Derivatives of pyridine and quinoline, method for their preparing, pharmaceutical composition, using compounds for treatment of dpp-iv-associated diseases

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

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

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

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

16 cl, 1 tbl, 39 ex

 

The present invention relates to new derivatives of pyridine, to their preparation and use as pharmaceuticals. The invention primarily relates to compounds of formula (I)

where

R1means hydrogen or (ness.)alkyl,

R2means heterocyclyl, heterocyclyl, independently mono-, di - or tizamidine group (ness.)alkyl, (ness.)alkoxy, PERFLUORO(ness.)alkyl, amino or halogen, aryl or aryl independently mono-, di - or tizamidine group halogen, (ness.)alkyl, (ness.)alkoxy, amino or PERFLUORO(ness.)alkyl,

R3and R4together with the carbon atoms to which they are attached, form phenyl, optionally independently mono-, di - or tizamidine group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy, or 5-, 6-or 7-membered saturated cycle, optionally containing a heteroatom selected from N, O and S, and optionally and independently mono-, di - or tizamidine group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy, and specified a saturated cycle condensed in anthopology with a 5 - or 6-membered aromatic cycle, optionally containing a heteroatom selected from N, O and S, and the specified aromatic cycle is optionally independently mono-, di - or triamese Deputy selected from the group comprising halogen, (ISS.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy,

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 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 patients with impaired glucose tolerance and diabetes mellitus type 2 with increasing concentrations of insulin decreases the intensity of hyperglycemia and accordingly reduces the risk of tissue damage. Thus, 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 non-insulin dependent diabetes mellitus and/or impaired Toler is nutnosti to glucose, 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 colitis, Crohn's disease, obesity 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 inhibitors of DPP-IV, known from the prior art, for example, in the context of pharmacokinetic properties and bioavailability.

Unless otherwise stated, terms used in the description to illustrate and define the nature and scope of the invention, 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, who appoints 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 carbon atoms, 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. Preferably (ness.)alkyl residues denote methyl and ethyl, especially preferred methyl.

The term "PERFLUORO(ness.)alkyl" means (ness.)alkyl group, where all hydrogen atoms (ness.)the alkyl group are replaced with fluorine. Preferred PERFLUORO(ness.)alkyl groups include trifluoromethyl, pentafluoroethyl and heptafluoropropyl primarily 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 primarily preferred methoxy.

The term "heterocyclyl" means a saturated, unsaturated or aromatic monovalent cyclic radical containing at least about the ins heteroatom, selected from nitrogen atoms, sulfur and oxygen, or a combination of both. Examples heterocyclyl residues are 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, 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 or naphthyl, preferably phenyl, optionally independently mono-, di - or tizamidine group (ness.)alkyl, (ness.)alkoxy, halogen, amino or PERFLUORO(ness.)alkyl, preferably (ness.)alkyl, (ness.)alkoxy and halogen.

The term "pharmaceutically acceptable salt" includes salts of compounds of formula (I) inorganic or organic acids, such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, the other acid, methansulfonate 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, more preferred hydrochloride.

In one embodiment of the present invention R means (ness.)alkyl, preferably methyl.

In another embodiment, R2means heterocyclyl, optionally and independently mono-, di - or tizamidine group (ness.)alkyl, (ness.)alkoxy or halogen. Preferred heterocyclyl residues R2are the unsubstituted thienyl and unsubstituted benzo[1,3]dioxole. In a preferred embodiment, R is aryl, preferably phenyl, optionally and independently ortho-, meta - or para-, preferably ortho - and para-substituted by a group (ness.)alkyl, (ness.)alkoxy, halogen, amino or PERFLUORO(ness.)alkyl, preferably halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy. Most preferably, R2means 2,4-dichlorophenyl.

In another embodiment, R3and R4together with the carbon atoms to which they are attached, form phenyl, optionally independently mono-, di - or tizamidine group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy. Preferably specified phenyl residue nezam the puppy or monogamist halogen, preferably chlorine, or PERFLUORO(ness.)the alkyl, preferably trifluoromethyl.

In another embodiment, R3and R4together with the carbon atoms to which they are attached, form a 5-, 6 - or 7-membered saturated cycle (cycle A), optionally containing a heteroatom selected from N, O and S, and optionally and independently mono-, di - or tizamidine group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy, and specified a saturated cycle condensed in anthopology with a 5 - or 6-membered aromatic cycle (cycle C), optionally containing a heteroatom selected from N, O and S, and the specified aromatic cycle is optionally independently mono-, di - or triamese group halogen, such as fluorine, chlorine and bromine, (ness.)alkyl, such as methyl, PERFLUORO(ness.)alkyl, such as trifluoromethyl, or (ness.)alkoxy, such as methoxy.

This cycle And preferably unsubstituted or substituted by a group (ness.)alkyl, such as methyl, cycle preferably means phenyl or thienyl primarily preferred phenyl, optionally independently mono-, di - or tizamidine group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy.

Preferred examples of this option are the following groups:

where phenyl optionally substituted as indicated above, a R' means (ness.)alkyl, preferably methyl. More preferred

and

where phenyl optionally substituted as above, and R' means (ness.)alkyl, preferably methyl.

Preferred compounds of the present invention are the compounds of formula I, where R1means hydrogen, R2means phenyl, optionally and independently ortho-, meta - or para-, preferably ortho - and para-substituted by a group (ness.)alkyl, such as methyl, halogen, such as chlorine and fluorine, (ness.)alkyl, such as methyl, PERFLUORO(ness.)alkyl, such as trifluoromethyl, or (ness.)alkoxy, such as methoxy, first of all, suppose the equipment 2,4-dichlorophenyl, a R3and R4together with the carbon atoms to which they are attached, form a 5-, 6 - or 7-membered saturated cycle, optionally and independently di - or tizamidine group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy, and specified a saturated cycle condensed in anthopology with a 5 - or 6-membered aromatic cycle, optionally containing a heteroatom selected from N, O and S, and aromatic cycle is optionally independently mono-, di - or triamese group halogen, such as fluorine, chlorine and bromine, (ness.)alkyl, such as methyl, PERFLUORO(ness.)alkyl, such as trifluoromethyl, or (ness.)alkoxy, such as methoxy.

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

3-aminomethyl-4-(2,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinoline-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-5H-indeno[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-7-methoxy-5H-indeno[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-7,8-dimethoxy-5H-indeno[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)benzo[4,5]furo[3,2-b]pyridine-2-ylamine,

2-aminomethyl-1-(2,4-dichlorophenyl)-10H-9-oxa-4-azaphenanthrene-3-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-5,6-dihydrothieno[2,3-h]quinoline-2-ylamine,

2-aminomethyl-1-(2,4-dichlorophenyl)-6-fluoro-10H-9-oxa-4-azaphenanthrene-3-ylamine,

2-aminomethyl-1-(2,4-dichlorophenyl)-10H-9-thia-4-azaphenanthrene-3-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-5-methyl-5H-indeno[1,2-b]pyridine-2-ylamine,

2-aminomethyl-1-(2,4-dichlorophenyl)-N-10-thia-4-azaphenanthrene-3-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-10-fluoro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine-2-ylamine,

2-aminomethyl-1-(2,4-dichlorophenyl)-10H-9-thia-4-azaphenanthrene-3-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-5-methyl-5H-indeno[1,2-b]pyridine-2-ylamine,

2-aminomethyl-1-(2,4-dichlorophenyl)-N-10-thia-4-azaphenanthrene-3-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-10-fluoro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-7-fluoro-5H-indeno[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-8-methyl-5H-indeno[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-9-methoxy-5,6-dihydro-benzo[b]quinoline-2-ylamine,

2-aminomethyl-6-chloro-1-(2,4-dichlorophenyl)-10H-9-thia-4-azaphenanthrene-3-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)vs.-7.9bn-dimethyl-5,6-dihydrobenzo[b]quinoline-2-ylamine,

2-aminomethyl-1-(2,4-dichlorophenyl)-6-methyl-10H-9-oxa-4-azaphenanthrene-3-ylamine,

3-aminomethyl-7-bromo-4-(2,4-dichlorophenyl)-5H-indeno[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-paratrechina-2-ylamine,

3-aminomethyl-6-chloro-4-(2-forfinal)quinoline-2-ylamine,

3-aminomethyl-6-chloro-4-(2-forfinal)quinoline-2-ylamine,

3-aminomethyl-4-phenyl-6-trifloromethyl-2-ylamine,

3-amino shall ethyl-4-(2-methoxyphenyl)quinoline-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)quinoline-2-ylamine,

3-aminomethyl-4-(2-chlorophenyl)quinoline-2-ylamine,

3-aminomethyl-4-(4-chlorophenyl)quinoline-2-ylamine,

3-aminomethyl-4-phenylindolin-2-ylamine, and their pharmaceutically acceptable salts.

The compounds of formula I, where R means orthotamine phenyl may exist in the form of optically pure enantiomer or racemate. The invention includes all such forms.

Preferred variants of the present invention are the compounds of formula (I), and pharmaceutically acceptable salts of compounds of formula (I).

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.

In scheme I, R3and R4together with the carbon atoms to which they are attached, form a 5-, 6 - or 7-membered saturated cycle, optionally containing a heteroatom selected from N, O and S, and optionally and independently mono-, di - or tizamidine group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy, and specified a saturated cycle condensed in anthopology with a 5 - or 6-membered aromatic cycle, long is Ino containing a heteroatom, selected from N, O and S, and optionally and independently mono-, di - or tizamidine group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy, and R1and R2have the values specified above.

In scheme II, R3and R4together with the carbon atoms to which they are attached, form a phenyl cycle, optionally and independently mono-, di - or tizamidine group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy, and R1and R2have the values specified above.

The present invention relates also to a method for producing compounds of formula I and V. These methods include the restoration of the NITRILES of the formula II and VI with the formation of amines of the formula Ia and Ib, respectively. The restoration carried out by the known methods. For example, recovery can be a metal hydride, such as hydride layalina, in an inert solvent.

The NITRILES of the formula II get by known methods. One of such methods is the reaction of arylidenaminoimidazo III, such as 2-(2,4-dichlorobenzamide)malononitrile, with ketone IV, such as alpha-tetralone. For example, the reaction can be conducted by heating in the presence of ammonium acetate in an inert solvent, such as methanol.

The NITRILES of the formula VI can be obtained from 2-amino-4-bronchioles-3-carbonitrile and arylboronic to the slot means, known as "condensation Suzuki". For example, the reaction is carried out by heating in the presence of palladium compounds such as Pd(OAc)2, bases, such as3PO4and optionally in the presence of additives, such as phosphines, for example, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)diphenyl, in an inert solvent. 2-Amino-4-bronchioles-3-carbonitrile can be obtained in several stages of the anhydride isatool acid known methods.

Compounds of formulas Ic and Id can be obtained from corresponding compounds of formula Ia and Ib, 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 and obtained as 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 non-insulin dependent diabetes mellitus, impaired glucose tolerance, disease of the digestive tract, ulcerative colitis, Crohn's disease, obesity and/or metabolic syndrome, preferably insulinnezawisimy diabetes mellitus and/or impaired glucose tolerance. In addition, the compounds of the present invention can in order to use as diuretic agents and 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 non-insulin dependent 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 prevention insulinnezawisimogo 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 DPP IV, such as diabetes, especially non-insulin dependent diabetes mellitus, impaired glucose tolerance, disease of the digestive tract, carried elficiency ulcerative colitis, Crohn's disease, obesity and/or metabolic syndrome, preferably for the treatment and/or prophylaxis of non-insulin-dependent 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 the hypertension where 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 non-insulin dependent 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 non-insulin-dependent 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 relates to the use of the above compounds to obtain drugs intended for the treatment and/or prevention of Zabol the requirements, associated with DPP IV, such as diabetes, especially non-insulin dependent 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 prevention insulinnezawisimogo diabetes mellitus 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 non-insulin dependent diabetes mellitus, impaired glucose tolerance, obesity and/or metabolic syndrome, preferably non-insulin dependent diabetes mellitus and/or impaired glucose tolerance.

The compounds of formula (I) are obtained by the following methods, according to the methods described in the 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, indicated in the examples or known methods.

The activity of the soybean is ineni 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 is 100 ál. 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 helpanimals, 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 person, and when fluorimetric analysis of 2 ng of recombinant DPP-IV person in a total volume of 100 μl.

When fluorophenol analysis to the operation of the substrate using Ala-Pro-7-amido-4-triptorelin (firm Calbiochem, cat.№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 as KmVmax, Kithe concentration of the substrate is from 10 to 500 μm.

When the colorimetric analysis as the substrate used 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 asmVmaxToithe concentration of the substrate is from 100 to 2000 microns.

Fluorescence was measured on an LS 50 (firm 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 colorimetric sostrata, 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 calculated by the method of optimal linear regression.

The activity of DPP-IV is determined in 96-well tablets at 37°in the volume of the reaction mixture of 100 μl. The buffer is the first 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/H2O. 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(µm)
70,0027
30,045
90,018
10
251,91
281,59
320,366

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, or local manner, for example, in the form of ointments, creams or oils. Preferred oral route of administration.

Pharmaceutical drugs get in a known manner, for example by 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 solid or liquid carriers and, if necessary, pharmaceutical adjuvants, ready herbal form.

Suitable carriers include both inorganic and organic materials. For example, when the doctrine of tablets tablets in the shell, coated tablets 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, solid 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, liquid paraffins, liquid fatty alcohols, sterols, glycols and derivatives of cellulose.

As pharmaceutical adjuvants used various stabilizers, preservatives, wetting and emulsifying agents, agents for improving the texture, flavors, salts for regulating emotionladen, 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:

NMR spectroscopy nuclear magnetic resonance; MS - mass spectrometry, THF is tetrahydrofuran, DMF - dimethylformamide, DMSO is dimethylsulfoxide, TFU - triperoxonane acid, CT - room temperature, tfpTemperature fire.

Example 1

Synthesis of arylmethylidene.

2-(2,4-Dichlorobenzamide)malononitrile

2,4-Dichlorobenzaldehyde (30,00 g, 171 mmol) and malononitrile (13,59 g, 206 mmol) suspended in 1-booth is zero (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 and 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° (C): (7,45 (m, 1H), to 7.59 (m, 1H), 8,18 (m, 2H).

Example 2

Synthesis of 2-aminonicotinamide (scheme I, method 1)

2-Amino-4-(2,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile

A mixture of 2-(2,4-dichlorobenzamide)malononitrile (1,125 g, 5 mmol), alpha-tetralone (735 mg, 5 mmol), ammonium acetate (578 mg, 7.5 mmole) and toluene (5 ml) was stirred while boiling under reflux for 3 hours After cooling to room temperature, the mixture was transferred into ethyl acetate, was extracted with a saturated solution of NaHCO3, water and saturated NaCl solution, dried over Na2SO4and the solvent evaporated. The residue was purified by chromatography on a column of silica gel (eluent: hexane, atlacatl), when it got mentioned in the title compound (868 mg, 47%). MS: m/e RUB 365.9 (M+N+).

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

2-amino-4-(2,4-dichlorophenyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile was obtained from 1-indanone as a solid (322 mg, 18%), MS: m/e 352,0 (M+Hsup> +),

2-amino-4-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine-3-carbonitrile was obtained from 1-benzocoumarin in the form of a solid (730 mg, 38%), MS: m/e 379,9 (M+),

2-amino-4-(2,4-dichlorophenyl)-7-methoxy-5H-indeno[1,2-b]pyridine-3-carbonitrile was obtained from 5-methoxy-1-indanone in the form of solids (715 mg, 37%), MS: m/e 381,8 (M+),

2-amino-4-(2,4-dichlorophenyl)-7,8-dimethoxy-5H-indeno[1,2-b]pyridine-3-carbonitrile was obtained from 5,6-dimethoxy-1-indanone as a solid (180 mg, 9%), MS: m/e 412,0 (M+N+),

2-amino-4-(2,4-dichlorophenyl)benzo[4,5]furo[3,2-b]pyridine-3-carbonitrile received from benzofuran-3(2H)-it is in the form of a solid (128 mg, 13%), MS: m/e 354,0 (M+N+).

Example 3

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

3-Aminomethyl-4-(2,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinoline-2-ylamine

To a suspension of LiAlH4(162 mg, 4.26 deaths mmole) in THF (1 ml) in an argon atmosphere was slowly added a solution of 2-amino-4-(2,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile (200 mg, of 0.58 mmole) in THF (1 ml). The reaction mixture was stirred at room temperature for 2 h, cooled to -20°and added 0.2 ml of water. After 15 min, to the mixture was added ethyl acetate and filtered through dekalim. The organic phase was separated, washed with water and dried over sodium sulfate. The product was purified Express chromatography the raffia on silica gel (eluent: methanol, dichloromethane), to receive specified in the title compound in the form of solid yellow (53 mg, 26%). MS: m/e 369,9 (M+N+).

Example 4

3-Aminomethyl-4-(2,4-dichlorophenyl)-5H-indeno[1,2-b]pyridine-2-ylamine

Specified in the title compound was obtained as a solid (64 mg, 67%) of 2-amino-4-(2,4-dichlorophenyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile same way as described in example 3. MS: m/e 355,8 (M+).

Example 5

3-Aminomethyl-4-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine-2-ylamine

Specified in the title compound was obtained as a solid (40 mg, 25%) from 2-amino-4-(2.4-dichlorophenyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine-3-carbonitrile same way as described in example 3. MS: m/e 383,9 (M+).

Example 6

3-Aminomethyl-4-(2,4-dichlorophenyl)-7-methoxy-5H-indeno[1,2-b]pyridine-2-ylamine

Specified in the title compound was obtained as a solid (14 mg, 9%) of 2-amino-4-(2,4-dichlorophenyl)-7-methoxy-5H-indeno[1,2-b]pyridine-3-carbonitrile same way as described in example 3. MS: m/e 385,9 (M+).

Example 7

3-Aminomethyl-4-(2,4-dichlorophenyl)-7,8-dimethoxy-5H-indeno[1,2-b] pyridine-2-ylamine

Specified in the header connection recip is whether in the form of a solid (9 mg, 6%) of 2-amino-4-(2,4-dichlorophenyl)-7,8-dimethoxy-5H-indeno[1,2-b]pyridine-3-carbonitrile same way as described in example 3. MS: m/e 415,9 (M+).

Example 8

3-Aminomethyl-4-(2,4-dichlorophenyl)benzo[4,5]furo[3,2-b]pyridine-2-ylamine

Specified in the title compound was obtained as a solid (0.8 mg, 62%) of 2-amino-4-(2,4-dichlorophenyl)benzo[4,5]furo[3,2-b]pyridine-3-carbonitrile same way as described in example 3. MS: m/e 357,8 (M+).

Example 9

Preparative synthesis of 3-aminomethylpyridine-2-ylamino from arylmethylidene (scheme I, method 3)

2-Aminomethyl-1-(2,4-dichlorophenyl)-10H-9-oxa-4-azaphenanthrene-3-ylamine

2-(2,4-Dichlorobenzamide)malononitrile (95 mg, 0.4 mmole), chroman-4-one (59 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 filtrate 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/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 solid (28 mg) was dissolved in THF (1 ml) and cooled (0° (C) in argon atmosphere was added in the reaction is Oud with a suspension of 100 mg hydride layalina 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 is evaporated in a vacuum centrifuge (45° (C), 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), received 11 mg (7%) indicated in the title compounds as solids. MS: m/e 371,9 (M+H).

Example 10

3-Aminomethyl-4-(2,4-dichlorophenyl)-5,6-dihydrothieno[2,3-h]quinoline-2-ylamine

Specified in the title compound was obtained as a solid substance from 6,7-dihydro-5H-benzo[b]thiophene-4-it is the same as described in example 9. MS: m/e 376 (M+N+).

Example 11

2-Aminomethyl-1-(2,4-dichlorophenyl)-6-fluoro-10H-9-oxa-4-azaphenanthrene-3-ylamine

Specified in the title compound was obtained as solid from 6-ferroman-4-it is the same as described in example 9. MS: m/e 390,2 (M+N+).

Example 12

2-Aminomethyl-1-(2,4-dichlorophenyl)-10H-9-thia-4-azaphenanthrene-3-ylamine

Specified in the title compound was obtained as a solid substance from thiochroman-4-it is similar to t the th, as described in example 9. MS: m/e 388,2 (M+N+).

Example 13

3-Aminomethyl-4-(2,4-dichlorophenyl)-5-methyl-5H-indeno[1,2-h]pyridin-2-ylamine

Specified in the title compound was obtained as solid from 3-methylinden-1-it is the same as described in example 9. MS: m/e 370,1 (M+N+).

Example 14

2-Aminomethyl-1-(2,4-dichlorophenyl)-N-10-thia-4-azaphenanthrene-3-ylamine

Specified in the title compound was obtained as a solid substance from sociodrama-4-it is the same as described in example 9. MS: m/e 388,2 (M+N+).

Example 15

3-Aminomethyl-4-(2,4-dichlorophenyl)-10-fluoro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine-2-ylamine

Specified in the title compound was obtained as solid from 3-fluoro-6,7,8,9-tetrahydrobenzaldehyde-5-it is the same as described in example 9. MS: m/e 402,0 (M+N+).

Example 16

3-Aminomethyl-4-(2,4-dichlorophenyl)-7-fluoro-5H-indeno[1,2-b]pyridine-2-ylamine

Specified in the title compound was obtained as solid from 5-fluoro-1-indanone in the same way as described in example 9. MS: m/e 374,3 (M+N+).

Example 17

3-Aminomethyl-4-(2,4-dichlorophenyl)-8-methyl-5H-indeno[1,2-b]pyridine-2-ylamine

The decree is Noah in the title compound was obtained as solid from 6-methylinden-1-she just as described in example 9. MS: m/e 370,0 (M+N+).

Example 18

3-Aminomethyl-4-(2,4-dichlorophenyl)-9-methoxy-5,6-dihydrobenzo[h]quinoline-2-ylamine

Specified in the title compound was obtained as solid from 7-methoxy-3,4-dihydro-2H-naphthalene-1-it is the same as described in example 9. MS: m/e 400,3 (M+N+).

Example 19

2-Aminomethyl-6-chloro-1-(2,4-dichlorophenyl)-10H-9-thia-4-azaphenanthrene-3-ylamine

Specified in the title compound was obtained as solid from 6-hartihan-4-it is the same as described in example 9. MS: m/e 422,0 (M+).

Example 20

3-Aminomethyl-4-(2,4-dichlorophenyl)vs.-7.9bn-dimethyl-5,6-dihydrobenzo[h]quinoline-2-ylamine

Specified in the title compound was obtained as a solid substance from 5,7-dimethyl-3,4-dihydro-2H-naphthalene-1-it is the same as described in example 9. MS: m/e 398,0 (M+N+).

Example 21

2-Aminomethyl-1-(2,4-dichlorophenyl)-6-methyl-10H-9-oxa-4-azaphenanthrene-3-ylamine

Specified in the title compound was obtained as solid from 6-methylchromone-4-it is the same as described in example 9. MS: m/e 386,2 (M+N+).

Example 22

3-Aminomethyl-7-bromo-4-(2,4-dichlorophenyl)-5H-indeno[1,2-b]pyridine-2-ylamine

Specified in the title compound was obtained as solid from 5-bromantan-1-it is the same as described in example 9. MS: m/e 435,0 (M+N+).

Example 23

Synthesis of quinoline-3-carbonitrile

a) 2-Amino-4-hydroxyquinolin-3-carbonitril

To a solution of malononitrile (10 g, 151,4 mmole) in DMF (210 ml) solution was added sodium hydride (60%, 6,05 g, 151, 3mm mmole) and the mixture was stirred at RT for 30 min Then added istovy anhydride (22,2 g, 136,1 mmole) and the mixture was stirred at 60°C for 30 minutes the Mixture was poured into 1.4 l of a mixture of ice/water and filtered. The filtrate was acidified with 37% HCl, stirred for 1 h and the precipitate was separated. The product was dried at 40°in vacuum, the solid yellow color was dissolved in DMF (100 ml) and was heated at 120°C for 10 minutes Then the mixture was cooled to CT and poured into water (1.5 l), the precipitate was separated by filtration and dried at 50°With under reduced pressure, thus received is listed in the title compound in the form of a solid yellow (24,33 g, 96%). MS: m/e 185,1 (M+).

b) 2-Amino-4-bronchioles-3-carbonitril

2-Amino-4-hydroxyquinolin-3-carbonitrile (6 g, 32,4 mmole) suspended in acetonitrile (2 l)was added tribromide phosphorus (33 g, 11.5 ml, 122 mmole) and bromine (19,15 g, x 6.15 ml, 120 mmol) and the mixture is boiled under reflux during the night. The solvent is evaporated when the pony is hinnon pressure and the mixture was transferred into a 1 N. NaOH. The product was separated by filtration, washed with water and dried, to receive specified in the header of the connection (of 5.05 g, 62%). MS: m/e 248,2 (M+).

Example 24

Synthesis of 2-amino-4-originalen-3-carbonitrile (scheme II, method 4)

2-Amino-4-para-trilinolein-3-carbonitril

2-Amino-4-bronchioles-3-carbonitrile (248 mg, 1 mmol), 4-methylphenylimino acid (204 mg, 1.5 mmole), palladium (II) acetate (11 mg, 0.05 mmole), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)diphenyl (39 mg, 0.10 mmole) and K3RHO4(425 mg, 2 mmole) suspended in 4 ml of toluene (in argon atmosphere) and heated at 100°C for 21 h Then the reaction mixture was transferred into diethyl ether, washed with NaOH solution, brine and dried over Na2SO4. The solvent is evaporated, the residue was purified by chromatography on a column of silica gel (eluent: gradient diclomelan/methanol, 100:0 to 85:15), when this has been specified in the title compound (46 mg, 18%). MS: m/e 259,9 (M++H).

The following 2-amino-4-originalen-3-carbonitrile was obtained in the same way as described above:

2-amino-6-chloro-4-(2-forfinal)quinoline-3-carbonitrile received in the form of a solid (54 mg, 10%) by the reaction of 2-ftorhinolonovy acid and 2-amino-4-bromo-6-chlorhydrin-3-carbonitrile, MS: m/e 298,2 (M++N),

2-amino-6-chloro-4-phenylindolin-3-carbonitril received in the form of a solid in the society (60 mg, 11%) in the interaction of phenylboronic acid and 2-amino-4-bromo-6-chlorhydrin-3-carbonitrile, MS: m/e 279,8 (M++N),

2-amino-6-chloro-4-(2-chlorophenyl)quinoline-3-carbonitrile received in the form of a solid (33 mg, 5%) by the reaction of 2-Chlorfenvinphos acid and 2-amino-4-bromo-6-chlorhydrin-3-carbonitrile, MS: m/e 313,7 (M++N),

2-amino-4-(2-forfinal)-6-phenylindolin-3-carbonitril received in the form of a solid (72 mg, 12%) by the reaction of 2-ftorhinolonovy acid and 2-amino-4-bromo-6-phenylindolin-3-carbonitrile, MS: m/e 339,8 (M++N),

2-amino-4-phenyl-6-trifloromethyl-3-carbonitril received in the form of a solid (47 mg, 6%) in the interaction of phenylboronic acid and 2-amino-4-bromo-6-trifloromethyl-3-carbonitrile, MS: m/e 313,8 (M++N),

2-amino-4-(2-methoxyphenyl)quinoline-3-carbonitrile received in the form of a solid (35 mg, 5%) of 2-methoxyphenylacetic acid, MS: m/e 275,5 (M++N),

2-amino-4-(2,4-dichlorophenyl)quinoline-3-carbonitrile received in the form of a solid (8 mg, 2.4 per cent) of the 2.4-dichlorophenylamino acid, MS: m/e 314,0 (M++N),

2-amino-4-(2-chlorophenyl)quinoline-3-carbonitrile received in the form of a solid (61 mg, 11%) of 2-Chlorfenvinphos acid, MS: m/e 279,9 (M++N),

2-amino-4-(4-chlorophenyl)quinoline-3-carbonitrile received in the form of a solid (52 mg, 9%) of 4-Chlorfenvinphos acid, M is: m/e 279,9 (M ++H).

Example 25

Synthesis of 3-aminomethyl-4-originalen-2-ylamino (scheme II, method 5)

3-Aminomethyl-4-paratrechina-2-ylamine

To a suspension of LiAlH4(67,3 mg, or 1.77 mmole) in THF (1 ml) in an argon atmosphere was slowly added a solution of 2-amino-4-paratrechina-3-carbonitrile (46 mg, 0,177 mmole) in THF (0.5 ml) and the mixture was stirred at 40°C for 2 hours Then the mixture was cooled to -20°C, was added 0.3 ml of water and stirred at RT for 15 min, the Mixture was transferred into ethyl acetate and filtered through dekalim. The filtrate was washed with water and brine, dried (Na2SO4) and was evaporated. The residue was dissolved in 1 ml DMF and purified using avtomatizirovannoi 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 (230 nm), received 5 mg (11%) indicated in the title compound in the form of a solid substance.

Example 26

3-Aminomethyl-6-chloro-4-(2-forfinal)quinoline-2-ylamine

Specified in the title compound was obtained as a solid (4 mg, 8%) of 2-amino-6-chloro-4-(2-forfinal)quinoline-3-carbonitrile same way as described in example 25. MS: m/e 302,0 (M++H).

Example 27

3-Aminomethyl-6-chloro-4-phenylindolin-2-ylamine

Specified in the title compound was obtained as a solid (4 mg, 7%) of 2-amino-6-chloro-4-phenylindolin-3-carbonitrile same way as described in example 25. MS: m/e 283,1 (M++H).

Example 28

3-Aminomethyl-6-chloro-4-(2-chlorophenyl)quinoline-2-ylamine

Specified in the title compound was obtained as a solid (3 mg, 10%) from 2-amino-6-chloro-4-(2-chlorophenyl)quinoline-3-carbonitrile same way as described in example 25. MS: m/e 316,9 (M++H).

Example 29

3-Aminomethyl-4-phenyl-6-trifloromethyl-2-ylamine

Specified in the title compound was obtained as a solid (4 mg, 9%) of 2-amino-4-phenyl-6-trifloromethyl-3-carbonitrile same way as described in example 25. MS: m/e 317,3 (M++H).

Example 30

3-Aminomethyl-4-(2-methoxyphenyl)quinoline-2-ylamine

Specified in the title compound was obtained as a solid (1 mg, 2%) from 2-amino-4-(2-methoxyphenyl)quinoline-3-carbonitrile same way as described in example 25. MS: m/e 279,1 (M++H).

Example 31

3-Aminomethyl-4-(2,4-dichlorophenyl)quinoline-2-ylamine

Specified in the title compound was obtained as a solid (6 mg, 14%) of 2-amino-4-(2,4-dichlorophenyl)quinoline-3-carbonitrile anal is Gino to as described in example 25. MS: m/e is 317.1 (M++H).

Example 32

3-Aminomethyl-4-(2-chlorophenyl)quinoline-2-ylamine

Specified in the title compound was obtained as a solid (3 mg, 2%) from 2-amino-4-(2-chlorophenyl)quinoline-3-carbonitrile same way as described in example 25. MS: m/e 284,0 (M++H).

Example 33

3-Aminomethyl-4-(4-chlorophenyl)quinoline-2-ylamine

Specified in the title compound was obtained as a solid (2 mg, 6%) from 2-amino-4-(4-chlorophenyl)quinoline-3-carbonitrile same way as described in example 25. MS: m/e 284,0 (M++H).

Example 34

3-Aminomethyl-4-phenylindolin-2-ylamine

Specified in the title compound was obtained in the form of a solid light-yellow color (0.56 g, 12%) from 2-amino-4-phenylbenzophenone-3-carbonitrile same way as described in example 3. tfp.225-226°C

Examples herbal medicines of

Example

Coated tablets of the following composition receive the standard way:

Ingredients1 tablet mg
The nucleus;
The compound of formula (I)10,0200,0
MikroC istoricheskaya cellulose 23,543,5
The hydrated lactose60,070,0
Povidone K3012,515,0
Sodium starch glycolate12,5of 17.0
Magnesium stearate1,54,5
Mass of nucleus120,0350,0
Coverage:
The hypromellose3,57,0
Polyethylene glycol 60000,81,6
Talc1,32,6
Iron oxide (yellow)0,81,6
Titanium dioxide0,81,6

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 specified structure.

Example B

Capsules of the following composition receive the standard way:

Ingredient is s 1 capsule mg
The compound of formula (I)25,0
Lactose150,0
Corn starch20,0
Talc5,0

The components were screened, mixed and the mixture was filled in capsules of size 2.

The example In

The injectable solutions of the following composition receive the standard way:

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

The active ingredient was dissolved in a mixture of polyethylene glycol 400 and a portion 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 receive the standard way:

The capsule, mg:

The compound of formula (I)5,0
Yellow wax8,0
Hydrogenated soybean oil8,0
Partially hydrogenated p is Stateline
oil34,0
Soybean oil110,0
Mass content capsules165,0

Gelatin capsule:

Gelatin75,0
Glycerol 85%32,0
Karion 838,0 (dry)
Titanium dioxide0,4
Iron oxide (yellow)1,1

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

The bags of the following composition receive the standard way, mg:

The compound of formula (I)50,0
Lactose, fine powder1015,0
Microcrystalline cellulose (AVICEL PH 102)1400,0
Carboxymethylcellulose, sodium salt14,0
Polyvinylpyrrolidone K 3010,0
Magnesium stearate10,0
Flavors1,0

Active com is ANENT 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 R1means hydrogen;

R2means unsubstituted phenyl or phenyl independently mono - or disubstituted by the group halogen, (ness.)alkyl, (ness.)alkoxy, PERFLUORO(ness.)alkyl;

R3and R4together with the carbon atoms to which they are attached, form phenyl, optionally independently mono-, di - or tizamidine halogen or PERFLUORO(ness.)the alkyl, or form a 5-, 6 - or 7-membered saturated cycle, optionally containing a heteroatom selected from O and S, and optionally and independently monosubstituted (ness.)the alkyl, with the specified rich cycle condensed in the ortho-position with a 5-membered aromatic cycle, optionally containing S as a heteroatom, or phenyl, optionally independently mono-, di-substituted by the group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy,

and their pharmaceutically acceptable salts.

2. Compounds according to claim 1, where R2means phenyl, optionally and independently ortho-, meta-or para-substituted by a group (NISS)alkyl, (ness.)alkoxy, halogen or PERFLUORO(ness.)alkyl.

3. Compounds according to claim 2, where R2means 2,4-dichlorophenyl.

4. Compounds according to claim 1, where R3and R4together with the carbon atoms to which they are attached, form a phenyl cycle, optionally and independently mono-, di - or tizamidine group, halogen or PERFLUORO(ness.)alkyl.

5. Compounds according to claim 4, where R3and R4together with the carbon atoms to which they are attached, form unsubstituted phenyl cycle or phenyl cycle, monosubstituted by a group halogen or PERFLUORO(ness.)alkyl.

6. Compounds according to claim 1, where R3and R4together with the carbon atoms to which they are attached, form a 5-, 6 - or 7-membered saturated cycle, optionally containing a heteroatom selected from O and S, and optionally and independently monosubstituted (ness.)the alkyl, with the specified rich cycle condensed in the ortho-position with a 5-membered aromatic cycle, optionally containing S as a heteroatom, or phenyl, optionally independently mono-, di-substituted by the group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy.

7. Compounds according to claim 6, where R3and R4together mean

where the phenyl residue optionally and independently mono-, disamament group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy, and R' means (ness.)alkyl.

8. Compounds according to claim 6, where R3and R4together mean

and

where the phenyl residue optionally and independently mono-, disamament group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy, and R' means (ness.)alkyl.

9. Compounds according to claim 1, where R1means hydrogen, R2means phenyl, optionally and independently ortho-, meta - or para-substituted by a group (ness.)alkyl, halogen, PERFLUORO(ness.)alkyl or (ness.)alkoxy, and R3and R4together with the carbon atoms to which they are connected is ineni, form a 5-, 6 - or 7-membered saturated cycle, optionally containing a heteroatom selected from O and S, and optionally and independently monosubstituted (ness.)the alkyl, with the specified rich cycle condensed in the ortho-position with a 5-membered aromatic cycle, optionally containing S as a heteroatom, or phenyl, optionally independently mono-, disubstituted group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy.

10. Compounds according to claim 1, where R1means hydrogen, R2means phenyl, optionally and independently ortho and/or para-substituted by a group (ness.)alkyl, halogen or (ness.)alkoxy, and R3and R4together with the carbon atoms to which they are attached, form a phenyl cycle, optionally monosubstituted by a group halogen or PERFLUORO(ness.)alkyl, or R3and R4together with the carbon atoms to which they are attached, form a 5-, 6 - or 7-membered saturated cycle, optionally containing a heteroatom selected from O and S, and optionally and independently monosubstituted (ness.)the alkyl, with the specified rich cycle condensed in the ortho-position with a 5-membered aromatic cycle, not necessarily in a loop containing the S atom, or phenyl, optionally independently mono-, disubstituted group halogen, (ness.)alkyl, PERFLUORO(ness.)alkyl or (ness.)alkoxy.

11. The connection is to be placed according to claim 1, selected from the group including

3-aminomethyl-4-(2,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinoline-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-5H-indeno[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-7-methoxy-5H-indeno[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-7,8-dimethoxy-5H-indeno[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)benzo[4,5]furo[3,2-b]pyridine-2-ylamine,

2-aminomethyl-1-(2,4-dichlorophenyl)-10H-9-oxa-4-azaphenanthrene-3-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-5,6-dihydrothieno[2,3-b]quinoline-2-ylamine,

2-aminomethyl-1-(2,4-dichlorophenyl)-6-fluoro-10H-9-oxa-4-azaphenanthrene-3-ylamine,

2-aminomethyl-1-(2,4-dichlorophenyl)-10H-9-thia-4-azaphenanthrene-3-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-5-methyl-5H-indeno[1,2-b]pyridine-2-ylamine,

2-aminomethyl-1-(2,4-dichlorophenyl)-N-10-thia-4-azaphenanthrene-3-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-10-fluoro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine-2-ylamine,

2-aminomethyl-1-(2,4-dichlorophenyl)-10H-9-thia-4-azaphenanthrene-3-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-5-methyl-5H-indeno[1,2-b]pyridine-2-ylamine,

2-aminomethyl-1-(2,4-dichlorophenyl)-N-10-thia-4-azaphenanthrene-3-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-10-fluoro-6,7-dihydro-5 is-benzo[6,7]cyclohepta[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-7-fluoro-5H-indeno[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-8-methyl-5H-indeno[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)-9-methoxy-5,6-dihydro-benzo[b]quinoline-2-ylamine,

2-aminomethyl-6-chloro-1-(2,4-dichlorophenyl)-10H-9-thia-4-azaphenanthrene-3-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)vs.-7.9bn-dimethyl-5,6-dihydro-benzo[b]quinoline-2-ylamine,

2-aminomethyl-1-(2,4-dichlorophenyl)-6-methyl-10H-9-oxa-4-azaphenanthrene-3-ylamine,

3-aminomethyl-7-bromo-4-(2,4-dichlorophenyl)-5H-indeno[1,2-b]pyridine-2-ylamine,

3-aminomethyl-4-para-trilinolein-2-ylamine,

3-aminomethyl-6-chloro-4-(2-forfinal)quinoline-2-ylamine,

3-aminomethyl-6-chloro-4-phenylindolin-2-ylamine,

3-aminomethyl-6-chloro-4-(2-chlorophenyl)quinoline-2-ylamine,

3-aminomethyl-4-phenyl-6-trifloromethyl-2-ylamine,

3-aminomethyl-4-(2-methoxyphenyl)quinoline-2-ylamine,

3-aminomethyl-4-(2,4-dichlorophenyl)quinoline-2-ylamine,

3-aminomethyl-4-(2-chlorophenyl)quinoline-2-ylamine,

3-aminomethyl-4-(4-chlorophenyl)quinoline-2-ylamine,

3-aminomethyl-4-phenylindolin-2-ylamine,

and their pharmaceutically acceptable salts.

12. The method of obtaining compounds of formula (I) according to any one of claims 1 to 11, including

(a) restoration of a nitrile of the formula

DG is R 2, R3and R4have the meanings indicated in claims 1 to 11, with the formation of the amine of the formula

where R2, R3and R4have the meanings indicated in claims 1 to 11, or (b) alkylation of an amine of the formula

where R2, R3and R4have the meanings indicated in claims 1 to 11, with obrazovanie the compounds of formula

where R1, R2, R3and R4have the meanings indicated in claims 1 to 11.

13. Compounds according to claim 1, obtained by the method according to item 12.

14. Pharmaceutical composition having inhibitory activity against dipeptidylpeptidase DPP IV containing the compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier and/or adjuvant.

15. Compounds according to claim 1, intended for use as therapeutically active substances for the treatment and/or prevention of diseases associated with DPP-IV.

16. The use of compounds according to any one of claims 1 to 11 as a therapeutic agent for the treatment and/or prevention of human or animal diseases associated with DPP-IV such as diabetes, particularly insulin-independent diabetes mellitus, impaired glucose tolerance, disease of the digestive tract, ulcerative colitis, Crohn's disease, obesity and/or metabolic syndrome.



 

Same patents:

FIELD: agriculture, organic chemistry.

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

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

2 tbl, 3 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

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

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, biochemistry, pharmacy.

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

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

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

14 cl, 11 sch, 7 tbl, 13 ex

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

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

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, medicine, hematology.

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

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

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

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to 2-aminomethylthieno[2,3-d]pyrimidines of the general formula (I): wherein R1 and R2 in common with C-atoms with which they are bound form 5-7-membered monounsubstituted cycloalkenyl ring; R3 and R4 are similar or different and represent independently of one another (C1-C8)-alkoxy-group or halogen atom; R5 and R6 can be similar or different and represent independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl group that can be substituted with one or more hydroxyl, (C1-C8)-alkoxy-group, amine, mono-(C1-C8-alkyl)-amine or di-(C1-C8-alkyl)-amine groups, or in common with nitrogen atom to which they are bound form a heterocyclic ring that comprises optionally one or more additional nitrogen atoms and substituted with one or more hydroxyl, (C1-C8)-alkoxy- or (C1-C8)-alkylol groups. Compounds elicit the inhibitory effect with respect to activity of phosphodiesterase V and can be used in treatment of cardiovascular system states and in disturbance in the potency injury. Also, invention describes a medicinal preparation based on compounds said, a method for its preparing and a method for preparing compounds.

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

6 cl, 1 tbl, 16 ex

FIELD: pharmaceutical chemistry, medicine.

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

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

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

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

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

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

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

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of tetracyclic derivatives of isoquinolone. Invention describes a method for synthesis of derivatives of 3,5-dihydro-1,11-dimethylfuro[2',3':3,4]cyclohepta[c]isoquinoline-5-one of the general formula (1a-f): wherein (1a): R means hydrogen atom (H); R' means hydrogen atom (H); (1b): R means chlorine atom (Cl); R' means hydrogen atom (H); (1c): R means bromine atom (Br); R' means hydrogen atom (H); (1d): R means iodine atom (J); R' means hydrogen atom (H); (1e): R means methoxy-group (-OCH3); R' means hydrogen atom (H); (1f): R means -OCH3; R' means -OCH3. Method involves boiling derivatives of 3,5-dihydro-1,11-dimethylfuro[2',3':3,4]cyclohepta[c]isochromen-5-one in formamide medium in the ratio 0.01 mole of the parent substance per 45 ml of formamide for 25-120 min. Invention provides preparing new compounds that possess the potential useful biological properties.

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

2 tbl, 6 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, medicine, pharmacy.

SUBSTANCE: invention relates to crystalline polymorphic modifications of strong acting epotilone analog of forma A and forma B represented by the formula (I): Invention proposes a crystalline substance representing a mixture of form A and form B of epotilone analogs. Invention proposes two variants of a method for preparing crystalline polymorphic modification representing form A. Also, invention proposes a pharmaceutical composition inhibiting angiogenesis and comprising an active component that represents crystalline polymorphic modification of epotilone analog of form A, form B or a crystalline polymorphic modification of epotilone analog of the formula (I) wherein this modification has no amorphous component, and a pharmaceutically acceptable carrier. Also, invention proposes a method for treatment of cancer comprising administration in mammal the effective dose of crystalline polymorphic modification of epotilone analog. Invention provides preparing crystalline polymorphic modifications of strong acting epotilone analog of the formula (I) characterizing by improved properties for using in therapy of cancer species.

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

16 cl, 9 dwg, 7 tbl, 5 ex

FIELD: organic chemistry, biochemistry, pharmacy.

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

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

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes phenyl-substituted heterocyclic 1,3-ketoenols of the formula (I): wherein R1 and R3 mean independently of one another ethyl or (C1-C2)-alkoxy-group; Q means the group of the formula (Q1): or (Q2): wherein R4 and R5 in common with atoms to which they are joined form 5-7-membered cycle that can comprise additionally anellated alkylene chain consisting of 2-6 carbon atoms that, in turn, can comprise two heteroatoms taken among oxygen atom, and indicated cycle can be substituted with halogen atom, hydroxy-group, (C1-C6)-alkoxy-group, (C1-C6)-alkoxy-(C1-C6)-alkoxy-group, (C1-C4)-alkylcarbonyloxy-group, hydroxy-(C1-C4)-alkoxy-group, hydroxycarbonyl-(C1-C2)-alkoxy-group, methoxycarbonyl-(C1-C2)-alkoxy-group, methoxyimino-, methoxyethoxyethoxy-group; R6 and R7 means (C1-C10)-alkyl; R8 means hydrogen atom; X means oxygen atom; R20 means (C1-C10)-alkyl, and also agronomically acceptable salts and isomers of these compounds. Also, invention describes a method for preparing compounds of the formula (I), herbicide agent and a method for control of weed growth based on compounds of the formula (I). Invention provides preparing compounds possessing the herbicide activity.

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

5 cl, 28 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

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

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, peptides, medicine, pharmacy.

SUBSTANCE: invention relates to peptide derivatives named as memnopeptides that are used as an active component for manufacturing a medicinal preparation used in treatment of bacterial infection. Invention proposes compound of the formula (I): wherein radicals R1, R2, R3, R4, R5, R6, R7, R8 and (A)n have corresponding values, or its salt. Compounds of the formula (I) are prepared by culturing microorganism Memnoniella echinata FH 2272, DSM 13195 under suitable conditions in the nutrient medium containing at least one source of carbon atoms and at least one source of nitrogen atoms and the process is carrying out until the accumulation of at least one compound of the formula (I) in the nutrient medium followed by isolation of indicated compound. The attained technical result involves the development of a pharmaceutical composition eliciting an antibacterial activity. The development of the preparation provides expanding assortment of agents used in treatment of diseases said above.

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

10 cl, 2 tbl, 7 ex

FIELD: pharmaceutical chemistry, medicine.

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

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

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

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

The invention relates to new derivatives of 2,3-benzodiazepine of the formula 1

where R1-R4have the meanings specified in the description, has a neuroprotective effect, as well as to methods for their preparation, pharmaceutical compositions and method of treatment of symptoms, followed by all types of acute and chronic neurodegeneration

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to R-2-aminoarylpropionic acid amides and pharmaceutical composition comprising thereof that can be used for prophylaxis and inhibition of recruiting and activation of leukocytes, and in treatment of pathologies directly dependent on indicated activation. Invention proposes compound of the general formula (1): wherein A, q, Ph and R have corresponding values, or its pharmaceutically acceptable salt. Also, invention describes a method for preparing amide of the formula (1) and pharmaceutical composition used in prophylaxis of leukocytes activation. Invention provides the development of pharmaceutical composition that can be used for prophylaxis and treatment of damaged tissues caused by enhancing activation of neutrophile granulocytes (polymorphonuclear leukocytes) in inflammation foci. Also, the invention relates to R-enantiomers 2-(aminoaryl)-propionylamides of the formula (1) that can be used for suppression of neutrophyles hemotaxis caused by IL-8. Also, compounds of this invention can be sued in treatment of psoriasis, ulcerous colitis, glomerulonephritis, acute respiratory insufficiency and rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds.

8 cl, 16 ex

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