfinal)-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(2-formanilide)malononitrile similar to the method described in example 11. MS: m/e 294,9 (M+N+).

Example 64

5-Aminomethyl-2-phenyl-6-(2-triptoreline)pyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(2-triphtalocyaninine)malononitrile similar to the method described in example 11. MS: m/e 345,1 (M+N+).

Example 65

5-Aminomethyl-2-benzofuran-2-yl-6-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained in the form of solid substances from benzofuran-2-carboxamidine and 2-benzylidenemalononitrile similar to the method described in example 11. MS: m/e 316,7 (M+N+).

Example 66

5-Aminomethyl-6-(4-forfinal)-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(4-fluoro-benzylidene)malononitrile similar to the method described in example 11. MS: m/e of 294.8 (M+N+).

Example 67

5-Aminomethyl-2-(3,4-acid)-6-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as a solid substance of 3,4-dimethoxybenzamide and 2-benzylidenemalononitrile similar to the method described in example 11. MS: m/e 336,8 (M+H+).

Example 68

5-Aminomethyl-6-phenyl-2-pyridine-4-Yeremey-4-ylamine

Specified in the title compound was obtained as a solid substance of isonicotinamide and 2-benzylidenemalononitrile similar to the method described in example 11. MS: m/e 278,0 (M+N+).

Example 69

5-Aminomethyl-6-(3-chlorophenyl)-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(3-chlorobenzylidene)malononitrile similar to the method described in example 11. MS: m/e 31,0 (M+H+).

Example 70

5-Aminomethyl-6-phenyl-2-thiophene-2-Yeremey-4-ylamine

Specified in the title compound was obtained as a solid substance from thiophene-2-carboxamidine and 2-benzylidenemalononitrile similar to the method described in example 11. MS: m/e 282,8 (M+N+).

Example 71

5-Aminomethyl-6-(3-forfinal)-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(3-formanilide)malononitrile similar to the method described in example 11. MS: m/e of 294.8 (MN +).

Example 72

5-Aminomethyl-2,6-diphenylpyridine-4-ylamine

Specified in the title compound was obtained as solid from 2-benzylidenemalononitrile similar to the method described in example 11. MS: m/e 276,9 (M+N+).

Example 73

5-Aminomethyl-6-(4-methoxyphenyl)-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 2-(4-methoxybenzylidene)malononitrile similar to the method described in example 11. MS: m/e 306,9 (M+N+).

Example 74

5-Aminomethyl-2-phenyl-6-thiophene-3-Yeremey-4-ylamine

Specified in the title compound was obtained as solid from 2-thiophene-3-eletromechanical similar to the method described in example 11. MS: m/e 283,0 (M+N+).

Example 75

5-Aminomethyl-6-(3-methoxyphenyl)-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained as solid from 4-amino-6-(3-methoxyphenyl)-2-phenylpyrimidine-5-carbonitrile similar to the method described in example 11. MS: m/e 307,2 (M+N+).

Example 76 (scheme I, method 6)

6-(2,4-Dichlorophenyl)-5-methylaminomethyl-2-phenylpyrimidine-4-ylamine

To a solution of 4-amino-6-(2,4-dichlorophenyl)-2-phenyl shall eremein-5-carbonitrile (60 mg, 0,174 mmole) in THF (1 ml) in an argon atmosphere was added 9-BBN (0,348 ml of 0.5 M solution in hexane, 0,174 mmole) and the mixture was stirred at RT for 2.5 h and Then was added tert-butyl potassium (20 mg, 0,174 mmole), and after 10 min was added dropwise modesty methyl. The mixture was stirred overnight, then was added ethanolamine (11 mg, 0,174 mmole) and the mixture was heated at 50°C for 3 hours the Mixture was cooled, filtered and the filtrate was evaporated. The residue was dissolved in 1 ml DMF and purified using the automated system for preparative GHUR (column YMC CombiPrep C18, 50×20 mm, eluent: gradient of CH3CN/water+0.1% of TFU, from 5% to 95%, the rate of elution of 40 ml/min, the time of 6.0 min, λ 230 nm), thus received is listed in the title compound (12 mg, 19%) as a foam. MS: m/e 358,9 (M+N+).

Example 77

Synthesis of 2-aminonicotinamide (scheme II, method 7)

2-Amino-4-(2,4-dichlorophenyl)-6-familycommunity

A mixture of 2-(2,4-dichlorobenzamide)malononitrile (1,125 g, 5 mmol), acetophenone (601 mg, 5 mmol), ammonium acetate (578 mg, 7.5 mmol) and toluene (5 ml) was boiled under reflux with stirring for 3 hours the mixture is Then cooled to room temperature, transferred into ethyl acetate, was extracted with a saturated solution of NaHCO3, water, saturated NaCl and dried over Na2SO4. The solvent is evaporated, the residue was purified by chromatography nakaloke silica gel (eluent: hexane, the ethyl acetate), was obtained is listed in the title compound (600 mg, 35%). MS: m/e 339,5 (M+N+).

1H NMR (300 MHz, CDCl3, 25°): δ 5,38 (.s, 2H), 7,13 (s, 1H), 7,30-7,58 (m, 6N), 7,95-8,02 (m, 2H).

The following 2-aminonicotinamide was obtained in the same way as described above:

2-amino-4-(2,4-dichlorophenyl)-5-methyl-6-familycommunity received from propiophenone in the form of a solid (425 mg, 24%). MS: m/e 353,9 (M+N+).

Example 78

Synthesis of 3-aminomethylpyridine-2-ylamino (scheme II, method 8)

3-Aminomethyl-4-(2,4-dichlorophenyl)-6-phenylpyridine-2-ylamine

To a suspension of LiAlH4(324 mg, charged 8.52 mmole)in THF (2 ml) in an argon atmosphere was slowly added a solution of 2-amino-4-(2,4-dichlorophenyl)-6-fenilcetonuria (580 mg, 1,71 mmole) in THF (2 ml) and the resulting mixture was stirred at room temperature for 2 h Then the reaction mixture was cooled to -20°and added water (0.4 ml). After 15 min was added ethyl acetate and the mixture was filtered through dekalim. The organic phase was separated, washed with water and dried over sodium sulfate. The product was purified Express chromatography on silica gel (eluent: methanol, dichloromethane), to receive specified in the title compound in the form of solid light yellow (36 mg, 6%). MS: m/e 343,8 (M+N+).

1H NMR (300 MHz, CDCl3, 25°): δ 3,40 (d, J 10 Hz, 1H)and 3.59 (d, J 10 Hz, 1H), of 6.49 (.s, 2H), 6.90 to (s, 1H), 7,30-of 7.55 (m, 5H), EUR 7.57 (s, 1H), of 7.90-8,10 (m, 2H).

Example 79

3-Aminomethyl-4-(2,4-dichlorophenyl)-5-methyl-6-phenylpyridine-2-ylamine

Specified in the title compound was obtained as a solid (22 mg, 9%) of 2-amino-4-(2,4-dichlorophenyl)-5-methyl-6-fenilcetonuria similar to the method described in example 78. MS: m/e 357,9 (M+).

Example 80

Preparative recovery of carbonitriles with the formation of aminomethyl-compounds (schemes I and II, method 9)

[5-Aminomethyl-6-(4-chlorophenyl)-2-pyridin-3-Yeremey-4-yl]methylamine

Preparative recovery of carbonitriles with the formation of aminomethyl connections

4-(4-Chlorophenyl)-6-(dimethylamino)-2-(3-pyridinyl)-5-pyrimidinamine (firm Bionet) (50 mg, 0,155 mmol) was dissolved in THF (1 ml) and was added into the flask with cooled (0° (C) suspension of 100 mg of sociallyengaged in 1 ml THF. The reaction mixture was shaken at RT for 2 h and then at 40°C for 4 h the Mixture was cooled, carefully added water and the mixture was filtered. The filtrate was evaporated in a vacuum centrifuge (45°). The residue was dissolved in 1 ml DMF and purified using the automated system for preparative GHUR (column YMC CombiPrep 18, 50×20 mm, eluent: gradient of CH3CN/water +0.1% of TFU, from 5% to 95%, the rate of elution of 40 ml/min, the time of 6.0 min λ 230 nm), thus received is listed in the title compound (17 mg, 34%)as a solid. MS: m/e of 326.0 (M+N+).

Example 81

5-Aminomethyl-6-benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)pyrimidine-4-ylamine

Specified in the title compound was obtained from 4-amino-6-benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)pyrimidine-5-carbonitrile similar to the method described in example 80. MS: m/e 351,0 (M+N+).

Example 82

5-Aminomethyl-6-benzo[1,3]dioxol-5-yl-2-phenylpyrimidine-4-ylamine

Specified in the title compound was obtained from 4-amino-6-benzo[1,3]dioxol-5-yl-2-phenylpyrimidine-5-carbonitrile similar to the method described in example 80. MS: m/e 321,0 (M+N+).

Example 83

[5-Aminomethyl-6-(4-chlorophenyl)-2-pyridin-3-Yeremey-4-yl]Isopropylamine

Specified in the title compound was obtained from 4-(4-chlorophenyl)-6-(isopropylamino)-2-(3-pyridinyl)-5-pyrimidinecarbonitrile similar to the method described in example 80. MS: m/e 354,1 (M+N+).

Example 84

(5-Aminomethyl-2,6-diphenylpyridine-4-yl)methylamine

Specified in the title compound was obtained from 4-(methylamino)-2,6-diphenyl-5-pyrimidinecarbonitrile (Bionet) similar to the method described in example 80. MS: m/e 290,9 (M+N+).

Example 85

3-aminomethyl-4-(4-chlorophenyl)-5-methyl-6-phenylpyridine-2-ylamine

Specified in the title compound was obtained from 2-amino-4-(4-chlorophenyl)-5-methyl-6-fenilcetonuria (Bionet) similar to the method described in example 80. MS: m/e 323,9 (M+N+).

Example 86

3-Aminomethyl-4-(4-chlorophenyl)-6-phenylpyridine-2-ylamine

Specified in the title compound was obtained from 2-amino-4-(4-chlorophenyl)-6-fenilcetonuria (Bionet) similar to the method described in example 80. MS: m/e 310,3 (M+N+).

Example 87

3-Aminomethyl-4,6-bis-(4-forfinal)pyridin-2-ylamine

Specified in the title compound was obtained from 2-amino-4,6-bis-(4-forfinal)nicotinanilide similar to the method described in example 80. MS: m/e 311,9 (M+N+).

Example 88

(scheme II, method 10)

3-Aminomethyl-4-benzo[1,3]dioxol-5-yl-6-vinylpyridin-2-ylamine

4-Benzo[1,3]dioxol-5-eletromechanical (79 mg, 0.4 mmole), benzophenone (48 mg, 0.4 mmole), ammonium acetate (78 mg, 1.2 mmole) and toluene (4 ml) were placed in the reaction vessel was shaken at 118°With during the night. The mixture is then cooled and filtered, the solution was evaporated in a vacuum centrifuge (45° (C), the residue was purified using an automated system for preparative GHUR (column YMC CombiPrep C18, 50×20 mm, eluent: gradient of CH3CN/in the Yes+0.1% of TFU, 5% to 95%, the rate of elution of 40 ml/min, the time of 6.0 min, λ 230 nm). The obtained solid (28 mg) was dissolved THF (1 ml) in an argon atmosphere was added into the reaction flask with cooled (0° (C) suspension of 100 mg of sociallyengaged in 1 ml THF. The mixture was shaken at RT for 2 h and then at 40°C for 4 h the Mixture was cooled, carefully dallali water and filtered. The filtrate was evaporated in a vacuum centrifuge (45°). The residue was dissolved in 1 ml DMF and purified using the automated system for preparative GHUR (column YMC CombiPrep C18, 50×20 mm, eluent: gradient of CH3CN/water +0.1% of TFU, from 5% to 95%, the rate of elution of 40 ml/min, the time of 6.0 min, λ 230 nm), thus received is listed in the title compound (11 mg, 7%) as a solid. MS: m/e 320,1 (M+N+).

Examples herbal medicines of

Example

Coated tablets of the following composition was obtained in the standard way:

Ingredients1 tablet
Engine:
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
The hydrated lactose60,0 mg 70.0 mg
Povidone K3012.5 mg15,0 mg
Sodium starch glycolate12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
Mass of nucleus120,0 mg350,0 mg
Coverage:
The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mg1.6 mg
Talc1.3 mg2.6 mg
Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide0.8 mg1.6 mg

The active compound was screened and mixed with microcrystalline cellulose, and then the mixture was granulated in a mixture with a solution of polyvinylpyrrolidone in water. The granulate was mixed with sodium starch glycolate and magnesium stearate, extruded to form the core tablets weighing 120 or 350 mg, respectively. The core was coated with an aqueous solution/suspension of the above composition.

Example B

Capsules of the following composition was obtained in the standard way:

Ingredients1 capsule is
The compound of formula (I)25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
Talc5.0 mg

The components were screened, mixed and the mixture was filled in capsules size

2.

The example In

The injectable solutions of the following composition was obtained in the standard way:

The compound of formula (I)3.0 mg
The polyethylene glycol 400150,0 mg
Acetic acidq.s. to pH 5.0
Water for injectionsto 1.0 ml

The active ingredient was dissolved in a mixture of polyethylene glycol 400 and volume parts of water for injection. Was added acetic acid to pH 5.0 and made up to 1.0 ml by adding the rest of the water. The solution was filtered, poured into bottles and sterilized.

Example D

Soft gelatin capsules of the following composition was obtained in the standard way:

The capsules composition

The compound of formula (I)5.0 mg
Yellow wax8.0 mg
Hydrogenated soybean oil8.0 mg
Partially hydrogenated races is sustained fashion
oil34.0 m
Soybean oil110,0 mg
Mass content capsules165,0 mg

Gelatin capsule

Gelatin75,0 mg
Glycerol 85%32,0 mg
Karion 838.0 mg (dry)
Titanium dioxide0.4 mg
Iron oxide (yellow)1.1 mg

The active ingredient was dissolved in warm molten mixture of other ingredients and the mixture was filled in soft gelatin capsules of suitable size. Filled soft gelatin capsules were processed in a standard way.

Example D

Bags sleduyuscheego composition was obtained in the standard way:

The compound of formula (I)50.0 mg
Lactose, fine powder1015,0 mg
Microcrystalline cellulose (AVICEL PH 102)1400,0 mg
Carboxymethylcellulose, sodium salt14,0 mg
Polyvinylpyrrolidone K 3010.0 mg
Magnesium stearate10.0 mg
Flavors 1.0 mg

The active ingredient was mixed with lactose, microcrystalline cellulose and sodium salt of carboxymethyl cellulose were granulated in a mixture with a solution of polyvinylpyrrolidone in water. The granules were mixed with magnesium stearate and flavorings, and then Packed up in bags.

1. The compounds of formula (I)

where X is N or C-R5,

R1and R2independently mean hydrogen, C1-6-alkyl,

R3means saturated or aromatic 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, possibly condensed with 1 or 2 benzene rings, saturated or aromatic 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, possibly condensed with 1 or 2 benzene rings, independently mono-, di or tizamidine C1-6-alkyl, C1-6-alkoxy, PERFLUORO-C1-6-alkyl or halogen;

phenyl; naphthyl;

phenyl or naphthyl, independently mono-, di - or tizamidine halogen, C1-6-alkyl, C1-6-alkoxy or PERFLUORO-C1-6-alkyl,

R4means (lower) alkyl, (lower) alkoxy, (lower) alkylthio, saturated or aromatic 5-7 membered heterocyclyl containing 1-2 heteroatoms selected and the nitrogen sulfur and oxygen, possibly condensed with 1 or 2 benzene rings, saturated or aromatic 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, possibly condensed with 1 or 2 benzene rings, independently mono-, di - or tizamidine C1-6-alkyl, C1-6-alkoxy, PERFLUORO-C1-6-alkyl or halogen;

phenyl; naphthyl;

phenyl or naphthyl, independently mono-, di - or tizamidine halogen, C1-6-alkyl, C1-6-alkoxy, amino or PERFLUORO-C1-6-alkyl; 4-formaniacs-C1-6-alkyl or C3-C6cycloalkyl,

R5means hydrogen or C1-6-alkyl,

in addition to the compounds where R4- CH3Oh, R3-Ph, R1, R2-H, X Is N, and their pharmaceutically acceptable salts.

2. Compounds according to claim 1, where R1means hydrogen.

3. Compounds according to claim 1, where R2means hydrogen.

4. Compounds according to claim 1, where X is N.

5. Compounds according to claim 1, where R3means heterocyclyl, selected from the group comprising a pyridyl, pyrimidinyl, furyl, thienyl, indolyl, benzo[1,3]dioxole, benzofuranyl, benzothiophene, dibenzofuran, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolin, pyridil, pyrimidinyl, pyrazinyl, pyrrolidinyl, azepane, morpholine, and specified heterocyclyl the optional is positive and independently mono-, di - or triamese halogen, PERFLUORO-C1-6-alkyl, C1-6-alkyl or C1-6-alkoxy.

6. Compounds according to claim 5, where R3means the unsubstituted thienyl or unsubstituted benzo[1,3]dioxole.

7. Compounds according to claim 1, where R3means phenyl, optionally and independently ortho-, meta-or para-substituted C1-6-alkyl, C1-6-alkoxy, halogen or PERFLUORO-C1-6-alkyl.

8. Compounds according to claim 7, where R3means 2,4-dichlorophenyl.

9. Compounds according to claim 1, where R4means phenyl, optionally and independently ortho-, meta - and/or para-substituted with halogen, amino, C1-6-alkyl, PERFLUORO-C1-6-alkyl or C1-6-alkoxy.

10. Compounds according to claim 1, where R4means C1-6-alkoxy.

11. Compounds according to claim 1, where R4means C1-6-alkylthio.

12. Compounds according to claim 1, where R4means a heterocyclic residue selected from the group comprising a pyridyl, thienyl, indolyl, benzo[1,3]dioxole, benzofuranyl, benzothiophene, dibenzofuran, pyrrolidinyl, azepane, morpholine, and specified heterocyclyl optionally and independently mono-, di - or triamese halogen, amino, and PERFLUORO-C1-6-alkyl, C1-6-alkyl or C1-6-alkoxy.

13. The compound according to claim 1, where X is N, R1and R2mean hydrogen, R3means 2,4-dichlorophenyl and R4means met the XI, methylthio, heterocyclic residue selected from pyrrolidinyl and azepane, or phenyl residue optionally and independently ortho-, meta - and/or para-substituted by fluorine, stands or methoxy.

14. The compound according to claim 1, where X denotes N or C-R5, R1means hydrogen or C1-6-alkyl, R2means hydrogen or C1-6-alkyl, R3means the unsubstituted thienyl, unsubstituted benzo[1,3]dioxole, or phenyl, independently of ortho, meta and/or para-substituted C1-6-alkyl, C1-6-alkoxy, halogen or PERFLUORO-C1-6-alkyl, R4means lower alkyl, lower alkoxy, lower alkylthio, NW-C6cycloalkyl, heterocyclyl selected from a number of pyridyl, thienyl, indolyl, benzo[1,3]dioxole, benzofuranyl, benzothiophene, dibenzofuran, pyrrolidinyl, azepane, morpholine, and specified heterocyclyl residue independently mono - or Disaese C1-6-alkyl or C1-6-alkoxy, naphthyl, monosubstituted C1-6-alkoxy, phenyl, independently of ortho, meta and/or para-substituted with halogen, amino, C1-6-alkyl, PERFLUORO-C1-6-alkyl or C1-6-alkoxy; or 4 formaniacs-C1-6-alkyl, and R5means hydrogen or C1-6-alkyl.

15. Compounds according to claim 1, selected from the group including

5-aminomethyl-6-(2,4-dichlorophenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2-enyl-6-p-tolylboronic-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3-methoxyphenyl)pyrimidine-4-ylamine,

5-aminomethyl-2-phenyl-6-o-tolylboronic-4-ylamine,

5-aminomethyl-6-(2,4-differenl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-m-tolylboronic-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3,4,5-trimethoxyphenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dimetilfenil)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3,5-acid)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3-forfinal)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(4-forfinal)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(4-methoxy-1-methyl-1H-indol-6-yl)pyrimidine-4-ylamine,

5-aminomethyl-2-benzofuran-2-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(1H-indol-2-yl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-m-tolylboronic-4-ylamine,

2-(4-amino-3-methoxyphenyl)-5-aminomethyl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-2-azepin-1-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3,4-differenl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-pyrrolidin-1-Yeremey-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-methylsulfonylamino-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3,4-acid)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-thiophene-2-Yeremey-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(2-forfinal)pyrimidine-4-ylamine,

5-aminomethyl-2-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-methoxypyridine-4-ylamine,

5-aminomethyl-2-cyclopropyl-6-phenylpyrimidine-4-ylamine

5-aminomethyl-6-(2,4-dichlorophenyl)-2-p-tolylboronic-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(4-methoxyphenyl)pyrimidine-4-ylamine,

5-aminomethyl-2-benzo[1,3]dioxol-5-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3-triptoreline)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-morpholine-4-Yeremey-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(4-triptoreline)pyrimidine-4-ylamine,

5-aminomethyl-2-(3-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-methylpyrimidin-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-naphthalene-2-Yeremey-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-naphthalene-1-Yeremey-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3-methoxyphenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(3,5-differenl)pyrimidine-4-ylamine,

5-amine the Teal-6-(2,4-dichlorophenyl)-2-(2-methoxyphenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(4-ethylphenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-isopropylpyrimidine-4-ylamine,

5-aminomethyl-2-(2-chloro-4-forfinal)-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-2-benzo[b]thiophene-2-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(6-methoxynaphthalene-2-yl)pyrimidine-4-ylamine,

5-aminomethyl-2-phenyl-6-m-tolylboronic-4-ylamine,

5-aminomethyl-6-(4-chlorophenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2-phenyl-6-(4-triptoreline)pyrimidine-4-ylamine,

5-aminomethyl-6-(2-methoxyphenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-o-tolylboronic-4-ylamine,

5-aminomethyl-2-(3,5-bis-triptoreline)-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-dichlorophenyl)-2-(4-forfinancial)pyrimidine-4-ylamine,

5-aminomethyl-6-(2-chlorophenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2-bromophenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2-dibenzofuran-2-yl-6-(2,4-dichlorophenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-bis-triptoreline)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2-fluoro-4-methoxyphenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(2,4-acid)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2-(1H-indol-2-yl)-6-penile is kidin-4-ylamine,

5-aminomethyl-6-benzo[1,3]dioxol-5-yl-2-cyclopropylamino-4-ylamine,

5-aminomethyl-6-(2-forfinal)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2-phenyl-6-(2-triptoreline)pyrimidine-4-ylamine,

5-aminomethyl-2-benzofuran-2-yl-6-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-(4-forfinal)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2-(3,4-acid)-6-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-phenyl-2-pyridine-4-Yeremey-4-ylamine,

5-aminomethyl-6-(3-chlorophenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-6-phenyl-2-thiophene-2-Yeremey-4-ylamine,

5-aminomethyl-6-(3-forfinal)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2,6-diphenylpyridine-4-ylamine,

5-aminomethyl-6-(4-methoxyphenyl)-2-phenylpyrimidine-4-ylamine,

5-aminomethyl-2-phenyl-6-thiophene-3-Yeremey-4-ylamine,

5-aminomethyl-6-(3-methoxyphenyl)-2-phenylpyrimidine-4-ylamine,

6-(2,4-dichlorophenyl)-5-methylaminomethyl-2-phenylpyrimidine-4-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-6-phenylpyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-5-methyl-6-phenylpyridine-2-ylamine,

[5-aminomethyl-6-(4-chlorophenyl)-2-pyridin-3-Yeremey-4-yl]-methylamine,

5-aminomethyl-6-benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)pyrimidine-4-ylamine,

5-aminomethyl-6-benzo[1,3]dioxol-5-yl-2-phenylpyrimidine-4-Ilam is h,

[5-aminomethyl-6-(4-chlorophenyl)-2-pyridin-3-Yeremey-4-yl] -Isopropylamine,

(5-aminomethyl-2,6-diphenylpyridine-4-yl)-methylamine,

3-aminomethyl-4-(4-chlorophenyl)-5-methyl-6-phenylpyridine-2-ylamine,

3-aminomethyl-4-(4-chlorophenyl)-6-phenylpyridine-2-ylamine,

3-aminomethyl-4,6-bis-(4-forfinal)-pyridine-2-ylamine, and

3-aminomethyl-4-benzo[1,3]dioxol-5-yl-6-vinylpyridin-2-ylamine,

and pharmaceutically acceptable salts of such compounds.

16. The method of obtaining compounds of formula (I) according to any one of claims 1 to 15, where R2means hydrogen, including the restoration of the nitrile of General formula (IVa) or (IV):

or

where X is N or C-R5, R1, R3, R4and R5have the meanings indicated in claims 1 to 15, with the formation of the amine of the formula (Ia):

where X has the values specified above, R1, R3and R4have the meanings indicated in claims 1 to 15.

So obtain compounds of formula (I) according to any one of claims 1 to 15, where R2means C1-6-alkyl, comprising the alkylation of an amine of General formula (Ia):

where X is N or C-R5, R1, R3, R4and R5have the meanings indicated in claims 1 to 15, with the formation of compound(Ib):

where X and R2have the meanings indicated above, a R1, R3and R4have the meanings indicated in claims 1 to 15.

18. Pharmaceutical compositions having the properties of the inhibitor dipeptidylpeptidase IV(DPP IV), including compounds according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier or adjuvant.

19. Compounds according to claim 1, having the properties of the inhibitor dipeptidylpeptidase IV(DPP IV).

20. Compounds according to claim 1, to obtain drugs suitable for use in the treatment and/or prevention of diseases associated with DPP IV.

21. The use of compounds according to any one of claims 1 to 15 for the treatment and/or prevention of diseases associated with DPP IV, such as diabetes type II.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel class of 5-membered heterocyclic compounds of the general formula (I): or cosmetically acceptable salts. Invention describes a compound represented by the formula (I) and its pharmaceutically or cosmetically acceptable salt wherein R1 is chosen from linear or branched (C1-C12)-alkyl, (C3-C7)-cycloalkyl, phenyl, naphthyl, C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatoms when they present are chosen independently from oxygen (O), nitrogen (N) or sulfur (S) atom and substituted optionally wherein substitutes are chosen from the first group comprising halogen atom, hydroxy0, nitro-, cyano-, amino- oxo-group and oxime, or from the second group comprising linear or branched (C1-C8)-alkyl wherein a substitute from indicated second group is optionally substituted with R10, or wherein heteroaryl is substituted with -CH2-C(O)-2-thienyl; Y is absent or chosen from the group consisting of (C1-C12)-alkyl-Z or (C2-C8)-alkyl wherein Z is chosen from sulfur, oxygen or nitrogen atom; A and B are chosen independently from nitrogen atom (N), -NH, -NR6, sulfur, oxygen atom to form heteroaromatic ring system; R2, R3 and R4 are chosen independently from the first group comprising hydrogen, halogen atom, or R3 and R4 form phenyl ring in adjacent positions; R5 is absent or chosen from the group comprising -CH2-phenyl, -CH2(CO)R7, -CH2(CO)NHR8 and -CH2(CO)NR8R9 that are substituted optionally with R10; R6, R7, R8 and R are chosen independently from the group comprising linear or branched (C1-C8)-alkyl, (C3-C7)-cycloalkyl, C5-heterocycloalkyl, benzylpiperidinyl, phenyl, naphthyl, heteroaryl, alkylheteroaryl, adamantyl, or R8 and R9 form piperidine ring, and R means 3,4-ethylenedioxyphenyl wherein substitutes in indicated group are substituted optionally with R10, and heteroaryl means C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatom when they present are chosen independently from O, N or S; R10 is chosen from halogen atom, hydroxy-, nitro-, cyano-, amino-, oxo-group, perhalogenalkyl-(C1-C6) or oxime; X means halide ion under condition that when groups/substitutes present at the same or at adjacent carbon or nitrogen atoms then can form optionally 5-, 6- or 7-membered ring optionally containing one o some double bonds and containing optionally one or some heteroatoms chosen from O, N or S. Also, invention describes a method for synthesis of these compounds, their therapeutic and cosmetic using, in particular, in regulation of age and diabetic vascular complications. Proposed compounds show effect based on the triple effect as agent destroying AGE (terminal products of enhanced glycosylation), inhibitors of AGE and scavengers of free radicals that do their suitable in different therapeutic and cosmetic using. Also, invention relates to pharmaceutical and cosmetic compositions comprising these compounds and to methods for treatment of diseases caused by accumulation of AGE and/or free radicals in body cells. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

73 cl, 4 tbl, 63 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of novel derivatives of 4,5-dihydro-1H-pyrazole that are strong antagonists of cannabinoid (CB1) receptor and useful in treatment of diseases associated with disorders of cannabinoid system. Compounds have the general formula (Ia) or (Ib) wherein symbols are given in the invention claim. Also, invention relates to method for synthesis of these compounds, their using, intermediate compounds for synthesis of proposed compounds and to a pharmaceutical composition comprising at least one of these compounds as an active component.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 1 tbl, 100 ex

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

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing 3,4-diaryl(hetaryl)maleimides of the formula (I): wherein R means (C1-C4)-alkyl or benzyl, or phenyl; R1 means bromine atom (Br) or aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group; Ar means aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group with exception for 3,4-di-(2,5-dimethyl-3-thienyl)-1-butylmaleimide. Method involves interaction of aryl(hetaryl)boronic acid of the formula: ArB(OH)2 wherein Ar has abovementioned values with N-substituted 3,4-dibromomaleimide of the formula (III): or N-substituted 3-bromo-4-aryl(hetaryl)maleimide of the formula (IV) wherein R and Ar have abovementioned values and with using palladium catalyst in the presence of base in organic solvent medium. Also, invention to some new derivatives of 3,4-diaryl(hetaryl)maleimides that show photochrome properties.

EFFECT: improved preparing method.

7 cl, 2 dwg, 14 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising S-isomer of compound of the formula (I) or its pharmaceutically acceptable salts and solvates in common with a pharmaceutically acceptable vehicle. Also, invention relates to a method for synthesis of compound S-isomer of the formula (I), and to a method for treatment of disease relating to the group comprising respiratory diseases, allergic diseases, dermatological diseases, gastroenteric diseases and ophthalmic diseases. The composition provides avoiding adverse sedative effects in treatment of indicated diseases.

EFFECT: valuable medicinal properties of compounds.

14 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

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

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

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

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

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the formula (I) or their pharmaceutically acceptable salts wherein X means -CA1NR5R6 or -CA1-R8 wherein A1 and A2 mean independently oxygen atom; R1 means hydrogen atom (H), (C1-C20)-alkyl, (C6-C10)-aryl or -CH2-R1a wherein R1a means (C6-C10)-aryl; R3 means H, -NO2, nitrooxy-group, C≡N, azido-group, -COOH, amido-group, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, -COR11 wherein R11 means (C1-C12)-alkyl; R3a means H, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C6-C10)-aryl; R5 and R6 are similar or different and each means independently H, (C1-C6)-alkyl, and R8 means -OH and wherein each alkyl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, isothiocyanate, -OH, -NO2, -CN, azido-group, (C3-C6)-cycloalkyl and (C6-C10)-aryl;, and wherein each (C6-C10)-aryl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, -NH2, -NO2, azido-group, (C1-C6)-alkoxy-group, (C1-C6)-alkyl and (C1-C6)-halogenalkyl, and wherein each alkenyl can be substituted independently with at least one substitute chosen from halogen atom and -OH, and under condition that at least one radical among R and R3a differs from H, and when compound represent a mixture of possible isomers then X means -CONR5R6; A2 means oxygen atom, and R1 means H, -CH3, -C2H5, -C3H7, and when each R1 and R3a means H and A2 means oxygen atom and X means -CONR5R6 then R3 differs from -COOH, -CH, -COOR11, amido-group, naphthyl, phenyl rings substituted with (C1-C6)-alkoxy-group or halogen atom in para-position in naphthyl or phenyl ring. Compounds of the formula (I) can be used in pharmaceutical compositions for treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain.

EFFECT: improved method of synthesis, valuable medicinal properties of derivatives and pharmaceutical compositions.

27 cl, 3 tbl, 9 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to novel coumarone derivatives of the general formula (1): wherein two OH-substitutes in phenyl moiety are in ortho-position with respect to one to another; R1 is in ortho-position with respect to one hydroxyl group; X means oxygen atom (O); R1 represents -NO2; R2 represents hydrogen atom or (C1-C6)-alkyl; R3 means -(Y)n-(B)m-COOH or -(Y)n-(B)m-R8 wherein m = 0 or 1; n = 0; Y represents -CO-; B represents (C1-C6)-alkylene; R8 represents phenyl or 5- or 6-membered heterocycle with one-four heteroatoms chosen from nitrogen atom (N) wherein indicated phenyl is substituted optionally with one substitute chosen from halogen atom, -NO2 or (C1-C6)-alkyl; or R2 and R3 form in common -(CH2)r- wherein r = 3, 4 or 5; R4 and R5 form in common -O; R6 means hydrogen atom (H), or to their pharmaceutically acceptable salts or pharmaceutically acceptable esters that are inhibitors of enzyme - catechol O-methyltransferase (COMT). Invention provides preparing novel coumarone derivatives possessing the valuable biologically active effect.

EFFECT: valuable biochemical property of derivatives.

9 cl, 1 tbl, 13 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing 3,4-diaryl(hetaryl)maleimides of the formula (I): wherein R means (C1-C4)-alkyl or benzyl, or phenyl; R1 means bromine atom (Br) or aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group; Ar means aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group with exception for 3,4-di-(2,5-dimethyl-3-thienyl)-1-butylmaleimide. Method involves interaction of aryl(hetaryl)boronic acid of the formula: ArB(OH)2 wherein Ar has abovementioned values with N-substituted 3,4-dibromomaleimide of the formula (III): or N-substituted 3-bromo-4-aryl(hetaryl)maleimide of the formula (IV) wherein R and Ar have abovementioned values and with using palladium catalyst in the presence of base in organic solvent medium. Also, invention to some new derivatives of 3,4-diaryl(hetaryl)maleimides that show photochrome properties.

EFFECT: improved preparing method.

7 cl, 2 dwg, 14 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing 5-(1-piperazinyl)-benzofuran-2-carboxamide. Method involves reaction of bromosalicylic aldehyde with compound of the formula (I): L-CH2-COOR1 (I) wherein L represents Cl, Br or J atoms, or reactive esterified group -OH; R1 means (C1-C6)-alkyl or benzyl followed by reaction with formamide to yield 5-L-benzofuran-2-carboxamide (II) and the following its amination with R2-piperazine wherein R2 represents hydrogen atom (H) or amino-protecting group in the presence of a catalyst based on transient metals; in case if R2 is not H then R2 is removed, and/or prepared 5-(1-piperazinyl)-benzofuran-2-carboxamide is converted to one of its salts by treatment with acid. Except for, the invention proposes two additional methods for preparing 5-(1-piperazinyl)-benzofuran-2-carboxamide and intermediate compounds of the formula (V): wherein R2 represents H or amino-protected group; R3 means H or -CH2R6; R4 and R5 in common represent carbonyl; R6 means -CN, -COOH, -COOR7 or -CONH2; R7 means (C1-C6)-alkyl, and also their salts and solvates. Invention provides a new method for preparing the valuable intermediate compound used in preparing pharmaceutical preparations and increase of the yield of the end compound.

EFFECT: improved preparing methods.

6 cl, 10 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazine of the general formula (I):

wherein R1 means hydrogen (H) or halogen atom; R2, R3 and R5 mean hydrogen atom (H); R4 and R6 mean hydroxy-group optionally protected with acetyl or benzoyl group; A means oxygen atom (O); n = 0; Y means oxygen atom (O), or their salts. Compounds show the excellent anti-viral activity and useful as a therapeutic agent in treatment of viral infections. Also, invention describes a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 2 tbl, 15 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new stable crystalline forms of derivative of pyrimidine nucleoside of the formula (I) eliciting the excellent anti-tumor activity. Also, invention relates to pharmaceutical composition eliciting an anti-tumor effect, applying crystalline form for preparing medicinal agent and to a method for prophylaxis or treatment of tumor diseases.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of derivative.

10 cl, 2 tbl, 4 dwg, 9 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

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