Imidazolone derivatives, method for preparing, and biological use

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazolone derivatives used as drugs being kinase inhibitors, described by formula (I), wherein; R1 represents a C1-C3 alkyl radical or a hydrogen atom, and/or an aryl radical, Ar1 is specified in or , R represents the group R2-S-, R2 is thereby specified in the radicals like T1-(CH2)n, wherein n=0, 1, 2 or 3, and T1 represents a metal, vinyl, alkyl, alkynyl, nitrile, C3- or C4-cycloalkyl radical, hal, Z-O, Z-CO, wherein Z represents C1-C3 alkyl or hal, hal represents F, Cl, Br or I, or the group CCl3, or the group R3-NH-, R3 is thereby specified in the radicals like T2-(CH2)n, wherein n=0, 1 or 2, and T2 represents a metal, vinyl radical, Z-O, Z-CONH-, -CH-(OZ)2, ZCO, wherein Z represents H or C1-C4 linear or branched alkyl, NH2, C3-cycloalkyl, aryl, substituted aryl, or R3 represents H, or the group R4-CONH-, R4 is thereby specified in C3-C5 branched alkyl, or Ar2- or Ar2-3-, Ar2 is specified in a phenyl radical, substituted phenyl or benzodioxolyl; and have IC50 less than 5 mcM.

EFFECT: invention also refers to pharmaceutical compositions based on the compounds of formula I for treating neurodegenerative disorders and to using these compounds as DYRKIA inhibitors.

11 cl, 2 tbl, 8 ex

 

The object of the invention are derivatives of imidazolines. It also refers to the manner of their reception.

In addition, it relates to biological applications of these derivatives as inhibitors of kinases, in particular, for the treatment of neurodegenerative diseases (namely, Alzheimer's disease, diseases of the Peak, trisomy 21).

Most human pathologies include anomalies phosphorylation, often associated with abnormal regulation of certain protein kinases.

Thus, in recent years, the search for effective inhibitors of these kinases has become very active.

Based on long term experience in respect of the CDK kinases, GSK-3 and CK1, the inventors were interested in the development of selective inhibitors of the kinase DYRK1A (Kinase 1A dual specificity regulated by phosphorylation of tyrosine).

It is about the enzyme that autophosphorylated by its tyrosine 321 (which leads to its activation), which phosphorylates residues serine and threonine.

The gene of the protein kinase DYRK1A localized in a very specific division of chromosome 21, "critical Department of down syndrome", which completes the twenty genes responsible for trisomies phenotype. Many arguments support the hypothesis of significant contribution overexpression, even moderate (×1,5), DYRK1A in abnormal brain development observed in trisomy 21. To the ome, DYRK1A also seems to be heavily involved in Alzheimer's disease (which systematically and prematurely occurs in patients with trisomy 21 after 40 years (Kimura R, et al., 2006. The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer's disease. Hum. Mol. Genet. 16, 15-23; Ferrer I, et al., 2005. Constitutive DYRK1A is abnormally expressed in Alzheimer's disease, Down syndrome, Pick disease, and related transgenic models. Neurobiol. Dis. 20, 392-400).

Inhibitors of DYRK1A were found by virtual screening in silico structural model DYRK1A, based on the crystal structure of GSK-3 (Kim et al., Bioorg. Med. Chem. Lett., 2006 Jul. 15; 16 (14): 3712-6). In this approximation, from 182 selected compounds only 11 molecules showed inhibitory activity with IC50varying from 2.5 to 50 microns.

The work of inventors in search, optimization and characterization of pharmacological inhibitors of the kinase DYRK1A led them to the discovery that derivatives of imidazolines corresponding derivatives or analogues lacertina, are potent and selective pharmacological inhibitors of the kinase DYRK1A. Hereinafter, the term "connection" is also used to denote their derivatives and analogues.

Lacettis In is a marine alkaloid extracted from the sponge Leucetta microraphis, formula A

Lacettis

The extension searches led the authors from whom retene to develop ways of synthesis, allowing to obtain a family of compounds having the properties in respect of DYRK1A, which are of great interest, with IC50in most cases, less than 50 μm or even 10 μm up to 1 mm.

Thus, the aim of the invention is the use of derivatives imidazolones comprising analogues lacertina as medicines.

It also considers the method of obtaining these compounds.

In addition, the invention relates to compounds that comply with the new derivative imidazolones, and to their use as active principles of drugs.

In accordance with the first aspect, the invention relates also to the use in the production of pharmaceuticals for the treatment of neurodegenerative diseases derived imidazoline corresponding to the formula (I)

in which:

R1represents H, optionally substituted linear or branched C1-C5 alkyl radical; aryl group, or a 5 - or 6-membered heterocyclic group, aryl and a heterocyclic group optionally contain one or more identical or different substituents in any position;

Ar1represents an aryl group with an optional one or more substituents, two adjacent substituent can obrazovyvat - or 6-membered cycle, this cycle, if necessary, may be substituted; or an aromatic heterocycle with a heteroatom selected from N, S and O, optionally one or more substituents, and/or condensed with an aromatic 5 - or 6-membered cycle;

R is R2-S-, R3-NH-, R4CONH or Ar2where

R2represents a linear, branched or cyclic C1-C5 alkyl radical; vinyl or C1-C5 minimally radical, nitrile or C1-C5 initilally radical, aryl or benzyl radical, these radicals optionally substituted by one or more carbon atoms by one or more identical or different groups occupying any position, two adjacent substituent may form a 5 - or 6-membered cycle, this cycle, if necessary, can be replaced,

R3has the definition given above, and, in addition, may represent N;

Ar2represents a substituted or unsubstituted aryl radical, two neighboring substituent may form a 5 - or 6-membered cycle, this cycle may not necessarily be replaced.

The invention also considers the racemic forms of the derivatives listed above, as well as their enantiomeric forms, taken separately.

As illustrated by examples, more specifically, the above derivatives are selective in what ibitoye kinase DYRK1A with IC 50less than 5 microns down to less than 1 μm, especially preferred derivatives have IC50less than 0.1 microns.

In the above formula (I) "aryl" represents phenyl or naphthyl, and "heterocycle" represents a 5 - or 6-membered cycle with N, O and/or S as a heteroatom(s). The substituents in the R1, Ar1, Ar2and R is selected from: HE, OZ, SON, COZ, COOH, COOZ, NH2, NHalc., N(alc)2, NHCOOH, NHCOOZ, Z represents a linear or branched C1-C5 alkyl radical, benzyl, aryl or substituted benzyl, benzodioxolyl, one or more Halogens and/or group CCl3and alc. represents C1-C3 alkyl radical.

The invention mainly has the purpose of use as medicines derived imidazolines with IC50less than 5 microns and corresponding to the above formula I, in which:

R1represents C1-C3 alkyl radical or a hydrogen atom, and/or aryl radical

Ar1selected from the

R represents

the group R2-S-, R2thus selected from radicals of type T1-(CH2)nwhere n=0, 1, 2 or 3, and T1represents methyl, vinyl, alkyl, alkynylaryl, nitrile, C3 - or C4-cycloalkenyl radical, Z-O, Z-CO -, where Z is C1-C3 alkyl or hal, hal is F, Cl, Br or I, or group CCl3,

or

the group R3-NH-, R3still the way selected from radicals of type T 2-(CH2)nwhere n=0, 1, or 2, and T2represents methyl, vinyl radical, Z IS O, Z is-CONH-, -CH(OZ)2, ZCO, where Z represents H or C1-C4 linear or branched alkyl, NH2, C3-cycloalkyl, aryl, substituted aryl, or R3represents H,

or

the group R4-CONH-, R4thus selected from C3-C5 branched alkyl,

or

R is Ar2, Ar2selected from phenyl radical, substituted phenyl or benzodioxolyl.

Preferably the invention relates to the use as medicines derived imidazolines with IC50less than 1 μm and corresponding to the above formula I, in which:

R1represents N or CH3

Ar1selected from the

R represents

the group R2-S-, R2thus selected from radicals of type T1-(CH2)nwhere T1represents methyl, alkynylaryl, a nitrile radical, hal, CH3Oh, cyclopropyl or cyclobutyl, n=0, 1, 2 or 3, and "hal" represents a halogen atom or a group CCl3,

or

the group R3-NH-, R3thus selected from radicals of type T2-(CH2)nwhere T2represents C3-alkyl, HE, cyclopropyl, n=0, 1, or 2, phenyl, phenyl substituted IT, och3, COOH and HE, CH2HE, (CH3HE), CH2/sub> -CH2HE, CH2-COOH, benzodioxolyl, or R3represents H,

or

the group Ar2selected from para-hydroxyproline or benzodioxolyl group.

In a preferred group of derivatives of imidazoline formula (I)

R is R2S, R3HN or Ar2;

R1represents H or a linear or branched C1-C5 alkyl radical;

R2represents H or a linear or branched C1-C5 alkyl radical, optionally substituted by one or more radicals HE, C1-C5 alkoxy, (CH2)n-OH, or (CH2)n-COOH; or is a cyclic radical, optionally, the type -(CH2)n-cycloalkyl, cycloalkenyl radical has 3 to 5 members and n=1-5, a cyclic radical optionally substituted C1-C5-alkyl; or represents C1-C5 alkylenediamines radical; C1-C5 etkilenmenin; C1-C5 quinil;

R3represents a linear or branched C1-C5 alkyl radical, optionally substituted by one or more radicals C1-C5 alkoxy, HE or COOH; or is a cyclic radical, optionally, the type -(CH2)n-cycloalkyl; or represents a phenyl radical optionally substituted by one or more- (CH2)n-OH; alkoxy or COOH; or benzodioxolyl radical; or is a cyclic radical, the ri needed type -(CH2)n-cycloalkyl, cycloalkenyl radical has 3 to 5 members and n=1-5; NH2;

Ar1is benzodioxolyl radical;

Ar2is benzodioxolyl radical or phenyl, the latter optionally substituted by one or more-HE alkoxy.

In another preferred group of derivatives of imidazoline formula (I)

R is R2S, R3HN or Ar2;

R1represents H or a linear or branched C1-C5 alkyl radical;

R2represents a linear or branched C1-C5 alkyl radical, optionally substituted by one or more radicals HE, C1-C5 alkoxy, (CH2)n-OH; or is a cyclic radical, optionally, the type -(CH2)n-cycloalkyl, cycloalkenyl radical has 3 to 5 members and n=1-5; or represents C1-C5 alkylenediamines radical; C1-C5 etkilenmenin;

R3represents a phenyl radical optionally substituted by one or more- (CH2)n-OH; alkoxy; or benzodioxolyl radical; or is a cyclic radical, optionally, the type -(CH2)n-cycloalkyl, cycloalkenyl radical has 3 to 5 members and n=1-5; NH2;

Ar1is benzodioxolyl radical;

Ar2is benzodioxolyl radical or phenyl, the latter optionally substituted by one or more-HE.

In a particularly advantageous case, the derivatives of imidazolines used in accordance with the invention, selected from the following compounds, in which in the formula (I)

R is R2S

R2is CH2With≡CH; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R2is CH2With≡N; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R2is CH2CH2CL; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R2is CH3; R1is H; Ar1represents 1,3-benzodioxol-5-yl;

R2is CH2CH3; R1is H; Ar1represents 1,3-benzodioxol-5-yl;

R2is CH2CH2CH3; R1is H; Ar1represents 1,3-benzodioxol-5-yl;

R2is CH(CH3)2; R1is H; Ar1represents 1,3-benzodioxol-5-yl;

R2is CH2With≡N; R1is H; Ar1represents 1,3-benzodioxol-5-yl;

R2is CH2(CH2)2CH3; R1is H; Ar1represents 1,3-benzodioxol-5-yl;

R2is CH2CH2OCH3; R1is H; Ar1is ,3-benzodioxol-5-yl;

R2is CH2T1where T1is cyclopropyl; R1is H; Ar1represents 1,3-benzodioxol-5-yl;

R2is CH2T1where T1is cyclobutyl; R1is H; Ar1represents 1,3-benzodioxol-5-yl;

R is R3NH

R3is CH2CH3; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is CH2CH2HE; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is CH2T1where T1is cyclopropyl; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is CH2CH3; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is about-BUT-WITH6H4; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is6H5; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is p-BUT-WITH6H4; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is p-m BUT2C-C6H3; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;/p>

R3is p-m-och2O-C6H3; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is p-CH3-C6H3; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3represents NON2SNONCE2; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is p-m-och2CH2O-C6H3; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is p-CH3O-C6H4; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is m-NON2-C6H4; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is m-NESN(CH3)-C6H4; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is p-NON2CH2-C6H4; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is p-BUT2CLO2O-C6H4; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

R3is CH2CH2CH3; R1is H; Ar1represents 1,3-benzodioxol-5-yl;

R 3is CH2T1where T1is cyclopropyl; R1is H; Ar1represents 1,3-benzodioxol-5-yl;

R3is6H5; R1is H; Ar1represents 1,3-benzodioxol-5-yl;

R3is p-BUT-WITH6H4; R1is H; Ar1represents 1,3-benzodioxol-5-yl;

R3represents H; R1is H; Ar1is p-m-MeO-C6H3;

R is Ar2

Ar2is p-BUT-WITH6H4; R1is IU; Ar1represents 1,3-benzodioxol-5-yl;

Ar2is p-m-och2O-C6H3; R1is IU; Ar1represents 1,3-benzodioxol-5-yl.

In accordance with another aspect, the invention considers new derivatives of imidazolines.

Indeed, except for derivatives, the following, the above derivatives of the formula I are new derivatives, and as such are included in the scope of the invention.

Thus, as new products the invention considers derivatives imidazolone, characterized in that they correspond to the formula I according to claim 1 claims, except for derivatives, which

R is R2S, and

Ar1represents 1,3-benzo is dioxol-5-yl; R1is CH3and R2is CH3CH3CH2CH2=CH-CH2CH≡C-CH2CH3-CH2-OCO-CH2With6H4-CH2;

Ar1is p,m-och3; R1is CH3and R2is CH3CH2;

Ar1is m,m'-och3-C6H4; R1is CH3and R2is CH3CH2;

Ar1represents 1,3-benzodioxol-5-yl; R1represents n-butyl; R2is CH3CH3-CH2CH2=CH-CH2CH≡CH2With6H4-CH2; n-NO2-C6H4-CH2CH3CH2OCO-CH2;

Ar1represents 1,3-bromobenzoic-5-yl; R1represents n-butyl; R2is CH3-CH2;

Ar1is p,m-och3-C6H4; R1represents n-butyl; and R2is CH3CH2;

Ar1represents 1,3-benzodioxol-5-yl; R1is CH3; R2is6H6or p-HE6H4;

R is R3HN and

Ar1represents 1,3-benzodioxol-5-yl; R1is CH3; R2represents N, CH3-(CH2)2CH -(CH2)3p-COOH-C6H4CH2;

Ar1represents 1,3-benzodioxol-5-yl; R1is CH3-(CH2)3; R2is CH3-(CH2)2or CH3-(CH2)3;

Ar1represents 1,3-benzodioxol-5-yl; R1is6H5; R2is CH3-(CH2)2;

Ar1is p-HE-m-och3-C6H4or m,p-HE-C6H4; R1is N, and R2is N.

These new derivatives and their use as medicines are also included in the scope of the invention.

Thus, the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the derivatives of formula (I)defined above.

As shown by the values of the IC50in these examples, the compounds defined above, are powerful inhibitors of the kinase DYRK1A, and as such are useful both as pharmacological tools for basic research, and as therapeutic agents for the treatment of neurodegenerative diseases, particularly Alzheimer's disease and other chaupati, disease Peak and trisomy 21.

Derivatives of formula I, or a new derivative in accordance with the invention, really represents the t means, to explore the function of DYRK1A in different cell models, and the consequences of its expresii and abnormal activity. They are acting the beginning of medicines to counter the effects of overexpression/abnormal activation of DYRK1A in the above-mentioned pathologies.

In the production of pharmaceuticals, active start, used in therapeutically effective amounts, mixed with pharmaceutically acceptable carriers for the selected method of administration.

Thus, for oral administration of drugs prepared in the form of gelatin capsules, tablets, pills, capsules, pills, drops and the like. Such medicines can contain from 1 to 100 mg of active beginning in a single dose.

For the injection (intravenous, subcutaneous, intramuscular) of the medicinal product is presented in the form of a sterile or sterilizable solutions. Dose for a single reception can vary from 1 to 50 mg of active beginning. Daily dosage is chosen in such a way as to achieve a final concentration of analogue or derivative imidazolone in the blood being treated patient not more than 100 microns.

In accordance with another aspect, the present invention also relates to a method for obtaining derivatives of imidazoline formula I, defined above. This ways which differs it includes the use of arylidene derived thiohydantoin corresponding to the formula 3

in which

R1, R2, Ar1defined above.

According to the method of implementation of the related receivable derivative imidazolone formula I in which R represents R2S, the method of the invention involves the reaction of a derivative of thiohydantoin 3 halogen derivatives of 3' formula

where X represents Cl, Br or I,

under conditions that allow to obtain the derived imidazolone 4 according to the following scheme 4

Advantageous to conduct the reaction between compounds 3 and 3' in an organic solvent at a temperature of from 70 to 100 º C, namely from 80 ° C in the presence of carbonate.

For more specific derivatives of the formula (I)in which R2is aryl radical, the method of the invention involves the reaction of a derivative of thiohydantoin 3 with arylboronic acid 7' formula

in the conditions, you can proceed to the derivative of formula 8 according to scheme 1'

Satisfactory conditions correspond to the reactions under microwave irradiation thiohydantoin with Bronevoy acid in the presence of Cu(AcO)2(where AC is acetyl) and phenanthroline in organic p is storytale, such as dichloroethane.

The mixture is irradiated 50-100 minutes, namely between 60 to 90 minutes, at 70-90ºC, namely at 80 ° C, with a maximum power of approximately 300 Watts.

According to the method of implementation of the related receivable derivative imidazolone formula I in which R represents R3NH, the method of the invention includes

either reaction derived imidazolone 4, as described above, with an amine 4' formula

under conditions that allow to obtain according to scheme 2 below, derived imidazolone 5 formula

either reaction is derived as 3, as described above, with an amine 4' according to the following scheme 3

Preferably, the reaction of scheme 3 is performed on an oil bath or microwave irradiation. In the method of holding in the oil bath, the reaction mixture is heated to a temperature below the boiling point of the amine.

When working with microwaves, mixture it is advantageous to irradiate from 10 to 100 minutes to a suitable temperature with appropriate power.

The reaction of scheme 3 is advantageously carried out in a solvent such as methanol, in the presence of hydroperoxide.

According to the method of implementation of the related receivable derivative imidazolone formula I in which R represents R4CONH, the method of the invention involves the reaction of production is of underwater imidazolone 5 formula

with the acid chloride of the acid 5' of the formula

under conditions that allow to obtain the derived imidazolone 6 according to the following scheme 4:

The substituents in these different formulas defined above.

Suitable conditions for the reaction between these derivatives include the addition of triethylamine, then the carboxylic acid (5') to the solution derived imidazolone 5 in an organic solvent such as THF.

This reaction is advantageously carried out at a temperature of 20-25ºC.

To obtain the derivative imidazolone formula I, in which R is Ar2the method of the invention involves the reaction of a derivative of thiohydantoin formula 3 with Bronevoy acid 7'

under conditions that allow to obtain the derived imidazolone 7 according to the following scheme 5

This reaction is advantageously carried out in the presence of a catalyst such as Pd(PPh3)4and CuTC (thiophencarboxylic copper) in anhydrous organic solvent such as anhydrous THF. This reaction is advantageously carried out at a temperature of about 55-65 º C.

Especially preferred way, the derived thiohydantoin 3 receive response derived thiohydantoin 2 formula

with the derived aldimine formula 2'

the substituents defined above, and "alk" represents a C3-C5 alkyl radical, according to the following scheme 6

The reaction is advantageously carried out on an oil bath or by irradiation with microwaves.

In the method run in the oil bath reagents are mixed in an organic solvent, and the reaction mixture was kept boiling under reflux. Viscous oil which rapidly crystallized, isolated after filtration and optionally purified.

Among suitable organic solvents specified acetonitrile.

In the method of performing the irradiation of the microwaves in a mixture of thiohydantoin formula 2 and aldimine formula 2' is placed in a microwave reactor, placed in a microwave oven in which the mixture is irradiated, then, upon completion of the reaction and cooling to ambient temperature, produce the reaction product.

Suitable conditions include treatment for approximately 1 hour at 70-100ºC, namely at 80 ° C, with a maximum capacity of 80-100 Watts, more specifically 90 Watts.

Aldimine 2' receive, for example, on the basis of aldehyde 2" Ar1-CH=O and Propylamine 2"' CH3-(CH2)2-NH2. This reaction is advantageously carried out in a microwave reactor at a power of 300 Watts, for example at 20 to 80 ° C, namely 25-60 ° C for 2-5 minutes, and it is 3 minutes, ZAT is at 60-80 ° C at reduced output power of the order of 10-30%, namely 20%.

Derived thiohydantoin 2 is obtained by reaction of the hydrochloride methylglycine 1

with isothiocyanato 1' formula

according to the following scheme 7

Satisfactory reaction conditions include reaction 1 and 1' in the presence of triethylamine, in a solvent such as ether, boiling under reflux.

Intermediate compounds in these various stages of implementation are new, and as such are also included in the scope of the invention.

Other characteristics and advantages of the invention are given in the examples which follow the way of carrying out the invention aims to obtain derivatives of imidazoline according to the invention.

As an illustration, the experimental conditions of the reactions, labeled a to H shown in figure 1, are shown in the following experimental part.

The values of the IC50compounds according to the invention in microns against DYRK1A given in Table 2 in part related to the activity of the kinase DYRK1A.

Experimental part

Table 1

REACTION:

General method: a Mixture consisting of 7 mmol of isothiocyanate (R1N=C=S), 7 mmol (0.88 g) of the hydrochloride of methylglycine 1, 7 mmol (0.97 g) of triethyl is in 15 ml of ether is boiled for 14 hours under reflux with vigorous stirring with a magnetic stirrer. After cooling the reaction medium to ambient temperature the solvent is removed under reduced pressure on a rotary evaporator. Hydrochloride of triethylamine are planted with ethyl acetate. After filtering, the filter of sintered glass (porosity No. 4 the filtrate concentrated on a rotary evaporator under reduced pressure and get the expected product 2. The latter is then used without further purification.

Connection example 2:

3-Methyl-2-thioxo-imidazolidin-4-one (R1is IU).

Yield 95%. So pl. 170-172º.1H NMR (200 MHz, CDCl3, TMS) δ: with 3.27 (s, 3H, NCH3); 4,11 (s, 2H, -CH2-); to 7.64 (users, 1H, NH).13With NMR (75 MHz, CDCl3, TMS) δ: 27,5 (NCH3); to 48.6 (CH2-); 171,6 (C=O); 185,4 (C=S).

The REACTION B:

A common way to implement an oil bath In a vessel equipped with a magnetic stirrer, consistently load dichloromethane (20 ml), 6,9 mmol of thiohydantoin 2, then to 6.9 mmol freshly aldimine (*). The reaction mixture is then refluxed in dichloromethane, and the reaction is checked by chromatography in thin layer on silica gel 60F 254 (Merck). Once the reaction is finished, the reaction medium is cooled to ambient temperature, then dried over anhydrous MgSO4. After filtration through a folded paper filter solvent of f is ltrate removed by evaporation under reduced pressure and obtain a viscous oil, which quickly crystallizes at ambient temperature. Cleaning perform or recrystallization from pentane, or optional thin-layer chromatography on silica gel 60 F 254 (Merck) in a suitable solvent.

A common way to implement under microwave irradiation: a Mixture of 10 mmol of thiohydantoin 2 and 10 mmol (1 equivalent) aldimine (*)placed in a microwave reactor in the form of a cylinder (⌀ 4 cm). Then the reactor is placed in a microwave Syntheware 402 (manufacturer Prolabo, group Merck-Eurolab), equipped with paddle agitation system. The mixture is irradiated for 1 hour at 80°C (speed, 3 minutes) with a maximum capacity of 90 Watts (microwave Prolabo). After cooling to ambient temperature the reaction mixture was then concentrated on a rotary evaporator. To the residue after evaporation add mixed solution of chloroform/pentane (1/2). After processing, the mixture is filtered, the insoluble solid matter on the filter of sintered glass with porosity No. 4, and then dried under reduced pressure.

Connection example 3:

(5Z)-5-(1,3-Benzodioxol-5-ylmethylene)-3-methyl-2-dioxoimidazolidin-4-one (Ar1represents 1,3-benzodioxol-5-yl, R1is IU)

Yield 87%. Yellow powder, so pl. 253-255°C.1H NMR (200 MHz, DMSO-d6) δ: 3,18 (s, 3H, NCH3); 6,09 (s, 2H, och2 O); is 6.54 (s, 1H, C=CH); of 6.96 (d, 1H, J=8,1 Hz, H-5); 7,27 (d, 1H, J=8,1 Hz, H-6); was 7.45 (s, 1H, H-2); 12,22 (users, 1H, NH).13With NMR (75 MHz, DMSO-d6) δ: 27,6 (NCH3); 102,1 (och2O); 109,1 (C-5); 109,8 (C-2); 113,7 (C=CH); 125,1 (C=CH); 126,9 (C-6); 126,9 (S-1); OF 148.4 (C-4); OF 149.0 (C-3); 164,6 (C=O); 179,0 (C=S). Msvr, m/z: 262,0409 (calculated for C12H10N2O3S: 262,0412).

(*) General implementation method for the synthesis of aldimines: 20 mmol of aldehyde and 40 mmol (3.28 ml) Propylamine sequentially poured into a quartz reactor. This reaction medium is heated in a microwave reactor Synthewave (Pmax= 300 Watts, manufacturer Prolabo, group Merck-Eurolab) according to the following program (from 25 to 60°C for 3 minutes, then at 60°C for 30 minutes at a power of 20%). Excess Propylamine removed on a rotary evaporator under partial vacuum, then the residue of evaporation (solid phase) was transferred into a solution in dichloromethane (10 ml/g of product); the organic solution is then dried over MgSO4filter through a paper filter. The filtrate is concentrated on a rotary evaporator under reduced pressure.

Example aldimine:

N-[(1,3)-benzodioxol-5-ylmethylene]-N-Propylamine (Ar1represents 1,3-benzodioxol-5-yl):

Yield 97%. Yellow powder.1H NMR (200 MHz, CDCl3) δ: from 0.90 (t, 3H, J=7,3 Hz, NCH2CH2CH3); 1,64 (t, 2H, J=7,2 Hz, NCH2CH2CH3); 3,47 (t, 2H, J=6,9 Hz, NCH2 CH2CH3); 5,90 (s, 2H, och2O)of 6.71 (d, 1H, J=7.9 Hz, H-5), 7,02 (DD, 1H, J=1,3; 7.9 Hz, H-6); 7,37 (d, 1H, J=1.4 Hz, H-2); 8,10 (s, 1H, N=CH).13With NMR (75 MHz, CDCl3) δ: 12,2 (CH3); 24,5 (CH2CH3); 63,7 (NCH2); 101,8 (och2O); 107,0 (C-3); 108,4 (C-6); 124,5 (C-2); HUMIDITY 131.6 (C-1); OF 148.6 (C-5); 150,0 (C-4); 160,3 (N=CH).

REACTION:

A common method of implementation: In the vessel sequentially load 5-alligatoridae 3 (3.1 mmol, 1 EQ.), 20 ml of acetonitrile, halogenated derivatives of R2X, where X represents Cl, Br, I (3.1 mmol, 1 EQ.), and 0.21 g2CO3(1.5 mmol 0.5 EQ.). The reaction mixture is heated at 80°C for 14 hours under vigorous stirring with a magnetic stirrer. After cooling to ambient temperature, the acetonitrile is removed in a rotary evaporator under reduced pressure. In the reaction medium was added 20 ml of ether. After filtering off under partial vacuum insoluble inorganic products through a filter of sintered glass (porosity No. 4, the filtrate is dried over magnesium sulfate, and then filtered through a folded paper filter. The solvent of the filtrate is removed on a rotary evaporator under reduced pressure and get the expected imidazole 4 in the form of powder.

Connection example 4:

[(Z)-(4-benzo[1,3]dioxol-5-ylmethylene-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-2-ylsulphonyl)]acetate (Ar1 represents 1,3-benzodioxol-5-yl, R1is IU, R2is CH2CO2Et)

Yield 92%. Yellow powder, TPL 172-174°C.1H NMR (300 MHz, CDCl3) δ: 1.26 in (t, 3H, J=7,1 Hz, och2CH3); of 3.12 (s, 3H, NMe); was 4.02 (s, 2H, SCH2); to 4.23 (q, 2H, J=7,1 Hz, och2CH3); 5,96 (s, 2H, och2About); to 6.80 (d, 1H, J=8,1 Hz); at 6.84 (s, 1H, =CH); 7,52 (DD, 1H, J=8,1; 1.3 Hz); of 7.96 (d, 1H, J=1.3 Hz).13With NMR (75 MHz, CDCl3) δ: 14,1 (m, J=128 Hz, och2CH3); 26,6 (kV, J=144 Hz, NMe); 32,9 (t, J=144 Hz, SCH2); 62,3 (TCV, J=148 Hz, 4.6 Hz, och2); 101,5 (t, J=174 Hz, och2O)108,4 (d, J=165 Hz); 110,8 (dt, J=168 Hz, 6.9 Hz); 124,6 (dt, J=156 Hz; 4,1 Hz); 128,4 (dt, J=162 Hz; 6.0 Hz); 128,9 (d, J=7,6 Hz); 136,6 (); 148,0 (m, =C-O); 149,3 (m, =C-O); 162,0 (m, C-2); 168,0 (m, C=O(CO2Et)); 169,7 (m, C-4). Msvr, m/z: 348,0791 (calculated for C16H16N2O5S: 348,0780).

The REACTION D:

A common way to implement under microwave irradiation: a Mixture of (5Z)-5-arylidene-2-alkylthio-3,5-dihydroimidazole-4-it 4 (4 mmol, 1 EQ.) and 5-20 mmol of amerosport R3-NH2(from 1.5 to 5 equivalents) was placed in a microwave reactor in the form of a cylinder (⌀ 4 cm). Then the reactor is placed in a microwave Synthewave 402 (manufacturer Prolabo, group Merck-Eurolab), equipped with paddle agitation system. The mixture is irradiated for from 15 minutes to 90 minutes at a suitable temperature and power. After cooling, what about the ambient temperature, the reaction mixture was then concentrated on a rotary evaporator. To the residue from evaporation was added ethanol (1 ml/g of product). After grinding the mixture with ethanol insoluble solid is filtered on a filter of sintered glass (porosity No. 4, after dried under reduced pressure. Received optional recrystallized from ethanol.

The method implementation in the oil bath: Suspension consisting of (5Z)-5-arylidene-2-alkylthio-3,5-dihydroimidazole-4-it 4 (4 mmol, 1 EQ.) and aliphatic amine (40 mmol, 10 equivalents) is mixed under vigorous stirring with a magnetic stirrer and heated at a temperature which is 10°C lower than or equal to the boiling point of the amine (Texp.=Tcipline-10°C)for 3 to 7 days. After cooling to ambient temperature the volatile products are removed under reduced pressure, and the reaction medium was added ether (~ 10 ml). Then, products, insoluble in ether, separated by filtration on a filter of sintered glass (porosity No. 4. The solvent remaining in the connection 5, is removed under partial vacuum in a desiccator for 2 hours, and get the expected 2-amino-imidazole 5 as a yellow powder.

Example 2-amino-imidazolone 5:

(5Z)-5-benzo[1,3]dioxol-5-ylmethylene-1-methyl-2-propylamino-3,5-dihydroimidazole-4-one (Ar1represents 1,3-benzodioxol-5-yl, R1is IU, R3represents the t of CH 2CH2CH3)

Yield 48%. Yellow powder, TPL 190-192°C.1H NMR (300 MHz, CDCl3) δ: 1,02 (t, 3H, J=7.4 Hz); 1,74 (Sextus, 2H, J=7,3 Hz, NHCH2CH2); the 3.11 (s, 3H, NMe); of 3.54 (t, 2H, J=6.2 Hz, NHCH2C2H5); 4,95 (users, 1H, NH); 5,98 (s, 2H); 6,62 (s, 1H, =CH); for 6.81 (d, 1H, J=8,1 Hz); 7,34 (DD, 1H, J=8,1 Hz, 1.4 Hz); 7,99 (d, 1H, J=1.2 Hz).13With NMR (75 MHz, CDCl3) δ: 11,5 (square t, J=126; 4.0 Hz, N2H4Me); 22,8 (TCV, J=135; 3,7 Hz, N2CH2); 25,2 (kV, J=140 Hz, NMe); 43,7 (TCV, J=122 Hz; 7,0 Hz, N2); 101,1 (t, J=173 Hz, C-7'); 108,4 (d, J=164 Hz, C-2'); 110,3 (dt, J=166; 7,1 Hz; C-6); 116,8 (dt, J=157 Hz, 3.5 Hz); 126,1 (dt, J=163; 6,2 Hz; C-6'); is 130.2 (d, J=7.8 Hz, C-5'); 138,1 (s, C-5); 147,6 (m, C-3'); a 147.7 (m, C-4'); 157,2 (m, C-4); 170,4 (sm-2). Msvr, m/z: 287,1279 (calculated for C15H17N3About3: 287,1270).

RESPONSE E:

General method: To a solution of 0.2 mmol of 2-amino-imidazole 5 (R3represents H, R1is IU) in THF (2 ml) is added at 0°C triethylamine (2 equiv.), then the acid chloride of acid (1.5 equiv.). The reaction mixture was stirred at 25°C for 12 hours. Then the solution is evaporated under reduced pressure, and the residue purified flash chromatography on silica gel using a mixture of AcOEt/cyclohexane (9/1) as eluent.

Connection example 6:

N-[(4Z)-4-benzo[1,3]dioxol-5-ylmethylene-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-2-yl]-2,2-dimethylpropanamide (Ar1predstavljaet,3-benzodioxol-5-yl, R1is IU, R4is C(CH3)3).

The yield is 50%. Yellow powder, so pl. 145-147°C.1H NMR (300 MHz, CDCl3) δ: 1.28 (in s, C(CH3)3), N); 3,24 (s, CH3, 3H); 6,05 (s, och2Oh, 2H); 6,76 (s, =CH, 1H); 6,92 (d, J=8.0 Hz, Har, 1H); 6,93 (C, Har, 1H); 7,01 (d, J=8.0 Hz, Har, 1H).13With NMR (75 MHz, CDCl3) δ: 25,6 (C(CH3)3); to 26.7 (C(CH3)3); 39,7 (NCH3); 101,6 (och2About); 108,5; 111,2; 128,1; 129,1; 142,5; 146,5; 149,7; 161,8; 171,2; 179,2. Msvr, m/z: 329,1377 (calculated for C17H19N3About4: 329,1375).

The REACTION F:

General method: To a solution of 3 (0.80 mmol) in Meon (20 ml) is added 3 equivalents of tert-butylhydroperoxide TBHP (70% aqueous solution), followed by 20 equivalents of amine. The reaction mixture was stirred at 25°C for 3 days. Then the solution is evaporated under reduced pressure, and the residue purified flash chromatography on silica gel using a mixture of CH2Cl2/MeOH (94/6) as eluent.

Connection example 5:

(5Z)-5-benzo[1,3]dioxol-5-ylmethylene-1-methyl-2-ethylamino-3,5-dihydro-4H-imidazol-4-one (Ar1represents 1,3-benzodioxol-5-yl, R3is Et, R1is N).

Yield 40%. Yellow powder, so pl. 222-224°C.1H NMR (300 MHz, DMSO-d6) δ: 1,17 (t, J=6,9 Hz, CH3, 3H); to 3.34 (m, CH2, 2H); of 6.02 (s, och2Oh, 2H); 6,23 (s, =CH, 1H); 6,9 (d, J=8,1 Hz, Har, 1H); 7,20 (users, NH, 1H), 7,38 (d, J=8,1 Hz, Har, 1H), 7,93 (C, Har, 1H); for 10.68 (users, NH, 1H).13With NMR (75 MHz, DMSO-d6) δ: 15,5 (CH3); 36,4 (NHCH2); 101,4 (och2About); 108,7; 109,8; 125,3; 131,0; 140,6; 146,9; 147,6; 160,2; 174,5. Msvr, m/z: 259,0959 (calculated for C13H13N3About3: 259,0957).

The REACTION G:

A common method of implementation: Suspension consisting of 5 mmol aldimine Ar1CH=N-Pr, 5 mmol of thiohydantoin 2 (R1is Me, Bu, Ph), 7.5 mmol of halogenoalkane R2X, 0,345 g (2.5 mmol) of potassium carbonate, and optionally of 1.25 g (7.5 mmol) of KI (if used halogenated derivatives of R2X, where X represents Cl, Br) in 10 ml of acetonitrile is heated for 14 hours at a temperature close to the boiling temperature of halogenoalkane R2X (Texp.= T.R2X- 10°C). The reaction solvent is then removed on a rotary evaporator under reduced pressure. The solid obtained after evaporation, triturated with dichloromethane (10 ml/g of product), then the insoluble inorganic salts are removed by filtration through paper. After evaporation of the filtrate the crude reaction medium handle (1 g/10 ml) with a mixture of pentane/ethanol (1/1). Deposited expected product 4, then it is separated on a filter of sintered glass with porosity No. 4 and dried in a desiccator under partial vacuum.

Example connect the Oia 4:

(5Z)-5-(1,3-benzodioxol-5-ylmethylene)-3-methyl-2-(ethylthio)for 3,5-dihydro-4H-imidazol-4-one (Ar1represents 1,3-benzodioxol-5-yl, R1is IU, R3is Et):

Yield 40%. Yellow-orange powder, so pl. 152-154°C.1H NMR (300 MHz, CDCl3) δ: 1.55V (t, 3H, J=7,4 Hz, SCH2CH3); 3,17 (s, 3H, NCH3); 3,40 (q, 2H, J=7,4 Hz, SCH2CH3); 6,00 (s, 2H, och2O); PC 6.82 (d, 1H, J=8,1 Hz, H-5); 6,83 (s, 1H, =CH); 7,37 (DD, 1H, J=8,1; 1.0 Hz, H-6); with 8.05 (s, 1H, H-2).13With NMR (75 MHz, CDCl3) δ: 14,7 (SCH2CH3); 25,6 (SCH2CH3); 26,9 (NCH3); 101.8 (och2ABOUT); TO 108.8 (C-5); OF 111.2 (C-2); 124,0 (=CH); 128,4 (C-6); OF 129.5 (C-1); 137,5 (N=C); 148,3 (C-4); AT 149.5 (C-3); 164,1 (C-S); 170,3 (C=O). Msvr, m/z: found 290,0730 (calculated for C14H14N2About3S: 290,0725, M).

The REACTION H:

A common method of implementation: Solution, consisting of (5Z)-5-alligatoridae 3 (1 equivalent), Bronevoy acid Ar2B(OH)2(1.5 equivalent), Pd(PPh3)4(5 mole. %) and CuTC (3 equivalent) in anhydrous THF (0,06 M) contribute in a test tube Slinka. The reaction mixture was kept boiling under reflux in THF overnight under vigorous stirring with a magnetic stirrer. After cooling to ambient temperature the reaction medium is extracted with dichloromethane (2 times). The organic phase is washed with a solution of hydrosulfate n is Tria (1M), then a saturated solution of sodium chloride, and finally with a solution of sodium bicarbonate (1M). The organic phase is dried over MgSO4, filtered through paper, and the filtrate concentrated on a rotary evaporator under vacuum. To the residue evaporation add hot diethyl ether. After cooling, the crystals are separated by filtration on a filter of sintered glass (porosity No. 4 in a partial vacuum, then purified by chromatography on silica gel with a mixture of cyclohexane-ethyl acetate (70/30) as eluent. The chromatographic fraction is then concentrated on a rotary evaporator, dried in a partial vacuum, which leads to the expected product 7.

Connection example 7:

(5Z)-5-(1,3-benzodioxol-5-ylmethylene)-3-methyl-2-phenyl-3,5-dihydro-4H-imidazol-4-one (Ar1represents 1,3-benzodioxol-5-yl, R1is IU, R3is6H5):

Yield 46%. Yellow powder, so pl. 209-211°C.1H NMR (300 MHz, CDCl3) δ: at 3.35 (s, 3H, NCH3); 6,01 (s, 2H, och2O); at 6.84 (d, 1H, J=8,1 Hz, H-5'); 7,16 (s, 1H, C=CH); 7,47 (DD, 1H, J=8,1 Hz, J=1.2 Hz, H-6'); 7,53 (m, 3H, H-3", H-4"); to 7.84 (DD, 2H, J=7,4 Hz, J=2.2 Hz, H-2"); to 8.14 (d, 1H, J=1.2 Hz, H-2').13With NMR (75 MHz, CDCl3) δ: 29,1 (NMe); 101,5 (och2ABOUT); TO 108.5 (C-5'); 111,5 (C-2'); 128,7 (C-2'); TO 128.8 (C-3"); TO 128.8 (C=CH); 129,0 (C-6'); 129,4 (C-1'); TO 131.4 (C-4"); 137,5 (C=CH); 137,5 (C-1'); 148,1 (C-3'); 149,7 (C-4'); 161,4 (=N); 171,6 (C=O). Msvr, m/z: 306,0995 (calculated for C18H14N 2About3: 306,10044).

The REACTION I:

A common method of implementation: 0.4 mmol (5Z)-5-alligatoridae 3, 1.6 mmol (4 equivalents) Bronevoy acid, 0.4 mmol (1 equivalent) CuOAc2, 0.8 mmol (2 equivalent) phenanthroline and 4 ml of dichloroethane are placed in a microwave reactor in the form of a cylinder (⌀ 2.8 cm). The reactor is then placed in a microwave, equipped with paddle agitation system. The mixture is irradiated for 60 to 90 minutes at 80°C (speed for 2 minutes) at a maximum power of 300 Watts (microwave Prolabo). After cooling to ambient temperature the reaction mixture was then concentrated on a rotary evaporator under partial vacuum. The expected product 8 are cleaned on Almagel, elwira a mixture of pentane-ethyl acetate (85/15), followed by washing with pentane.

Connection example 8:

(5Z)-5-(1,3-benzodioxol-5-ylmethylene)-3-methyl-2-(phenylthio)for 3,5-dihydro-4H-imidazol-4-one (Ar1represents 1,3-benzodioxol-5-yl, R1is IU, Ar2is6H5):

Yield 49%. Yellow powder, so pl. 171-173°C.1H NMR (300 MHz, Acetone-d6) δ: 3,22 (s, 3H, NCH3); 6,03 (s, 2H, och2O); 6,77 (c, 1H, C=CH); PC 6.82 (d, 1H, J=8,1 Hz, H-5'); of 7.36 (DD, 1H, J=8,1 Hz, J=1.2 Hz, H-6'); 7,56 (d, 1H, J=1.7 Hz, H-2'); 7,58 (d, 2H, J=1.7 Hz, H-2"); for 7.78 (m, 2H, H-3"); 7,83 (d, 1H, J=1.3 Hz, H-4").13With NMR (75 MHz, DMSO-d6) δ: 26,6 (NMe); 01,5 (och 2ABOUT); TO 108.5 (C-5'); 109,9 (C-2'); 123,4 (C=CH); 125,1 (C-1'); 128,3 (C-6'); 128,4 (C-1'); 129,4 (C-2'); 130,0 (C-4"); 134,8 (C-3"); TO 136.5 (C=CH); IS 147.5 (C-4'); 148,9 (C-3'); 162,8 (=N); 168,5 (C=O). Msvr, m/z: 338,0738 (calculated for C18H14N2About3S: 338,07251).

The release activity of the kinase DYR1KA

Biochemical reagents

Orthovanadate sodium, EGTA, Mops, β-glycerol, phenylphosphate, dithiotreitol (DTT), glutathione-agarose, glutathione, nitrophenylphosphate, basic myelin protein, obtained from Sigma Chemicals. [γ-33P]-ATP provided by Amersham.

Getting kinase DYR1KA and the release of its enzymatic activity

Recombinant DYR1KA rats transplanted in E. coli as fusion protein GST. Its clear affinity chromatography on immobilized beads glutathione (elution free glutathione). Kinase depending on the swab (60 mm β-glycerol, 15 mm p-nitrophenylphosphate, 25 mm Mops (pH of 7.2), 5 mm EGTA, 15 mm MgCl2, 1 mm DTT, 1 mm sodium Vanadate, 1 mm phenylhistine) with 1 mg of the basic myelin protein/ml, in the presence of 15 μm [γ-33P]-ATP (3000 CI/mmol; 10 MCI/ml) in a final volume of 30 ml After 30 minutes incubation at 30°C. aliquots of 25 μl of the supernatant is applied on phosphocellulose filters Whatman P81, and the filters washed 5 times in a solution of phosphoric acid (10 ml/l of water). Then the radioactivity, which contains the substrate held on wet filters, and counted in the presence of scintillation liquid is ti ASC (Amersham). Subtract the amount of radioactivity for witnesses, and activity is expressed as % of maximum value, that is obtained in the absence of inhibitor. The values of the IC50calculate, on the basis of curves dose-response, and result in microns.

The results are shown in table 2 below:

Table 2
Links:
1: Microwave mediated solventless synthesis of new derivatives of marine alkaloid Leucettamine B. Jean Rene Cherouvrier, François Carreaux, Jean Pierre Bazureau, Tetrahedron Letters 2002, 43, 3581-3584.
2: The isolation and synthesis of polyandrocarpamines A and B. Two new 2-aminoimidazolone compounds from the Fiijian ascidian, Polyandrocarpa sp. Rohan A. Davis, William Aalbersberg, Semisi Meo, Rosan Moreira da Rocha, Chris M. Ireland, Tetrahedron 2002, 58, 3263-3269.

Links:

1: Microwave mediated solventless synthesis of new derivatives of marine alkaloid Leucettamine B. Jean Rene Cherouvrier, François Carreaux, Jean Pierre Bazureau, Tetrahedron Letters 2002, 43, 3581-3584.

2: Parallel solution phase synthesis of 2-alkylthio-3,5-dihydro-4H-imidazl-4-one by one-pot three-component domino reaction. Steven Renault, Sarah Bertrand, François Carreaux*, Jean Pierre Bazureau*. Journal of Combinatorial Chemistry 2007, 9, acceptee pour publication (attente d autorisation pour ACS en ASAP).

3: Synthesis of the marine alkaloid Leucettamine B, Nathalie Roue, Ian Bergman, Tetrahedron 1999, 55, 14729-14738.

4: The isolation and synthesis of polyandrocarpamines A and B. Two new 2-aminoimidazolone compounds from the Fidjian ascidian, Polyandrocarpa sp., Rohan A. Davis, William Aalbersberg, Semisi Meo, Rosan Moreira da Rocha, Chris M. Ireland, Tetrahedron 2002, 58, 3263-3269.

1. Derivatives imidazolines for use as drugs that are inhibitors of kinases, characterized in that these derivatives correspond to the formula (I)

in which: R1represents C1-C3alkyl radical or a hydrogen atom, and/or aryl radical, Ar1selected from

R represents a group R2-S-, R2thus selected from radicals of the type T1-(CH2)n,
where n=0, 1, 2 or 3, and T1is metal, vinyl, alkyl, alkynylaryl, nitrile, C3 - or C4-cycloalkenyl radical, hal, Z-O, Z-CO -, where Z is C1-C3 alkyl, or hal, hal is F, Cl, Br or I, or group CCl3,
or
the group R3-NH-, R3thus selected from radicals of type T2-(CH2)nwhere n=0, 1, or 2, and T2represents methyl, vinyl radical, Z IS O, Z is-CONH-, -CH(OZ)2, ZCO,
where Z represents H or C1-C4 linear or branched alkyl, NH2,C3-cycloalkyl, aryl, substituted aryl, or R3represents H,
or the group R4-CONH-, R4thus selected from C3-C5
branched alkyl,
orAr2-or Ar2-S-, Ar2selected from phenyl radical, substituted phenyl or benzodioxolyl;
and have the IC50less than 5 microns.

2. Derivative according to claim 1, characterized in that have the IC50less than 1 µm and corresponds to the formula (I), in which
R1represents H or CH3,
Ar1represents the radical

R2is
the group R2-S-, R2thus selected from radicals of type T1-(CH3)n,
where T1represents methyl, alkynylaryl, a nitrile radical, hal, CH3O, cyclopropyl or cyclobutyl, n=0, 1, 2 or 3, hal represents a halogen atom or a group CCl3,
or
the group R3-NH-, R3thus selected from radicals of type T2-(CH2)n,
where T2represents C3-alkyl, OH, cyclopropyl, n=0, 1, or 2, phenyl, phenyl substituted OH, OCH3, COOH and OH, CH2OH, CH (CH3, OH), CH2-CH2OH, CH2-COOH, benzodioxolyl, or R3represents H,
or
the group Ar2selected from para-hydroxyproline or benzodia allilnoj group.

3. Derivative according to claim 1 or 2, characterized in that they
selected from derivatives of formula (I)in which R represents R2-S;
R2is CH2C≡CH; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R2is CH2C≡N; R1is Me; Ar1is, 3-benzodioxol-5-yl;
R2is CH2CH2Cl; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R2is CH3; R1is H; Ar1represents 1,3-benzodioxol-5-yl;
R2is CH2CH3; R1is H; Ar1represents 1,3-benzodioxol-5-yl;
R2is CH2CH2CH3; R1is H; Ar1represents 1,3-benzodioxol-5-yl;
R2is CH(CH3)2; R1is H; Ar1represents 1,3-benzodioxol-5-yl;
R2is CH2C≡N; R1is H; Ar1represents 1,3-benzodioxol-5-yl;
R2is CH2(CH2)2CH3; R1is H; Ar1represents 1,3-benzodioxol-5-yl;
R2is CH2CH2OCH3; R1is H; Ar1represents 1,3-benzodioxol-5-yl;
R2is CH2T1where T1the present is built cyclopropyl; R1is H; Ar1represents 1,3-benzodioxol-5-yl;
R3is CH2T1where T1is cyclobutyl; R1is H; Ar1represents 1,3-benzodioxol-5-yl;
R is R3-NH-;
R3is CH2CH3; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is CH2CH2OH; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is CH2T1where T1is cyclopropyl; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is CH2CH3; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is o-HO-C6H4; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3represents C6H5; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is p-HO-C6H4; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is p-HO-m-HO2C-C6H3; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is p-m-OCH2O-C6H3; R1is Me; Ar1represents 1,3-benzodiox is l-5-yl;
R3is p-CH3-C6H3; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is HOCH2CHOHCH2; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is p-m-OCH2CH2O-C6H3; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is p-CH2O-C6H4; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is m-HOCH2-C6H4; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is m-HOCH(CH3)-C6H4; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is p-HOCH2CH2-C6H4; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is p-HO2CCH2O-C6H4; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
R3is CH2CH2CH3; R1is H; Ar1represents 1,3-benzodioxol-5-yl;
R3is CH2T1where T1is cyclopropyl; R1is H; Ar1is 1, 3-benzodioxol-5-yl;
R3represents C6H5 ; R1is H; Ar1represents 1,3-benzodioxol-5-yl;
R3is p-HO-C6H4; R1is H; Ar1represents 1,3-benzodioxol-5-yl;
R3represents H; R1is H; Ar1is p-HO-m-MeO-C6H3;
R is Ar3;
Ar2is p-HO-C6H4; R1is Me; Ar1represents 1,3-benzodioxol-5-yl;
Ar2is p-m-OCH3O-C6H4; R1is Me; Ar1represents 1,3-benzodioxol-5-yl.

4. Pharmaceutical compositions characterized in that they comprise a therapeutically effective amount of at least one derivative according to any one of claims 1 to 3.

5. The pharmaceutical composition according to claim 4, intended for the treatment of neurodegenerative diseases, in particular Alzheimer's disease and other chaupati.

6. The pharmaceutical composition according to claim 4, intended for the treatment of the disease Peak.

7. The pharmaceutical composition according to claim 4, intended for the treatment of trisomy 21.

8. The use of derivatives imidazolone according to any one of claims 1 to 3 as inhibitors of DYRK1A.

9. The method of obtaining derivatives of imidazoline formula I according to any one of claims 1 to 3, characterized in that it includes the use of arylidene derived thiohydantoin corresponding forms of the Les 3

in which R1, Ar1defined above,
and the fact that to obtain the derivative imidazolone formula I in which R represents R2-S, this method involves the reaction of a derivative of thiohydantoin 3 halogen derivatives of 3' formula

where X represents Cl, Br or I,
under conditions that allow to obtain the derived imidazolone 4 formulas

in which R1, R2, Ar1defined above,
and the fact that to obtain the derivative imidazolone formula (I)in which R is Ar2-S-, where R2is an aryl group, this method involves the reaction of a derivative of thiohydantoin 3 with arylboronic acid 7' formula

in the conditions, you can proceed to the derivative of formula 8

and the fact that to obtain the derivative imidazolone, in which R represents R3-NH-specified method includes
the reaction is derived as 3 with amine 4'

under conditions that allow to obtain the derived imidazolone 5 formulas

in which R1, R3, Ar1defined above,
and the fact that to obtain the derivative imidazolone, in which R is Ar2-specified method includes the reaction of the derived thiohydantoin formula 3 with arylboronic acid 7'

in terms of receiving to get derived imidazolone 1

in which R1, Ar1and Ar2defined above,

10. The method of obtaining derivatives of imidazoline formula (I)in which to obtain the derivative imidazolone, in which R represents R3NH-specified method includes
the reaction of the derived imidazolone formula 4

with amine 4' formulas

under conditions that allow to obtain the derived imidazolone 5 formulas

in which R1, R3, Ar1defined above.

11. The method of obtaining derivatives of imidazoline formula (I)in which R represents R4CONH-, this method involves the reaction of a derivative of imidazoline 5 formulas

with the acid chloride of the acid 5' formula

under conditions that allow to obtain the derived imidazolone 6 formulas

in which R1, R4, Ar1defined above.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 2H-chromen compound or a derivative thereof having action of a S1P1 agonist. The above may be used for preventing and/or treating a disease caused by undesired lymphocyte filtration, or a disease caused by abnormal cell proliferation or accumulation.

EFFECT: preparing the compounds for preventing and/or treating the disease caused by undesired lymphocyte filtration, or the disease caused by abnormal cell proliferation or accumulation.

8 cl, 131 tbl, 156 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of aminopyrazol with the formula of , where A, E, R1 and R2 have values specified in the invention claims, and to their pharmaceutically acceptable salts. Compounds of the formula (I) are agonists of the ALX receptor. Besides, the invention relates to a pharmaceutical composition on the basis of the compound of the formula (I) or its pharmaceutically acceptable salt and to application of these compounds for production of a medicinal agent for prevention or treatment of a disease selected from inflammatory diseases, wheezing diseases, allergic states, HIV-mediated retrovirus infections, cardiovascular diseases, neuroinflammations, neurological disorders, pain, prion-mediated diseases and amiloid-mediated diseases; and for modulation of immune responses.

EFFECT: higher efficiency of compound application.

23 cl, 1 tbl, 466 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: chemistry.

SUBSTANCE: described are novel chiral cis-imidazolines selected from a group which includes 2-{4-[(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-acetamide, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(1,1-dioxohexahydrothiopyran-4-yl)-piperazin-1-yl]-methanone, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(3-methanesulphonylpropyl)-piperazin-1-yl]-methanone, 2-{4-[(4S,5R)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxyethyl)-acetamide. 2-{1-[(48;5K)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidin-4-yl}-acetamide and others described by the general structural formula (I), and pharmaceutical composition containing said compounds.

EFFECT: compounds can be used as anti-cancer agents, particularly as agents for treating solid tumours.

8 cl, 217 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (I) in free form or in form of a pharmaceutically acceptable salt or solvate, which are useful in treating inflammatory or obstructive airways, pulmonary hypertension, pulmonary fibrosis, liver fibrosis, muscle diseases and systemic skeletal disorders and other diseases which are mediated by activity of the ALK-5 receptor or ALK-4 receptor. The invention also relates to a method of producing compounds of formula (I) and pharmaceutical compositions. In formula , T is a pyridin-2-yl which is optionally substituted in one position with R1; T1 is a pyridinyl which is optionally substituted in one or two positions with R1, R2, R5, C1-C4-alkoxy group, C1-C4-alkoxycarbonyl or cyano group; and Ra and Rb are independently hydrogen; C1-C8-alkyl, optionally substituted in one, two or three positions with R4; C3-C10-cycloalkyl, which is optionally substituted in one or two positions with a hydroxy group, amino group, C1-C8-alkyl, C1-C8-alkoxy group, halogen, cyano group, oxo group, carboxy group or nitro group; or C6-C15-aryl, optionally substituted in one, two or three positions with a halogen, hydroxy group, amino group, cyano group, oxo group, carboxy group, nitro group or R5; R1 is C1-C8-alkyl; R2 is C6-C15-aryl, optionally substituted in one, two or three positions with a halogen, hydroxy group, R1, R5, C1-C8-alkylthio group, amino group, C1-C8-alkylamino group, etc. The rest of the values of the radicals are given in the claim.

EFFECT: high efficiency of using said compounds.

20 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula III which possess the properties of JAK pathway inhibitors and JAK-kinase inhibitors. In formula III: X is specified in a group consisting of C1-C10alkyl, amino, halogen, carboxyl, carboxylic acid ester, C2alkynyl, substituted tri-C1-C6alkylsilyl; R represents hydrogen; the cycle A is specified in a group consisting of C6aryl, bicycloheptene, five-and sis-member mono- or 10-member bicyclic heteroaryl including 1 to 3 heteroatoms specified in a group of heteroatoms, including N, O or S, and five- or six-member mono- or 10-member bicyclic heterocycle, including 1 to 2 heteroatoms specified in a group of heteroatoms, including N or O; p means 0, 1, 2 or 3; each of R2 is independently specified in a group consisting of C1-C6alkyl, C1-C4alkyl substituted by 1 to 3 substitutes. The other substitute and radical values are specified in the patent claim.

EFFECT: compounds may be used in preparing a therapeutic agent for T-cell mediated autoimmune disease, for treating or preventing allograft rejection in a recipient, for treating or preventing a type IV hypersensitivity reactions, which includes administering the above agent containing the compound according to cl 1-11, in an amount effective to treat the autoimmune disease or the allograft rejection or the type IV hypersensitivity.

23 cl, 7 dwg, 12 tbl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds for treating cell-proliferative disorders having formula (II): wherein the values R1,R2, X, A, B, R6, R7, R9 are specified in cl. 1 of the patent claim with the exception of the compound of formula: .

EFFECT: there are presented compounds possessing anticancer activity.

95 cl, 27 dwg, 11 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I , as well as to enantiomers and salts thereof, wherein R1 and R1a are independently specified in H, Me, Et, CH=CH2, CH2OH, CF3, CHF2 or CH2F; R2 and R2a are independently specified in H or F; R5 represents H, Me, Et or CF3; A is presented by formula: ; wherein G, R6, R7, Ra, Rb ,Rc, Rd, R8, m, n and p are presented in cl. 1 of the patent claim.

EFFECT: compounds according to the invention may be used as the protein kinase Akt inhibitors and for treating hyperproliferative diseases, such as cancer.

15 cl, 1 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of 2-[3-(2,2-difluorobenzo[1,3]dioxol-5-ylamino)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazol4-yl]-N-ethylacetamide and/or pharmaceutically acceptable salts, or hydrate, or solvates, as well as to a method for preparing it; a pharmaceutical composition based on this compound and using its in therapy for prevention and treatment of mental disorders, intellectual disorders or diseases, inflammatory diseases or conditions wherein α7 nicotinic receptor modulation is considered to be favourable. The invention also refers to a product containing such compound and α7-nicotinic receptor agonist.

EFFECT: preparing the compounds applicable in therapy for prevention or treatment of mental disorders, intellectual disorders or diseases, inflammatory diseases or conditions wherein α7 nicotinic receptor modulation is considered to be favourable.

6 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 2H-chromen compound or a derivative thereof having action of a S1P1 agonist. The above may be used for preventing and/or treating a disease caused by undesired lymphocyte filtration, or a disease caused by abnormal cell proliferation or accumulation.

EFFECT: preparing the compounds for preventing and/or treating the disease caused by undesired lymphocyte filtration, or the disease caused by abnormal cell proliferation or accumulation.

8 cl, 131 tbl, 156 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of aminopyrazol with the formula of , where A, E, R1 and R2 have values specified in the invention claims, and to their pharmaceutically acceptable salts. Compounds of the formula (I) are agonists of the ALX receptor. Besides, the invention relates to a pharmaceutical composition on the basis of the compound of the formula (I) or its pharmaceutically acceptable salt and to application of these compounds for production of a medicinal agent for prevention or treatment of a disease selected from inflammatory diseases, wheezing diseases, allergic states, HIV-mediated retrovirus infections, cardiovascular diseases, neuroinflammations, neurological disorders, pain, prion-mediated diseases and amiloid-mediated diseases; and for modulation of immune responses.

EFFECT: higher efficiency of compound application.

23 cl, 1 tbl, 466 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts wherein r represents 1; Ar is specified in and , R1 is specified in -COOR1a, -NHSO2R1b, -SO2NHR1d, -SO2OH, -O-CH(R1e)-COOH and tetrazol-5-yl, R1a represents H, -C1-6alkyl, -C1-3alkylenaryl, -C1-3alkyleneheteroaryl, - C3-7cycloalkyl, -CH(C1-4alkyl)OC(O)R1aa, or R1aa represents -O-C1-6alkyl or -O-C3-7cycloalkyl; R1b represents R1c; R1d represents -C1-6alkyl or -C0-4alkylenaryl; R1d represents -C(O)R1c or -C(O)NHR1c; R1e represents -C1-4alkyl; Y represents -C(R3)-, Z represents -N-, Q represents -C(R2)-, and W represents a bond; Y represents -N-, Z represents -C(R3)-, Q represents -C(R2)-, and W represents a bond; Y represents -C(R3)-, Z represents -N-, Q represents -N-, and W represents a bond; or Y represents -C(R3)-, Z represents -CH-, Q represents -C(R2)-, and W represents -C(O)-; R2 is specified in H, halogen, -C1-6alkyl, -C3-6dicloalkyl, and -C0-5alkylene-OR2b; wherein R2b is specified in H and -C1-6alkyl; R3 is specified in -C1-10alkyl and -C0-5alkylene-O-C0-5alkylene-R3b; and R3b represents -C1-6alkyl; X represents -C1-12alkylene-, where at least one group -CH2- in alkylene is substituted by the group -NR4a-C(O)- or -C(O)-NR4a-, wherein R4a is specified in H, -OH, and -C1-4aalkyl; R5 is specified in -C0-3 alkylene-SR5a, -C0-3alkylene-C(O)NR5bR5c, -C0-3alkylene-NR5b-C(O)R5d, -NH-C0-1alkylene-P(O)(OR5e)2, -C0-2alkylene-CHR5g-COOH and -C0-3alkylene-C(O)NR5h-CHR5i-COOH; R5a represents H or -C(O)-R5aa; R5aa represents -C1-6alkyl, -C0-6alkylene-C3-7cycoalkyl, -C0-6alkylenaryl, or -C0-6alkylenemorpholine; R5b represents -OH, -OC(O)R5ba, -CH2COOH or -OC(S)NR5bbR5bc; R5ba represents -C1-6alkyl, -OCH2-aryl or -CH2O-aryl; R5bb and R5bc independently represents -C1-4alkyl; R5c represents H; R5d represents H; R5e represents H; R5g represents H or -CH2-O-(CH2)2-O-CH3; R5h represents H; R5i represents -C0-3alkylenaryl; R6 is specified in -C1-6alkyl, -C0-3alkylenaryl, -C0-3alkyleneheteroaryl and -C0-3alkylene-C3-7cycloalkyl; and R7 represents H or together with R6 to form -C3-7cycloalkyl; where each ring in Ar and each aryl and heteroaryl in R1-3 and R5-6 are optionally substituted by 1-3 substitutes optionally specified in -C1-6alkyl, -CN, halogen, -O-C1-6alkyl, -phenyl, -NO2, wherein each alkyl is optionally substituted by 1-5 fluorine atoms; each carbon atom in X is optionally substituted by one or more groups R4b, and one group -CH2- in X may be substituted by -C4-8cycloalkylene- and -CH=CR4d-; where R4b is specified in -C0-5alkylene-COOR4c and benzene, where R4c represents H; and R4d represents -CH2-thiophen; each alkyl and each aryl in R1-3, R4a-4d and R5-6 are optionally substituted by 1-7 fluorine atoms; where aryl represents monovalent aromatic hydrocarbon having one ring or condensed rings, and contains 6-10 carbon atoms in the ring; and heteroaryl represents a monovalent aromatic group having one ring or two condensed rings, and having 5-10 atoms in large in the ring with one atom of the ring represents a heteroatom specified in nitrogen, oxygen and sulphur. Besides, the invention refers to a pharmaceutical composition based on the compound of formula

,

to a method for preparing the compound of formula (I), to intermediate compounds used in synthesis of the compound of formula (I), to the use of the compounds of formula (I).

EFFECT: there are prepared new compounds possessing activity of a type 1 angiotensin II (AT1) receptor antagonist and activity of neprilysin inhibition.

38 cl, 36 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of dihydroquinone and dihydronaphthyridinone of formula (I) or to its pharmaceutically acceptable salts, in which X represents group CR11 or N; Y represents group -C(O)R3, oxazolyl or isoxazolyl; Z represents phenyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, pyridinyl, pyrimidinyl or pyrazolyl, and is substituted with groups R1 and R2; R1 and R2 each independently represents H, halogen, CN group, C1-6alkyl or group -Y1-Y2-Y3-R8, or R1 and R2 together form group -O(CH2)nO-, where n represents 1 or 2; Y1 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O), -S-, -SO2- or bond; Y2 represents heterocycloalkylene, C1-6alkylene or bond, where heterocycloalkylene stands for cycloalkylene group, in which one, two carbon atoms are substituted with heteroatoms O or N, where heterocycloalkylene group also contains, at least, two carbon atoms and cycloalkylene represents ; Y3 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O)-, -SO2- or bond; R8 represents H, C1-6alkyl, C1-6alkoxy, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, or group -NR9R10, where R8, different from H, is optionally substituted with C1-6alkyl, halogen, group -CF3 or group -OH; R9 and R10 each independently represents H or C1-6alkyl; R3 represents OH, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)-C1-6alkoxy; R4 represents C1-6alkyl, phenyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclohexyl, tetrahydropyranyl or tetrahydrothiophene 1,1 -dioxide, and is optionally substituted with C1-6alkyl, hydroxyl group, C1-6alkoxy, halogen, nitro group, amino group, cyano group or halo-lower alkyl; R5 and R6 each independently represents H, halogen, C1-6alkyl, group -CF3, C1-6alkoxy; R7 represents H; R11 represents H. Invention also re4lates to pharmaceutical composition based on formula (I) compound.

EFFECT: obtained are novel dihydroquinone and dihydronaphthyridinone derivatives, useful for treatment of disease mediated by JNK kinase.

9 cl, 4 tbl, 38 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a benzylpiperidine derivative of formula

, or a pharmaceutically acceptable salt thereof, which can be used as a medicinal agent such as an antidepressant. In formula (1), R1 is a hydrogen atom or a methyl group; R2 is a group bonded in the para- or meta-position relative a methylene group, and is a chlorine atom bonded in the para-position, a bromine atom bonded in the para-position, a methyl group bonded in the para-position, a chlorine atom bonded in the meta-position, or a bromine atom bonded n the meta-position; X is a methylene group or an oxygen atom; and n is an integer from 1 to 3.

EFFECT: obtaining a benzylpiperidine derivative.

11 cl, 34 ex, 14 tbl, 7 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a co-crystal of propiconazole with 4,4'-dihydroxybiphenyl, where co-crystal gives an X-ray diffraction pattern with peaks at diffraction angle 2θ 7.689, 11.513, 16.964, 18.618, 19.178, 21.008, 21.357, 21.923, 22.415, 23.566, 26.254 and 26.958, having fungicidal activity, a method of producing said co-crystal, a fungicidal composition and a fungicidal agrochemical compound based thereon, as well as a method of preventing/controlling fungal infection on plants.

EFFECT: high activity.

6 cl, 12 ex, 13 tbl, 19 dwg

New compounds // 2458920

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or to its pharmaceutically acceptable salts wherein -A-(R1)a means a group; -B-(R2)b means a group specified in the patent claim 1, R3 means hydrogen; X means CH2 or O; and Y means CH2. Also, the invention refers to a pharmaceutical composition exhibiting FGFR inhibitor activity on the basis of the declared compound.

EFFECT: there are produced new compounds and based pharmaceutical composition which can find application in medicine for preparing a cancer drug.

8 cl, 1 tbl, 180 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I) presented below wherein the radicals and symbols have the values presented in the patent claim, and/or to its racemate, enantiomer, diastereomers or its pharmaceutically acceptable salts and/or esters. The invention also refers to a method for preparing it, using it in preparing a drug preparation and to drug preparations containing the compound of formula (I).

EFFECT: compound of formula has analgesic action and may be used as an active compound for pain management.

20 cl, 3 tbl, 33 ex

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