2-thio substituted derivatives of imidazole and their use in pharmaceuticals

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to 2-thio substituted derivatives of imidazole with formula I , where R1 represents aryl, which can be substituted by a halogen atom or halogen-C1-C6-alkyl; R2 is chosen from a group, containing a) aryl-C1-C4-alkyl, and b) C1-C6-alkyl; R3 is chosen from a group, containing (a) NR4R10, (b) NR7COR10, (c) OR10, (d) NH2; R4 represents H; R3 and R6, which can be the same or different, represent H, halogen, OH, C1-C6-alkoxy, C1-C6-alkyl or halogen-C1-C6-alkyl; R7 represents R4; R10 has one of the following values: (a) A-B, (b)-(e), (f) C1-C6-alkyl, which is substituted with 2 phenyl groups; A represents linear or branched C1-C6-alkylene; B is chosen from a group, containing (a) H, (b)-(e), (f) OC1-C6-alkyl, (g) OH; Hy represents 3-10-member non-aromatic, mono-, bi- or tricyclic carbocycle, which can be or not be condensed with a benzene ring; Ar represents 5- or 6- member aromatic heterocycle, which has 1 heteroatom, chosen from a group, consisting of O, S, and N, and which may not be condensed with a benzene ring, Het represents 5- or 6-member non-aromatic heterocycle, which has 1 heteroatom, which represents O, which may not be condensed with a benzene ring; m is 0,1 or 2; or its optical isomers or physiologically used salts. Compounds with formula I are used when making pharmaceutical compositions with inhibiting effect on release of cytokines.

EFFECT: obtaining of derivatives, which have inhibiting action to release of cytokine action.

13 cl, 4 tbl, 148 ex

 

The present invention relates to 2-tizanidine derivative of imidazole, which has an immunomodulatory and inhibiting cytokine activity, to pharmaceutical compositions comprising these compounds and their use as pharmaceuticals.

The pharmacologically active compounds of imidazole with anti-inflammatory activity are already known. Thus, among others, compounds having 4,5-di(hetero)arylamidine fragments were investigated in more detail and described their various pharmaceutical action. Also known compounds which are substituted in the 2-position. In U.S. patent 4585771 described derivatives of 4,5-diphenylimidazole, which are substituted in the 2-position pyrrolidinyl, indolinyl, imidazolinium or diazolidinyl radical and which have anti-inflammatory and antiallergic activity. In U.S. patent 4461770, 4528298 and 4584310 (EP A) describes derivatives of 4-(5-aryl)-5-(4-heteroaryl)imidazole, which are substituted in the 2-position by thio-, sulfanilic or sulfonyloxy group, a substituted or unsubstituted aliphatic hydrocarbon and which, among other things, anti-inflammatory action. The imidazole compounds having immunomodulatory and inhibiting cytokine action described in WO 02/066458, WO 02/076951 and DE 10222103. In addition, in WO 96/03387, EP 005545 (US 4440776, 355039, 4269847), EP 236628 (U.S. patent 4686231), the German patent 3504678, U.S. patent 4190666, U.S. patent 4402960 and U.S. patent 4585771 described imidazole derivatives having anti-inflammatory action. In patents EP 372445 (U.S. patent 5318984; U.S. patent 5166214) and U.S. patent 5364875 described compounds of imidazole with antihypercholesterolemic activity.

Patent WO 00/17192 (German patent 19842833) refers to a derivative of 4-heteroaryl-5-phenylimidazole, which are substituted in the 2-position of phenylalkyl group. These compounds act as anti-inflammatory compounds and inhibitors of cytokine release. In WO 99/03837 and WO 93/14081 described 2-substituted imidazoles that inhibit the synthesis of a number of inflammatory cytokines. Compounds described in WO 93/14081 are in the 2-position is attached through the sulfur atom of phosphorus Deputy or aryl, or heteroaryl Deputy. In WO 91/10662 and WO 91/13876 described imidazole derivatives, which inhibit the transferase acyl-coenzyme a:cholesterol O-acyl and binding of thromboxane TxA2. In WO 95/00501 described imidazole derivatives, which can be used as inhibitors of cyclooxygenase.

In J.Med.Chem., 1996, 39, 3927-37 described compounds having 5-lipoxygenase - and cyclooxygenase-inhibiting action, 2-(4-methylsulfinylphenyl)-4-(4-forfinal-5-(pyrid-4-yl)imidazole, with titoki the inhibitory action.

In addition, 2-tizanidine imidazole derivatives described in Japan patent 01-040467, patent of Russia 1415725, Acta Chim., 1969, 61-77, J.Pract. Chem., 1972, 314, 785-792 and German patent 10114775, Indian J.Chem., Sect.B, 1983, 22B(3), 268-269, Bioorganic & Medical Chem. Lett., Vol.5, No.2, 177-180, 1995, Phosphorus Sulfur 1988, 35(1-2), 83-88, Arch.Biochem.Biophys., Vol. 297, 258-164, 1992, J.Med.Chem. 1995, 38, 1067-1083, Helv.Chim.Acta 82, 1999, 290-296, Helv.Chim.Acta 81, 1998, 1585-1595.

Although known for many compounds, there remains a need for compounds with anti-inflammatory action, which inhibit cytokine.

The present invention is the development of such compounds.

It has been unexpectedly found that certain 2-substituted imidazole derivatives have high immuno-modulating and/or inhibiting cytokine activity.

Accordingly, the present invention relates to 2-tizanidine imidazole derivative of the formula I

where

R1represents a C1-C6-alkyl, C3-C7-cycloalkyl or aryl, which is unsubstituted or substituted by a halogen atom, a C1-C6-alkyl or halogen-C1-C6-alkyl;

R2selected from the group including

a) aryl-C1-C4-alkyl, where the aryl radical may have one, two or three substituent independently al the g from each other selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen, C1-C6alkylsulfanyl,1-C6-alkylsulfonyl,1-C6-alkylsulfonyl and hydroxyl, and

(b) (C1-C6-alkyl, which is unsubstituted or substituted by CN or halogen;

C)

d)

R3selected from the group including

a) NR4R10;

b) NR7COR10;

c) NR7COOR10;

d) NR7CONR7R10;

e) NR7CONR7COR10;

f) OR10;

g) S(O)mR10;

h) halogen;

i) OH;

j) N3;

k) NH2;

l) SH;

where R3is not HE, halogen, C1-C6-alkylthio or1-C6-alkoxy, if R2represents phenyl-C1-C4-alkyl, and the phenyl radical has From1-C6-alkylsulfanyl,1-C6-alkylsulfonyl or1-C6-alkylsulfonyl Deputy;

R4represents H or a physiologically tsepliaeva group,

R5and R6that may be the same or different, represent H, halogen, HE1-C6-alkoxy, C1-C6-alkyl, halogen-C1-C6-alkyl, C1-C6-alkylsulfanyl, NH2With1-C6/sub> -alkylamino or di-C1-C6-alkylamino;

R7is an R4With1-C6-alkyl or benzyl;

R10has one of the following values:

a)A-B
b)
c)
d)
e)

f)1-C6-alkyl, which is substituted by 2 or 3 phenyl groups;

g) trifluoromethyl (in particular, if R3represents one of the radicals b)-(f)).

But it represents a linear or branched C1-C6-alkylen,2-C6-albaniles or3-akinyan;

In selected from the group including

a)N
b)
c)
d)
e)

f) OC1-C6-alkyl;

g) NR11R12;

h) OH;

i) halogen;

j)1-C -alkylsulfanyl;

R11and R12that may be the same or different, represent H, C1-C6-alkyl or phenyl;

Hy is a 3-10-membered nonaromatic, mono-, bi - or tricyclic carbocycle, which may or may not be condensed with a benzene ring;

Ar represents a 5 - or 6-membered aromatic heterocycle which has 1, 2 or 3 heteroatoms, independently from each other selected from the group consisting of O, S and N, and which may or may not be condensed with a benzene ring;

Het represents a 5 - or 6-membered nonaromatic a heterocycle which has 1, 2 or 3 heteroatoms, independently from each other selected from the group consisting of O, S and N, which may or may not be condensed with a benzene ring, and which may or may not be bridged bicyclic or tricyclic;

m is 0,1 or 2;

n is 1, 2, 3, 4 or 5

and their tautomers, optical isomers and physiologically acceptable salts.

If the compounds according to the invention have centers of asymmetry, in the scope of the invention includes both the racemates and optical isomers (enantiomers, diastereomers). For compounds according to the invention may exist following tautomeric equilibrium:

Yes what a great invention covers both tautomeric forms.

The invention also covers the physiologically acceptable salts of the compounds of formula I. In this case, they in particular are acid additive salt. To obtain the acid additive salts using inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids such as tartaric acid, citric acid, maleic acid, fumaric acid, malic acid, mandelic acid, ascorbic acid, gluconic acid, and the like.

The term "alkyl" (also in combination with other groups, such as phenylalkyl, alkylsulfonyl, alkoxy, etc.) covers linear and branched alkyl groups having from 1 to 6 or 1 to 4 carbon atoms, such as methyl, ethyl, n - and isopropyl, n-, ISO - and tert-butyl, sec-butyl, n-pentyl, isoamyl, neopentyl and n-hexyl. Accordingly, this applies to the term "C1-C6-alkylen".

The term "carbocycle" includes saturated or unsaturated non-aromatic monocyclic, bicyclic and tricyclic hydrocarbons. The hydrocarbons may be condensed with one or two benzene rings. Monocyclic hydrocarbons are3-C6-cycloalkyl, such as cyclopropyl, cyclopentyl, cyclohexyl. Examples of bi - and tricyclic hydrocarbon is in and benzododecinium of carbocycles are indanyl, declines, tetralinyl, fluorenyl, dihydroanthracene, dibenzosuberyl, norbornyl or substituted. Examples of the substituted carbocycles are methylcyclopropyl or methylcyclohexyl. Preference is given to unsubstituted radicals.

The term "aryl" embraces aromatic ring system such as phenyl or naphthyl. The term "halogen" means fluorine atom, chlorine, bromine or iodine, in particular fluorine atom or a chlorine atom.

The term "halogen-C1-C6-alkyl" includes mono - and polygalacturonase linear and branched alkyl groups having from 1 to 6 and in particular from 1 to 4 carbon atoms. Preferably there are 1, 2, 3, 4 or 5 halogen atoms. Preferred halogen atoms are F and Cl. Examples of the halogen-C1-C6-are alkyl-CH2Cl, -CH2CH2Cl, -CH2CCl3, -CF3, -CHF2, -CH2F, -CH2CF3and CF2CF3. It is preferable CF3.

Physiologically tsepliaeva group is a group that can be chipped off from the remainder of the molecule under physiological conditions, enzymatic or chemically. Examples are-COR14, -CO2R14, -CONH2, -CONHR14, -CHR16-OR14, -CHR16-O-COR14, -COC(R16)2-OH, -COR15, SO2R15and-SO2R14where R14depict is to place a 1-C6-alkyl or CF3, R15represents phenyl or tolyl (in particular p-tolyl), and R16represents N or C1-C6-alkyl.

Aromatic 5 - or 6-membered heterocycle, in particular, represents unsubstituted (R5, R6=H) or substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, thiazolyl, imidazolyl, oxazolyl, isothiazolin, triazolyl or pyrimidyl. Preferred substituents are one or two groups independently from each other selected from the group comprising halogen, in particular Cl, and C1-C6-alkyl. Deputy(s) attached to the carbon atom or the nitrogen atom of the aromatic radical. Preferred are unsubstituted radicals. Examples of substituted radicals are chloranil, in particular 5-harpur-2-yl, examples of the condensed radicals are benzofuranyl, benzothiazolyl and benzothiophen.

Non-aromatic 5 - or 6-membered heterocycle may be saturated or unsaturated. Preferably it is unsubstituted or substituted tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, N-methylpyrrolidine, N-ethylpyrrolidin, piperazinil or morpholinyl, where the heterocycle may be attached through a heteroatom nitrogen or ring carbon atom or may be substituted. Preferred substituents is the fast one or two radicals, independently or one another selected from the group comprising halogen, in particular Cl, and C1-C6-alkyl. Preference is given to unsubstituted radicals.

represents a substituted or unsubstituted cyclopropyl, cyclobutyl, cycloheptyl and, in particular, cyclopentyl and cyclohexyl. R5and R6preferably, independently of one another, represent H, halogen or1-C6-alkyl. Examples of substituted cycloalkyl groups are methylcyclopropyl or methylcyclohexyl. Preference is given to unsubstituted radicals.

Phenyl-C1-C4-represents an alkyl, in particular benzyl, 1-phenylethyl or 2-phenylethyl.

R1preferably represents a phenyl radical and, in particular, halogen, CF3- or1-C6-alkyl-substituted phenyl radical, with particularly preferred is fluoro-substituted phenyl radical. Deputy preferably is 3 and, in particular, in the 4-position. Examples of substituted phenyl radicals are 4-forfinal, 2,4-differenl, 3-trifluoromethyl, 3-tolyl, or 3-chlorophenyl.

R2preferably represents benzyl,3-C6-cycloalkenyl,4-C7-methylcyclohexyl or1-C6-alkyl radical, where vanillaroma in the benzyl radical may be substituted, as specified above. Preferred substituents of the phenyl group in the benzyl radical are1-C6-alkylsulfanyl,1-C6-alkylsulfonyl and C1-C6-alkylsulfonyl. Examples R2are CH3CH3CH2, (CH3)2CH, CH2CN, CH2CF3, CF3and cyclopropyl.

R3preferably represents a radical of the formula

where R4, R5and R6and a are as defined above. R5and R6preferably represent H, methyl, methoxy or chlorine. If the phenyl ring in the group is substituted, the radicals R5and R6preferably located in the 3 - and/or 4-position.

In addition, R3preferably represents

a) NR4R10where R10is cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl or cycloheptyl;

b) NR4R10where R10represents a C1-C6-alkyl, in particular methyl, ethyl or isopropyl, or a 3,3-diphenylpropyl or 1,3-diphenylprop-2-yl;

C) NR4R10where R10represents a-C, and represents IT WITH1-C6-alkoxy, NR11R12or phenyl;

d) NR7COR10where R10made the focus of an a-b, and represents phenyl;

e) NR7COR10where R10represents a C1-C6-alkyl.

And preferably represents a C1-C6-alkylen and, in particular, ethylidene.

Especially preferred embodiment are the compounds of formula I in which R1is a 4-forfinal, R2represents a C1-C6-alkyl or benzyl, where the phenyl group in the benzyl radical may be substituted as indicated above; R3represents a radical of the formula

where R4, R5and R6and a are as defined above, and m is 0.

The following preferred embodiment are the compounds of formula I in which R2represents a C1-C6-alkyl, in particular methyl, and R1is halogenfree or halogen-C1-C6-alkylphenyl, in particular, 4-forfinal, 2,4-differenl, 4-triptoreline or 3-triptoreline. Then R3preferably represents the groups defined below:

a) halogen, in particular F or Cl;

b) OH or OC1-C6-alkyl, in particular methoxy, isopropoxy,

(C) phenylamino;

d) phenyl - or naphthyl-C1-C6-amino, where the phenyl group may be substituted by 1 or 2 Gal the genes, in particular F or Cl, With1-C6-alkoxy or C1-C6-alkyl. The amino group may optionally be substituted With1-C6-alkyl. Examples of such radicals are benzylamino, 4-methoxybenzylamine, 4-methylbenzylamino, 4-chlorobenzylamino, 3,4-dichloroaniline, 2-phenylethylamine, 1 phenylethylamine, 1-naphthas-1-yl-amino, 1-naphthas-2-ylamine; 1-phenylprop-3-ylamino, 3 phenylpropylamine-4-isobutylphenyl)ethylamino;

e)

,

where a represents a C1-C2-alkylen, R5and R6represent H, and

is thienyl, furyl, 2-, 3 - or 4-pyridyl, thiazolyl, oxazolyl, benzothiophene or benzofuran, where the heterocyclic radicals may be substituted by halogen, in particular F or Cl, or C1-C6-alkyl.

f)

,

where A, R5,R6and

are as defined in paragraph (e).

g) NH-C1-C6-alkyl, which is substituted by 2 or 3 phenyl groups, for example, 3,3-diphenylpropylamine, 1,3-diphenylprop-2-ylamino;

h)

,

where a represents a C1-C2-alkylen, R5and R6represent H, and

represents tetr hydrofuran, tetrahydropyranyl, pyrrolidine, N-methyl or N-ethylpyrrolidin;

i)

,

where R5,R6and

are as defined in paragraph (h);

j) -NHCOOR10where R10represents a C3-C6-cycloalkyl;

k) -NH-CO-other10where R10represents a C3-C6-cycloalkyl;

l) NH-COR10, where R10represents a C3-C6-cycloalkyl-C1-C4-alkyl, for example, cyclopentylmethyl, cyclohexylmethyl;

m) NHCONHCO;

n) -A-C3-C6-cycloalkyl, where a is a C1-C2-alkylen, for example, cyclopentylmethyl, cyclohexylethylamine.

Compounds according to the invention can be obtained accordingly in accordance with the methods described in this area and are listed in the beginning of this description, in particular, in WO 00/17192. Found that particularly suitable is a method of obtaining, in accordance with the following two-stage method. In the first stage, first get substituted imidazole-2-tion of formula II. In the second stage it is subjected to interaction so that they get 2-tizanidine imidazole derivatives of the formula I with the introduction of the desired substituent R2.

1) Obtaining imidazo the-2-thione

The imidazole-2-thiones, where R3=H, halogen (Br, Cl, F), O-alkyl or S-alkyl, receive according to methods a or B. as an example, the method As illustrated for compounds in which R1is a 4-forfinal, and R3is N; the method is illustrated for compounds in which R1is a 4-forfinal, and R3represents Cl, (25A), F (25b) or O-alkyl (25C, 25d). Numbers in parentheses refer to the numbers of the examples. 2-Tizanidine imidazole derivatives, where R3=NR4R10get not of the appropriate imidazole-2-thiones, where R3=NR4R10and otherwise in accordance with method C. 2-Tizanidine imidazole derivatives, where R3=O-alkyl or S-alkyl, can be obtained in accordance with the method, and in accordance with method C.

Method And

Synthesis of substituted imidazole-2-thiones, where R3represents H, is carried out in accordance with the reaction by scheme 1 using isonicotinate and 4-pertanyaannya as the original substances.

Educt transform during the condensation reaction with metallic sodium in alcohol, for example ethanol, 2-cyano-2-(4-forfinal)-1-(4-pyridyl)alanon (IIIa). The cyano is then removed by hydrolysis, for example, Hydrobromic acid, and decarbon what Yerevanian, getting 2-(4-forfinal)-1-(4-pyridyl)alanon (IVa). At the next stage IVa transform processing with a mixture of ammonium chloride/sodium acetate in an alcohol solvent such as methanol, in the oxime (Va). Interaction with p-toluensulfonate in pyridine latter is converted into toilet (VIa). From tosilata get tinove compound (IIa) treatment ethoxide sodium and interaction of the formed intermediate azirine with potassium thiocyanate.

Scheme 1.

Synthesis thiones according to the invention in accordance with the method And

Method In

Obtaining the compounds according to the invention, in which the pyridine radical is halogen, O-alkyl or S-alkyl substituent, carried out in accordance with scheme 2 through the corresponding 2-halogenopyrimidines imidazoline (the way In). Receiving data imidazolines illustrated using the example of 2-fluoro-substituted pyridine compounds (R3=2-F), where R1=p-forfinal. Imidazoline containing in position 4 alkyl and cycloalkyl radicals (R1= C1-C4-alkyl, C3-C7-cycloalkyl), get similarly, on the basis of appropriately substituted 2-fluoro-γ-picoline ketones.

Scheme 2.

γ-Picoline (R3=H) and halogen (R 3=F, Cl, Br, I), methoxy- (R3=Co3and methylthio- (24, R3=SCH3) substituted γ-pikolines subjected to introduction of lithium γ-methyl group in the absence of moisture in the solvents suitable for this purpose, such as hydrocarbons, ethers, and mixtures thereof (for example, hexane, tetrahydrofuran, glycol dimethyl ether) using diisopropylamide lithium (LDA), and then condense with suitable derivatives of carboxylic acids (R1-COOR, R1-CONR2, R1-CN). It is established that in this case particularly suitable are the amides of N,O-dimethylhydroxylamine (R1-CONCH3(OCH3), 20). With the use of nitrites and bases, for example a mixture of amyl nitrate/sodium methoxide, or using a nitrite of an alkali metal and acid generated γ-picolylamine (IVb) nitrosonium in γ-picoline position. Installed, which is especially convenient is the interaction γ-picolylamine dissolved in glacial acetic acid, with an aqueous solution of sodium nitrite. During the reaction nitrosomethane fully converted in tautomeric oximes of ketones (VIIb).

Oximes of ketones restore in ethanol solution in the presence of hydrogen and mineral acids such as HCl, using palladium-on-charcoal, receiving ammonium salt of aminoketones (VIIIb) (23 b).

Alternatively, the other oximes of ketones can be restored in an alcohol solution in the presence of mineral acids, for example, H2SO4using zinc dust, to obtain the corresponding ammonium ketones (23f).

Data ammonium ketones give, after the action of the thiocyanates of alkali metals, such as potassium thiocyanate, in dry dimethylformamide (DMF) at boiling under reflux, imidazoline formula IIb, where R3=F, Cl, Br, O-alkyl or S-alkyl, in the form of a yellow solid substance (24 b).

Obtaining the compounds according to the invention, in which the pyridine radical or contains a simple ether (R3=OR10), thioester (R3=SR10), or amino (R3=NR4R10's Deputy, carried out in accordance with scheme 4 or scheme 5 through the corresponding 2-haloperidol-substituted imidazoline (method, see below).

2) Getting 2-diimidazole connections

Connection 2-imidazoline formula II obtained in accordance with method a or b by substitution of the sulfur atom in the 2-position is converted into the compounds of formula I according to the invention. Substitution, as illustratively shown for some of the compounds in scheme 3, is carried out in the usual way using the reaction of nucleophilic substitution. In this case, the compound IIa or IIb is subjected to interaction with R2-X in an inert polar solvent such as alcohol. X represents an easily replaceable group such as Hal, is lastnosti Cl, Br, I, methylsulphonyl, tosyl etc. Suitable methods known to the person skilled in the art and described, for example, in WO 00/17192, EP 0372445 and U.S. patent 4440776. Connection R2-X are known or can be obtained by known methods as described, for example, in WO 00/17192.

Scheme 3

3. Substitution of sulfur by alkylhalogenide and aryl halides or alcohol sulfonates.

3.1.

Way

Compounds according to the invention, in which R3represents an amino substituent (R3=NR4R10), is obtained from 2-diimidazole using 4(5)-(2-halogenfrei-4-yl) substitution. Method (method C) is illustrated in scheme 4, using as example 2 benzylamino (R3=NH-CH2-Ph), where R1=p-forfinal.

The original substance (Ib) can be obtained as described above.

Scheme 4

4.1. 4-(2-Aminopyridin-4-yl)-substituted 2-tinidazole

4.2. 4-(2-Aryloxides-4-yl)-substituted 2-tinidazole

4.3. 4-(2-Aaltopiiri-4-yl)-substituted 2-tinidazole

4.4. 4-(2-Arylsulfonamides-4-yl)-substituted 2-tinidazole

It is advisable to conduct the reaction under consideration Amina, which predpochtitel what about the use in an amount of 5 to 20 molar equivalents, on a molar equivalent of the compound (Ib). The reaction temperature usually ranges from 100 to 200°C. If desired, it is also possible to use inert solvent, such as dioxane, dimethylformamide, diethylacetamide, tetramethylrhodamine, organic, etc. and suitable auxiliary additives, such as carbonates of alkali metals or halides of monovalent copper (to neutralize the released amount of acid or for the catalysis of the elimination of the halogen).

Compounds according to the invention, in which R3is a CNS Deputy or alkylthio Deputy (R3=O-C1-C6-alkyl, S-C1-C6-alkyl), can be obtained not only in the way In (on the basis of appropriately substituted pikolines), but also by the way, on the basis of 4(5)-(2-halogenfrei-4-yl)-substituted 2-diimidazole.

Method D

Compounds according to the invention, in which R3is a CNS Deputy (R3=O-C1-C6-alkyl), can be obtained not only by the way In or With, but also the way D from 4(5)-(2-halogenfrei-4-yl)-substituted 2-diimidazole. The method is illustrated in scheme 5 using the example of 2-isopropoxypyridine compounds (R3=Cos(CH3)2), where R1=p-forfinal.

The original substance (Ib) can be obtained by the above method is m

Scheme 5

4-(2-Alkoxyphenyl-4-yl)-substituted 2-tinidazole

It is advisable to conduct the reaction in alcohol, which is preferably used in an amount of 5 to 20 molar equivalents, on a molar equivalent of the compound (Ib), in the case of lower alcohols also up to one hundred mole equivalents, in the presence of a strong acid such as HCl or triperoxonane acid, methanesulfonate acid and so on, the reaction Temperature is usually in the range of boiling points lower alcohols, higher alcohols in the range from 100 to 200°C. it Was found that best is, for example, mixing alcohol with gaseous HCl or re-saturation in the reaction.

Alternatively, the substitution of fluorine on CNS group in the 2-position peredelnogo Deputy can be carried out at an earlier stage of the synthesis, for example, at the stage Asimov ketones or aminoketones. In such cases, the reactions take place under conditions that are comparable with the conditions just described for intermediate Ib (22c).

Methods E, F and G

Compounds according to the invention, in which R3is an amide substituent (R3=NR7COR10), first, is obtained from 4(5)-(2-halogenfrei-4-yl)-substituted 2-diimidazole. Method (method E) shown in figure 6.1 and the use as example 2 benzolamide (R 3=NHCOPh), R1=p-forfinal. Secondly, after hydrolysis of amides to aminosilane (R3=NR7N, other10) 2-diimidazole and subsequent acylation or conversion to amides, urea and urethane, can be obtained for more amide substituents (method F). This is illustrated in scheme 6.2. Third, 2-aminopyridine compound precursor can be obtained from 4(5)-(2-halogenfrei-4-ilen) compounds 4(5)-(2-azidopyridine-4-ilen) connection (method G). In this embodiment, the halogen nucleophile replace the alkali metal azide, and the azide group is converted into the amino group by methods of recovery, see diagram 6.3.

Way N

This interesting option also provides access to alkilirovanny amines of the aldehyde or ketone compounds predecessors. If the conversion of sidegroup in the amino group carried out under conditions of hydrogenation using a hydrogenation catalyst in the presence of these aldehydes and ketones, get alkylated amines where R3=NH-CH2-B or NHCH(alkyl) (method H, scheme 6.4). The same result is obtained when azide split phosphine with obtaining phosphamide, and these imides obtained by the reaction of Aza-Wittig with aldehyde (or ketone), restore to amines using complex hydrides (method H, scheme 6.5).

Source the e substances (Ib) can be obtained as described above.

Scheme 6

6.1. 4(2-Aminopyridin-4-yl)-substituted 2-tinidazole

It is advisable to conduct the reaction under consideration amide, which is preferably used in an amount of 5 to 20 molar equivalents, on a molar equivalent of the compound (Ib). The reaction temperature usually ranges from 100 to 200°C. If desired, it is also possible to use inert solvent, such as dioxane, dimethylformamide, diethylacetamide, tetramethylrhodamine, organic, etc. and suitable auxiliary additives, such as carbonates of alkali metals or halides of monovalent copper (to neutralize the released amount of acid or for the catalysis of the elimination of the halogen).

2-Aminopyridine compounds can be obtained from 2-aminoacridine by hydrolysis of (6.2) or, alternatively, by the substitution for azide 2-fluoro-substituted compounds and the subsequent recovery of 2-azidopyridine (6.3), for example, by hydrogenation on a palladium-on-coal in alcohol solvents.

Possible further conversion of the received amines (Ik, Id) by obtaining derivatives (method F). Using the reaction of amines Id and Ik as acid anhydrides, and acid chlorides to form the acids with additional amides, and reaction with chloroformate esters with getting urethanes, isocyanates with obtaining urea and arylisocyanate with getting allocation. The formation of these derivatives is illustrated in scheme 7.

Scheme 7

The conversion of amines (Ik, Id) amide, urethane and urea

Compounds according to the invention demonstrate together with immunomodulating and inhibitory cytokine activity in vitro and in vivo. Cytokines are proteins, such as TNF-α and IL-βthat play an important role in numerous inflammatory diseases. In the light of their inhibition of the cytokine activity of a compound according to the invention are suitable for treating disorders that are associated with a disorder of the immune system. They are suitable, for example, for the treatment of autoimmune diseases, cancer, rheumatoid arthritis, gout, septic shock, osteoporosis, neuropathic pain, HIV, dementia, HIV, viral myocarditis, insulin-dependent diabetes, periodontally disorders, restenosis, alopecia, reducing the number of T cells associated with HIV infection or AIDS, psoriasis, acute pancreatitis, reactions of rejection of allogeneic grafts, allergic pneumonia, arteriosclerosis, multiple sclerosis, part of the FIAC, Alzheimer's disease, stroke, asthma ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), ischemia, congestive heart failure, pulmonary fibrosis, hepatitis, glioblastomas, syndrome Guilin-Barr, systemic lupus erythematosus, respiratory distress syndrome in adults (ARDS) and respiratory distress syndrome.

Compounds according to the invention can be input or as an individual therapeutically active compounds or as mixtures with other therapeutically active compounds. Connection, you can enter by themselves; however, usually, they are added into the composition of the medicinal product and is administered in the form of pharmaceutical compositions, i.e. in the form of mixtures of active compounds with suitable pharmaceutical carriers or diluents. The compounds or compositions can be administered orally or parenterally; preferably they are administered in the form of an oral formulation of dosage forms.

The type of pharmaceutical composition or carrier, or diluent depends on the desired form of administration. Oral compositions, for example, can be represented in the form of tablets or capsules and may contain conventional excipients such as binding agents (e.g. syrup, Arabian gum, gelatin, sorbitol, tragakant or polyvinylpyrrolidone), fillers (for example, the varnish is oz, sugar, corn starch, calcium phosphate, sorbitol or glycerol), glidant (for example, magnesium stearate, talc, polyethylene glycol or silica), loosening substances (e.g., starch) or wetting agents (e.g. sodium lauryl sulphate). Liquid oral preparations can be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs or sprays and the like. They can also be a dry powder, the moisture content of which restore using water or other suitable media. Such liquid preparations may include conventional additives, for example, suspendresume agents, flavoring agents, diluents or emulsifiers. For parenteral administration may use solutions or suspensions with conventional pharmaceutical carriers.

The compounds or compositions according to the invention it is possible to enter a mammal (human or animal) in a dose from about 0.5 mg to 100 mg per kg of body weight per day. They can be administered as a single dose or in multiple doses. Spectrum of activity of the compounds as inhibitors of the release of cytokines was investigated using the following system tests, as described C.Donat and S.Laufer in Arch.Pharm.Pharm.Med.Chem., 333, suppl.1, 1-40, 2000.

Test in vivo using whole human blood

The investigated substances is the primary objective was added to the samples potassium-EDTA whole blood (400 μl each) and samples pre-incubated in incubator with CO 2(5% CO2; 95% moisture saturated air) at 37°C for 15 minutes. The samples are then stimulated with 1 μg/ml LPS (E. coli 026:B6) at 37°C incubator with CO2(5% CO2; 95% moisture saturated air) for 4 hours. The reaction was stopped by placing the samples on ice, adding DPBS buffer and then centrifuger at 1000 g for 15 minutes. Then using ELISA determined the amount of IL-1β and TNF-α in the supernatant plasma.

Test in vitro using PBMCs

1) Menagerie cells (PBMCs) of potassium-EDTA whole blood diluted 1:3, was isolated by gradient density centrifugation (Histopaque®-1.077). Cells were washed twice with DPBS buffer, re-suspended in makropoulou environment SFM and brought up to the number of cells 1×106cells/ml

The resulting suspension of PBMCs (sample in each case 390 μl) and the test substance is pre-incubated at 37°C incubator with CO2(5% CO2; 95% moisture saturated air) for 15 minutes. The samples are then stimulated in each case 1 μg/ml LPS (E. coli 026:B6) at 37°C incubator with CO2(5% CO2; 95% moisture saturated air) for 4 hours. The reaction was stopped by placing the samples on ice, adding DPBS buffer and then centrifuger when 15880 g for 12 minutes. Then using ELISA determined the amount of IL-1β and TNF-α in the supernatant plasma./p>

2) Kinase analysis

At 37°microtiter tablets covered for one hour with 50 μl of a solution F2 (20 µg/ml). The tablets were washed three times with water and the wells were added 50 μl of kinase mixture (50 mm Tris-HCl, 10 mm MgCl2, 10 mm β-glycerophosphate, 10 μg/ml BSA, 1 mm DTT, 100 µl of ATP, 100 μm Na3VO4, 10 ng of activated Rα) in the presence or in the absence of inhibitor and the plates were incubated at 37°C for 1 hour. The tablets were washed three times and then incubated with phosphorus-ANF-2 antibody for one hour. Tablets are again washed three times and goat IgG against rabbit antibodies labeled with alkaline phosphatase was added at 37°and was left for one hour (for fixation of complex antibody-phosphorylated protein/substrate). Tablets thrice washed and a solution of alkaline phosphatase/substrate (3 mm 4NPP, 50 mm NaHCO3, 50 mm MgCl2100 µl/well) was added at 37°and was left for 1.5 hours. Education 4-nitrophenolate was measured at 405 nm using a microtiter reader for tablets. Expected value IC50.

The results of in vitro testing is shown below in table 1.

Table 1.

The results of the tests
Connection # IC50(µm)

R 38
IC50(ám) TNF-± PBMCA

IL-1β
K50(µm)

TNF-α
Whole blood

IL-1β
25a2,20,35
25bthe 3.82,80,30
25c8,74,62,77,22,2
25d1,90,15
25e3,10,50
25f0,650,63to 0.108
25g0,790,640,056
25h0,830,670,085the 17.322,3
25i0,950,500,1514,813,3
25j0,700,720,23
25k0,130,340,030
25l 0,240,350,03114,917,1
25m0,380,160,0392,70,99
25n0,340,170,041
25o0,900,370,044
26a60,01,8
26b4,240,52,9
-26 C1,423,20,20
26d0,382,70,045
26e21,00,18
27ato 12.02,1
27b9,36,92,45
27c1,452,00,47
27d0,270,91 0,04010,015,7

The following examples illustrate the invention without limiting it.

Example 1

a) 4-(4-Forfinal)-5-pyridin-4-yl-1,3-dihydroimidazole-2-tion

2-(4-forfinal)-3-hydroxy-3-pyridin-4-lacrimonasal (A1)

A mixture of utilitarianist (75,8 g; 0.5 mol) and 4-perforaciones (67,6 g; 0.5 mol) was added dropwise to a solution of metallic sodium (17.3 g; 0.7 mol) in absolute ethanol (250 ml). The reaction mixture was stirred at 100°C for 15 minutes. Then the reaction mixture was cooled in an ice bath and added to 600 ml of distilled water. When the mixture was acidified with concentrated HCl (90 ml), at pH 1 was formed yellow precipitate hydrochlorideA1. The precipitate was filtered off, washed with H2O and dried under reduced pressure over P2About5. TPL 226°C.

2-(4-Forfinal)-1-pyridin-4-ylatason (A2)

SolutionA1(40.6 g; 0.15 mol) in 48%Hydrobromic acid (130 ml) was stirred at the boil under reflux for 19 hours. The mixture was cooled in an ice bath and the precipitate (4-florfenicol acid) was filtered and washed with N2O. When the filtrate is neutralized aqueous ammonia (80 ml)wereA2in the form of a dark green precipitate, which was filtered off, washed with N2O and dried under reduced pressure over P 2About5; light grey/beige powder. TPL 215°C.

The reaction of 2-(4-forfinal)-1-pyridin-4-ratanana (A3)

In suspensionA2(21,5 g; 0.1 mol) in 50%methanol (350 ml) was injected sodium acetate (36,1 g; 0.44 mol) and hydroxylamine hydrochloride (22,0 g; 0.32 mol). The reaction mixture was stirred at the boil under reflux for 1 hour. When cool, the solution was cooled in an ice bath,A3received in the form of a beige precipitate, which was filtered off, washed with N2O and dried under reduced pressure over P2About5.

TPL 155°C.

O-[(4-Were)sulfonyl]the reaction of 2-(4-forfinal)-1-pyridin-4-ratanana (A4)

In an argon atmosphere A3 (10.1 g; 0.04 mol) was dissolved in absolute pyridine (50 ml). The solution was cooled to 6°and gradually with the passage of time was added toluenesulfonyl chloride (10.1 g; 0.05 mol). Upon completion of addition, the reaction mixture was stirred at room temperature for 20 hours. Then the mixture was poured into 500 ml of ice water. Sediment (A4) was filtered off, washed with cold N2O and dried in a drying chamber at 50°C. TPL 201°C.

a) 4-(4-Forfinal)-5-pyridin-4-yl-1,3-dihydroimidazole-2-tion (1A)

In an argon atmosphere a solution ofA4(10.0 g; 0.03 mol) in absolute ethanol (56 ml) was cooled to 5°and was added dropwise a freshly prepared solution of metallic sodium (075 g; 0.03 mol) in absolute ethanol (30 ml). The reaction mixture was stirred at 5°C for 5 hours. After adding diethyl ether (500 ml), stirring was continued for 30 minutes. The precipitate (TosOH) was filtered and washed with diethyl ether (4×50 ml). The combined ethereal phase was extracted with 10% hydrochloric acid (3×90 ml). The aqueous extract was concentrated to approximately volume of 40 ml was added potassium thiocyanate (5.0 g; 0.05 mol). The reaction mixture was stirred at the boil under reflux for 1 hour. When the mixture is neutralized with 5%sodium bicarbonate solution (270 ml)wereA5in the form of a beige precipitate, which was filtered off, washed with N2O and dried in a drying chamber at 60°C. the Yield 5.6 g (79%); TPL 382°C.

1H-NMR (DMSO-d6): δ (ppm) to 7.1 (m, 2H, 4-F-Ph), and 7.3 (m, 2H, 4-Pyr), 7.5 (m, 2H, 4-F-Ph), 8,5 (m, 2H, 4-Pyr), 12.7mm (d, 2H, exchangeable, NH).

Accordingly there were obtained the following compounds.

1b: 3-(4-forfinal)-5-pyridin-4-yl-1,3-dihydroimidazole-2-tion

1C 4-(4-chlorophenyl)-5-pyridin-4-yl-1,3-dihydroimidazole-2-tion

1d: 4-(4-bromophenyl)-5-pyridin-4-yl-1,3-dihydroimidazole-2-tion

1st: 4-phenyl-5-pyridin-4-yl-1,3-dihydroimidazole-2-tion

Example 2

1-Chloromethyl-4-methylsulfonylbenzoyl (2)

4-Methylsulfonylbenzoyl alcohol (30.5 g; 0.2 mol) was dissolved in dichloromethane (180 ml). The solution tioning orida (23,8 g; 0.2 mol) in dichloromethane (120 ml) was added dropwise to an initial mixture which is kept at the boil under reflux. The reaction mixture was stirred at the boil under reflux additionally for 2 hours. The solution was cooled to room temperature, washed with N2About (2×250 ml), dried over N2SO4and concentrated. The oily residue (6) was purified column chromatography (Al2O3CH2Cl2).

1H-NMR (CDCl3): δ (ppm) to 2.46 (s, 3H, CH3), and 4.5 (s, 2H, CH2), 7,2-7,3 (kV, 4H, 4-MeC-Ph).

Example 3

1-Chloromethyl-4-methansulfonate (3)

Solution2(17.3 g; 0.1 mol) in glacial acetic acid (150 ml) was cooled to 10°C. To initially loaded to the solution was added dropwise a solution of N2About2(35% solution of 35%concentration; 13,1 g; 0.13 mol) in glacial acetic acid. The reaction mixture was stirred at room temperature for 2 hours. The mixture was cooled in an ice bath, was added ice (200 g) and the mixture was neutralized by ammonia water (290 ml). The aqueous phase was extracted with ethyl acetate (2×300 ml). The organic phase is washed with N2About (2×300 ml), dried over Na2SO4and concentrated. Rubbing and cooling the oily sludge was received3in crystalline form.

1H-NMR (CDCl3): δ (ppm) 2,73 (3, 3H, C 3), and 4.6 (s, 2H, CH2), 7.5 (d, 2H, 4-MeC(O)-Ph), and 7.6 (d, 2H, 4-MeC(O)-Ph).

Example 4

1-Chloromethyl-4-methansulfonate (4)

m-Chloroperbenzoic acid (70%; 8.6 g; 0.04 mol) was introduced into a solution of 3 (3.0 g; 0.02 mol) in chloroform (50 ml). The reaction mixture was stirred at the boil under reflux for 4 hours. The mixture was cooled to room temperature and filtered. The filtrate was washed with saturated solution of NaHCO3(2×) and dried over Na2SO4. After concentration of the organic phase the residue was received4in the form of a crystalline white solid. TPL 102°C.

1H-NMR (CDCl3): δ (ppm) of 3.07 (s, 3H, CH3), and 4.6 (s, 2H, CH2), and 7.6 (d, 2H, 4-MeCO2-Ph), and 7.9(d, 2H, 4-MeCO2-Ph).

Example 5

Methyl-5-chlorosulfonyl-2-hydroxybenzoate (5A)

5Awas obtained from methyl salicylate (10.0 g; and 65.7 mmol) using the method described for the synthesis of5s.

1H-NMR (CDCl3): δ (ppm) of 4.05 (s, 3H, CH3), 7,18 (d, 1H, 8,9 Hz, C3(H)of 8.09 (DD, 1H, 2,5/9,0 Hz, C4(H)to 8.57 (d, 1H, 2.5 Hz, C6(H)for 11.55 (s, 1H, exchanged, phenol-HE).

Methyl 5-chloro-3-chlorosulfonyl-2-hydroxybenzoate (5b)

5bwas obtained from methyl(5-chloro)musk (16.0 g; of 85.7 mmol) using the method described for the synthesis of5s.

1H-NMR (CDCl3): δ (ppm) 4,06 (s, 3H, CH3), 8,11 (d, 1H, 2.7 Hz, C6-H), 8,19 (d, 1H, 2,7 the C, C4(H)12,09 (s, 1H, exchanged, phenol-HE).

Ethyl 3-chlorosulfonyl-4-methoxybenzoate (5s)

A solution of ethyl(4-methoxy)benzoate (15.7 g; 87,2 mmol) in CCl4(60 ml) was cooled to -15°and added dropwise within 15 minutes chlorosulfonic acid (17.5 ml; 263 mmol), which resulted in a temperature rise to -10°C. Upon completion of addition, the reaction mixture was stirred at room temperature for 2 hours and then was heated at 50°until starting material had not ceased to be detected according to thin-layer chromatography. With ice cooling and vigorous stirring, the reaction mixture was added to a suspension of ice (50 g) in CCl4(100 ml). The mixture was intensively stirred for 3 minutes. The organic phase was separated and the aqueous phase was extracted with CH2Cl2(3×100 ml). The combined organic extracts were washed with saturated solution of NaCl (3×), dried over Na2SO4and concentrated. Rubbing the oily brown residue with diethyl ether resulted in precipitation of5sin the form of a white crystalline substance.

1H-NMR (CDCl3): δ (ppm) of 1.41 (t, 3H, 7,1 Hz, CH3), 4,14 (s, 3H, CH3), was 4.42 (q, 2H, 7,1 Hz, CH2), 7,18 (d, 1H, 8,8 Hz, C5(H)of 8.37 (DD, 1H, 2,1/8,8 Hz, C6(H)8,63 (d, 1H, 2.1 Hz, C2-H).

Example 6

2-Hydroxy-5-mercaptobenzoic KIS the PTA ( 6A)

6Areceived from5A(0.50 g; 2.0 mmol) using the method described for the synthesis of7Cwithout the alkylation dimethylsulfate.

1H-NMR (DMSO-d6): δ (ppm) 5,39 (users, 1H, exchanged, carboxyl-HE), of 6.90 (d, 1H, 8.7 Hz, With3-N), was 7.45 (DD, 1H, 2,5/8.6 Hz, With4-N), of 7.75 (d, 1H, 2,5 GHz, With6-N), phenol-IT is not visible.

Example 7

2-Hydroxy-5-methylsulfonylbenzoyl acid (7a)

7areceived from5A(10.0 g; 40.0 mmol) using the method described for the synthesis of7C.

1H-NMR (CDCl3): δ (ppm) 2,48 (s, 3H, CH3), 6,97 (d, 1H, 8.7 Hz, C3(H)7,51 (DD, 1H, 2,5/8,7 Hz, C4-H), 6,97 (d, 1H, 8.7 Hz, C3-H), 7,87 (d, 1H, 2.4 Hz, C6-H), 10,26 (users, 1H, phenol OH), CO2N is not visible.

5-Chloro-2-hydroxy-3-methylsulfonylbenzoyl acid (7b)

7breceived from5b(13,0 g; of 45.6 mmol) using the method described for the synthesis of7C.

1H-NMR (DMSO-d6): δ (ppm)2,47 (s, 3H, CH3), 7,33 (d, 1H, 2.4 Hz, C6-H), 7,52 (d, 1H, 2.4 Hz, C4-H), phenol-HE and CO2N not visible.

4-Methoxy-3-methylsulfonylbenzoyl acid (7C)

Triphenylphosphine (20,5 g, 78.2 mmol) was slowly introduced into the solution5s(5,1 g; and 18.3 mmol) in toluene (50 ml). The reaction mixture was stirred at room temperature for 4.5 hours. The precipitate (triphenylphosphine) was filtered and the yellow Phi is Trat was extracted with aqueous sodium hydroxide solution 10%concentration (4× ). To the combined aqueous extract was added dimethylsulfate (2 ml) and the reaction mixture was stirred at room temperature for 2 hours. The precipitate was dissolved by heating to the boiling temperature under reflux. The clear solution was cooled and brought to pH 1 using hydrochloric acid 20%concentration. Sediment (7C) was filtered off, washed with N2O and dried under reduced pressure over CaCl2.

1H-NMR (CD3OD): δ (ppm)2,43 (s, 3H, S-CH3), 3,93 (s, 3H, O-CH3), 6,98 (d, 1H, 8,4 Hz, C5(H)7,79-7,86 (m, 2H, C2-A/C6-H)

4-Hydroxy-3-methylsulfonylbenzoyl acid (7d)

Suspension7C(0.5 g, 2.5 mmol) in a mixture of glacial acetic acid/48%Hydrobromic acid (1+1.7 ml) was stirred by heating at boiling under reflux for 6 hours. The reaction mixture was cooled, added to N2O (20 ml) and brought to pH 2 using a solution of Na2CO310%concentration. The aqueous solution was extracted with diethyl ether (4×20 ml). The combined organic extract was washed with saturated solution of NaCl (2×), dried over Na2SO4and concentrated. When stored at room temperature, dirty-brown oily residue (7d) crystallized. The crystals are triturated with N2Oh, tfilter is Ali and dried.

1H-NMR (CDCl3): δ (ppm)of 2.38 (s, 3H, CH3), 7,05 (d, 1H, 8.5 Hz, C5(H)8,02 (DD, 1H, 2,2/8,5 Hz, C6-H), 8,29 (d, 1H, 2.2 Hz, C2(H)phenol-HE and CO2N not visible.

Example 8

2-Hydroxymethyl-4-methylsulfinylphenyl (8A)

8Aderived from7a(1.5 g, 8.1 mmol) using the method described for the synthesis of8s.

1H-NMR (CDCl3): δ (ppm)to 2.42 (s, 3H, CH3), 4,79 (s, 2H, CH2), for 6.81 (d, 1H, 8,4 Hz, C6(H)7,01 (d, 1H, 2.1 Hz, C3-H), 7,17 (DD, 1H, 2.3 and 8.4 Hz, C3(H)IT is not visible.

4-Chloro-2-hydroxymethyl-6-methylsulfinylphenyl (8b)

8bderived from7b(2.2 g; 10.1 mmol) using the method described for the synthesis of8s.

1H-NMR (DMSO-d6): δ (ppm)of 2.38 (s, 3H, CH3), to 4.52 (s, 2H, CH2), 5,3-5,5 (users, 1H, exchangeable, Oh-OH), 7,03 (d, 1H, 2.6 Hz, With5-N), 7,11 (d, 2.4 Hz, With3-N), 9,02 (users, 1H, exchanged, phenol-OH)

4-Hydroxymethyl-2-methylsulfinylphenyl (8s)

Under ice cooling a solution of7d(1,37 g; 7.4 mmol) in absolute tetrahydrofuran (THF; 15 ml) was added to a suspension of LiAlH495%purity (0.55 g; 14 mmol) in absolute THF in a three-neck flask (which had been dried by heating and purging with argon) in such a way that happens only moderate gas evolution. Upon completion of addition, the cooling was removed and the reaction mixture is stirred at room temperature and at 55-65° With in the next 21 hours. Under ice cooling to the reaction mixture were added ice-cold water. The precipitate Al(OH)3was dissolved by adding sulfuric acid 10%concentration and acidic aqueous solution (pH 1) was extracted with diethyl ether (3×50 ml). The combined ether extracts were extracted with an aqueous solution of sodium hydroxide 10%concentration (2×25 ml). The combined sodium hydroxide solution was neutralized with hydrochloric acid 20%concentration. Sediment (8s) was filtered off, washed with N2Oh and dried. An additional portion of8swas obtained by extraction of a neutral aqueous solution in diethyl ether. The ether extract was washed with saturated solution of NaCl, dried over Na2SO4and concentrated, obtaining a crystalline white solid.

1H-NMR (CDCl3):δ (ppm)of 2.34 (s, 3H, CH3), 4,60 (s, 2H, CH2), 6,97 (d, 1H, 8,3 Hz, C6(H)of 7.24 (DD, 1H, of 2.0 and 8.4 Hz, C5(H)to 7.50 (d, 1H, 2.0 Hz, C3(H)IT is not visible.

Example 9

2-Hydroxy-5-methylsulfonylbenzoyl (9a)

Specified in the title compound was obtained as a side product during the synthesis of8A.

1H-NMR (CDCl3): δ (ppm) 2,48 (s, 3H, CH3), of 6.96 (d, 1H, 9.8 Hz, With3-N), of 7.48-rate of 7.54 (m, 2H, WITH4-/S6-N), 9,87 (s, 1H, exchangeable, OH), 10,91 (s, 1H, aldehyde-N).

Example 10

4-(3-Chlore the Il)benzosulphochloride ( 10A)

Under ice cooling (2-chloroethyl)benzene (14.0 g; 0.1 mol) was added dropwise over 40 minutes to chlorosulfonic acid (72 g). The brown solution was stirred at room temperature for 24 hours, cooled in an ice bath and slowly added to ice, where he formed a viscous substance that cannot be filtered. The aqueous solution was extracted with ethyl acetate (3×). The combined organic extract was washed with a solution of NaHCO310%concentration, dried over Na2SO4and concentrated. The oily residue was placed in a mixture of tert-butyl methyl ether/petroleum ether. The solution is rubbed with a glass rod and cooled. White crystals were filtered off and dried. The additional amount of reaction product was obtained from the mother liquor. The crude product was used without further purification for the synthesis of11a.

1H-NMR (CDCl3): δ (ppm)3,20 (t, 2H, 6.8 Hz, CH2), with 3.79 (t, 2H, 6.8 Hz, CH2), 7,46-7,53 (m, 2H, phenyl), 7,97-of 8.04 (m, 2H, phenyl).

4-(3-Chlorpropyl)benzosulphochloride (10b)

10breceived from (3-chloropropyl)benzene (15.5 g; 0.1 mol) using the method described for the synthesis of10A. The crude product was used without further purification for the synthesis of11b.

Mass spectrum: m/z (%) 253 (90, M+), 217 (100, M+-Cl), 189 (35), 153 (97, M +-SO2Cl), 125 (94), 119 (65, phenylpropylamine+), 91(90), 77 (29, phenyl+).

Example 11

1-(3-Chloroethyl)-4-methylsulfonylbenzoyl (11a)

11areceived from10A(12.0 g; 0.05 mol) using the method described for the synthesis of 11b.

1H-NMR (CDCl3): δ (ppm)2,47 (s, 3H, CH3), to 3.02 (t, 2H, 7.4 Hz, CH2), 3,68 (t, 2H, 7.5 Hz, CH2), 7,11-7,25 (m, 4H, phenyl).

1-(3-Chloropropyl)-4-methylsulfonylbenzoyl (11b)

At room temperature the solution10b(12.7 g; 5.0 mmol) in diethyl ether (75 ml) was added dropwise over 2.5 hours to a suspension of LiAlH4(2.9 g; 7.6 mmol) in diethyl ether (50 ml). Upon completion of addition, the reaction mixture was stirred at room temperature for from time to time adding LiAlH4up until starting material is no longer detected by thin layer chromatography (2.5 hours). Under ice cooling to the reaction mixture was introduced ice and the aqueous phase was acidified with 10% hydrochloric acid (pH 1). The organic phase was removed and the aqueous phase was extracted with diethyl ether (3×). The combined organic extract was washed with an aqueous solution of sodium hydroxide 10%concentration (4×50 ml) until then, until it becomes visually clear. To the combined solution of sodium hydroxide was added dimethylsulfate (9.0 g; 7.0 mmol) and the mixture was stirred at room themes is the temperature value for 16.5 hours. The oily residue was placed in diethyl ether. The organic phase was separated and the aqueous phase was again extracted with diethyl ether (2×). The combined organic extract was dried over Na2SO4and concentrated. The brown oily residue was subjected to distillation using a tube with a ball extension (0.2 mbar. 250°).

1H-NMR (CDCl3): δ (ppm)2,01-2,11 (m, 2H, CH2), the 2.46 (s, 3H, CH3), by 2.73 (t, 2H, 7,1 Hz, CH2), 3,51 (t, 2H, 6.5 Hz, CH2), 7,09-7,25 (m, 4H, phenyl)

Example 12

1-(2-Chloroethyl)-4-methanesulfonate (12A)

Upon cooling to a solution of11a(1.5 g, 8.0 mmol) in glacial acetic acid (20 ml) was added a solution of N2About235%concentration (0.9 g; 9.3 mmol). Upon completion of addition, the reaction mixture was stirred at room temperature for 2.5 hours, diluted with cooling with ice water and brought to pH 8 with ammonia water 25%concentration. Oily white precipitate was placed in diethyl ether and the aqueous phase was extracted with diethyl ether (3×). The combined organic extracts were dried over Na2SO4and concentrated.

1H-NMR (CDCl3): δ (ppm)by 2.73 (s, 3H, CH3), 3,14 (t, 2H, 7,1 Hz, CH2), 3,76 (t, 2H, 7,1 Hz, CH2), 7,38-7,42 (m, 2H, phenyl), 7,60-to 7.64 (m, 2H, phenyl).

1-(3-Chloropropyl)-4-methanesulfonate (12b/b> )

12breceived from11b(2.0 g; 10.0 mmol) using the method described in the synthesis of12A. TPL 46°

General methods of preparing compounds of formula I.

Getting 2-arylalkyl or alkylsulfonamides (General method A)

A suspension of the appropriate imidazole-2-thione (1 equivalent), the appropriate base (1.2 equivalent) and the appropriate arylalkyl or alkylhalogenide (1 equivalent) in a mixture of ethanol/THF (8+2) was stirred at boiling under reflux until until imidazol-2-tion no longer be detected according to thin-layer chromatography. The reaction mixture was cooled to room temperature and filtered. The filtrate, which in most cases had a red/orange color, concentrated and the residue was purified column chromatography, recrystallization or rubbing. Thus obtained compound13a-C,14a-Cand17a-m.

Getting 2-benzylbenzimidazole containing phenolic functional group in the radical R2(General method).

Adding hydrochloric acid 10%concentration (10-15 drops), imidazol-2-tion1A(1 equivalent) was dissolved in glacial acetic acid (5 ml). To the original mixture, which has a light yellow color, was added the corresponding benzyl alcohol (1 equivalent) and the reaction mixture was stirred at under Odesa temperature (temperature/time) as long while1Ano longer be detected according to thin-layer chromatography. In the case of sulfoxidov18g-isolution was added N2About235%concentration and the reaction mixture was stirred at room temperature for additional 4 hours. The reaction mixture was diluted with H2O (5 ml) and brought to pH 8 with ammonia water 25%concentration. The precipitate was filtered and washed with water. The crude product was purified column chromatography, recrystallization or rubbing. Thus received imidazol-2-ylsulphanilamide18a-i.

Obtaining N-substituted 2-aminopyridines (General method C)

In argon atmosphere, the corresponding 5-(2-halogenfrei-4-yl)imidazole (1 equivalent) is suspended in an appropriate Amina (about 10 equivalents). The reaction mixture was stirred at the appropriate temperature up until starting material was no longer detected by thin-layer chromatography. The reaction mixture was cooled to room temperature and poured into 10%citric acid, which previously brought to pH 5 with NaOH 20%concentration. The aqueous emulsion was extracted with ethyl acetate (3×). The combined organic extract was washed with 10%citric acid/pH 5 (1×), a solution of Na2CO310%concentration (2×)and saturated NaCl (1× ), dried over Na2SO4and concentrated. The oily residue was separated column chromatography. Aminopyridines25f-p,-26 C-eand27c-dreceived thereby.

Example 13

3-[5-(4-Forfinal)-2-(4-methylsulfonylbenzoyl)-3H-imidazol-4-yl]pyridine (13A)

Using the General method As specified in the title compound was obtained from1b(0,42 g; 1.5 mmol) and2(0.25 g; 1.4 mmol) after conducting the reaction for 4.5 hours and the separation column chromatography (SiO260, CH2Cl2/EtOH 9+1).

TPL 163°C.

IR (ATR) (damped total reflection): 1505, 1493, 1222 (C-F), 837, 806 cm-1.

1H-NMR (DMSO-d6): δ (ppm)of 2.45 (s, 3H, CH3), to 4.38 (s, 2H, CH2), 7,19-7,49 (m, 10H, 3-Pyr, 4-F-Ph and 4-MeS-Ph), 7,78-of 7.82 (m, 1H, 3-Pyr), 8,45-of 8.47 (m, 1H, 3-Pyr), 8,61 (s, 1H, 3-Pyr), 12,71(users, 1H, exchangeable, NH).

3-[5-(4-Forfinal)-2-(4-methanesulfonylaminoethyl)-3H-imidazol-4-yl]pyridine (13b)

Using the General method As specified in the title compound was obtained from1b(0,42 g; 1.5 mmol) and3(0.27 g; 1.5 mmol) after conducting the reaction for 8 hours and the separation column chromatography (SiO260, CH2Cl2/EtOH 9+1)/

TPL 127°C.

IR (ATR): 1506, 1222 (C-F), 1027 (S=O), 1013, 838, 811 cm-1.

1H-NMR (DMSO-d6): δ (ppm)3,19 (s, 3H, CH3), to 4.46 (s, 2H, CH2), 7,16-7,46 (m, 5H, 3-Pyr and 4-F-Ph), 7,56-7,66 (m, 4H, 4-MeS(O)-Ph), 7,72-7,81 (m, 1H, 3-Pyr), to 8.41-to 8.62 (m, 2H, 3-Pyr), 12,77(users, 1H, exchangeable, NH).

3-[5-(4-Forfinal)-2-(4-methanesulfonylaminoethyl)-3H-imidazol-4-yl]pyridine (13c)

Using the General method As specified in the title compound was obtained from1b(0,42 g; 1.5 mmol) and4(0.29 grams; of 1.43 mmol) with the addition of Na2CO3(0,43 g; 4.1 mmol) after conducting the reaction for 6.5 hours and trituration with hot ethyl acetate. TPL 129°C.

IR (ATR): 1506, 1296 (SO2), 1222 (C-F), 1145 (SO2), 1089, 839, 812 cm-1.

1H-NMR (DMSO-d6): δ (ppm)3,19 (s, 3H, CH3), 4,50 (s, 2H, CH2), 7,17 was 7.45 (m, 5H, 3-Pyr and 4-F-Ph), of 7.64-of 7.90 (m, 5H, 3-Pyr and 4-MeSO2-Ph), 8,43-8,61 (m, 2H, 3-Pyr), 12,78(users, 1H, exchangeable, NH).

Example 14

4-[5-(4-Chlorophenyl)-2-(4-methylsulfonylbenzoyl)-3H-imidazol-4-yl]pyridine (14a)

Using the General method As specified in the title compound was obtained from1s(0.26 g; 0.9 mmol) and6(0.15 g; 0.87 mmol) with the addition of Na2CO3(two portions on the tip of a spatula) after conducting the reaction for 6.5 hours and the separation column chromatography (SiO260, CH2Cl2/EtOH 9+1). TPL 236°C.

IR (ATR): 1600, 1492, 1094, 1005, 968, 829, 684 (C-Cl), 561 cm-1.

1H-NMR (DMSO-d6): δ (ppm) of 2.44 (s, 3H, CH3), to 4.38 (s, 2H, CH2), 7,18-7,56 (m, 10H, 4-Pyr, 4-Cl-Ph and 4-MeS-Ph), 8,45-8,55 (m, 2H, 4-Pyr), 12,86(users, 1H, obmanivay the first, NH).

4-[5-(4-Chlorophenyl)-2-(4-methanesulfonylaminoethyl)-3H-imidazol-4-yl]pyridine (14b)

Using the General method As specified in the title compound was obtained from1s(0.26 g; 0.9 mmol) and3(0.16 g; 0.85 mmol) with the addition of Na2CO3after the reaction for 6.5 hours and the separation column chromatography (SiO260, CH2Cl2/EtOH 9+1). TPL 224°C.

IR (ATR): 1600, 1510, 1490, 1033 (S=O), 1001, 967, 829, 677 (C-Cl) cm-1.

1H-NMR (DMSO-d6): δ (ppm)2,70 (s, 3H, CH3), 4,47 (s, 2H, CH2), 7,31-the 7.65 (m, 10H, 4-Pyr, 4-Cl-Ph and 4-MeS(O)-Ph), 8,44-8,54 (m, 2H, 4-Pyr), 12,87(users, 1H, exchangeable, NH).

4-[5-(4-Chlorophenyl)-2-(4-methanesulfonylaminoethyl)-3H-imidazol-4-yl]pyridine (14C)

Using the General method As specified in the title compound was obtained from1s(0.26 g; 0.9 mmol) and3(0.16 g; 0.85 mmol) with the addition of Na2CO3(two portions on the tip of a spatula) after conducting the reaction for 6.5 hours and the separation column chromatography (SiO260, CH2Cl2/EtOH 9+1). TPL 232°C.

IR (ATR): 1603, 1490, 1300 (SO2), 1141 (SO2), 1086, 1002, 952, 829, 681 (C-Cl), 550 cm-1.

1H-NMR (DMSO-d6): δ (ppm)3,19 (s, 3H, CH3), to 4.52 (s, 2H, CH2), 7,32-7,58 (m, 6H, 4-Pyr and 4-Cl-Ph), to 7.67 (d, 2H, 8,2 Hz, 4-MeSO2-Ph), 7,88 (d, 2H, 8,3 Hz, 4-MeSO2-Ph), 8,45-8,55 (m, 2H, 4-Pyr), 12,89(users, 1H, exchangeable, NH).

Example 1

4-[5-(4-Bromophenyl)-2-(4-methylsulfonylbenzoyl)-3H-imidazol-4-yl]pyridine (15A)

Using the General method As specified in the title compound was obtained from1d(0.25 g; 0.75 mmol) and2(0,13 g; to 0.72 mmol) after carrying out the reaction for 5 hours and the separation column chromatography (SiO260, CH2Cl2/EtOH 9+1).

IR (ATR): 1600, 1517, 1490, 1089, 1069, 1003, 968, 826 cm-1.

1H-NMR (DMSO-d6): δ (ppm)2,43 (s, 3H, CH3), 4,36 (s, 2H, CH2), 7,16-7,87 (m, 10H, 4-Pyr, 4-Br-Ph and 4-MeS-Ph), 8,45-8,55 (m, 2H, 4-Pyr), 12,90(users, 1H, exchangeable, NH).

4-[5-(4-Bromophenyl)-2-(4-methanesulfonylaminoethyl)-3H-imidazol-4-yl]pyridine (15b)

Using the General method As specified in the title compound was obtained from1d(0.25 g; 0.75 mmol) and3(0.14 g; to 0.72 mmol) after conducting the reaction for 10 hours and the separation column chromatography (SiO260, CH2Cl2/EtOH 9+1).

TPL 222°C.

IR (ATR): 1604, 1487, 1035 (S=O), 1010, 1000, 966, 822 cm-1.

1H-NMR (DMSO-d6): δ (ppm)a 2.71 (s, 3H, CH3), 4,48 (s, 2H, CH2), 7,40 to 7.62 (m, 20H, 4-Pyr, 4-Br-Ph and 4-MeS(O)-Ph), 8,49-to 8.57 (m, 2H, 4-Pyr), 12,90(users, 1H, exchangeable, NH).

4-[5-(4-Bromophenyl)-2-(4-methanesulfonylaminoethyl)-3H-imidazol-4-yl]pyridine (15C)

Using the General method As specified in the title compound was obtained from1d(0.25 g; 0.75 mmol) and4(0.15 g; 0,72 shall mol) after the reaction for 5 hours and the separation column chromatography (SiO 260, CH2Cl2/EtOH 9+1).

TPL 226°C.

IR (ATR): 1605, 1318, 1303 (SO2), 1145 (SO2), 1003, 967, 957, 827, 822 cm-1.

1H-NMR (DMSO-d6): δ (ppm)3,18 (s, 3H, CH3), 4,50 (s, 2H, CH2), 7,33-7,89 (m, 10H, 4-Pyr, 4-Br-Ph and 4-MeSO2-Ph), 8,45-8,54 (m, 2H, 4-Pyr),12,89(users, 1H, exchangeable, NH).

Example 16

4-[2-(4-Methylsulfonylbenzoyl)-5-phenyl-3H-imidazol-4-yl]pyridine (16A)

Using the General method As specified in the title compound was obtained from1E(0,38 g; 1.5 mmol) and2(0.25 g; 1.4 mmol) after carrying out the reaction in the course of 5.75 hours and separation column chromatography (SiO260, CH2Cl2/EtOH 9+1).

TPL 213°C.

IR (ATR): 1601, 1491, 1417, 1094, 1004, 967, 828, 771, 700 cm-1.

1H-NMR (DMSO-d6): δ (ppm)of 2.44 (s, 3H, CH3), to 4.38 (s, 2H, CH2), 7,18-7,58 (m, 11H, 4-Pyr, Ph and 4-MeS-Ph), 8,44-of 8.47 (m, 2H, 4-Pyr), 12,82(users, 1H, exchangeable, NH).

4-[2-(4-Methanesulfonylaminoethyl)-5-phenyl-3H-imidazol-4-yl]pyridine (16b)

Using the General method As specified in the title compound was obtained from1E(0,38 g; 1.5 mmol) and3(0.27 g; 1,43 mmol) after conducting the reaction for 5.5 hours and the separation column chromatography (SiO260, CH2Cl2/EtOH 9+1).

TPL 189°C.

IR (ATR): 1603, 1494, 1051 (S=O), 1003, 833, 701 cm-1.

1H-NMR (DMSO-d6): δ (ppm)a 2.71 (s, 3H, CH 3), 4,48 (s, 2H, CH2), 7,32-7,52 (m, 7H, 4-Pyr and Ph), EUR 7.57-to 7.67 (m, 4H, 4-MeS(O)-Ph), 8,45-8,54 (m, 2H, 4-Pyr), 12,84(users, 1H, exchangeable, NH).

4-[2-(4-Methanesulfonylaminoethyl)-5-phenyl-3H-imidazol-4-yl]pyridine (16C)

Using the General method As specified in the title compound was obtained from1E(0,38 g; 1.5 mmol) and4(0.29 grams; of 1.43 mmol) after carrying out the reaction in the course of 4.25 hours and separation column chromatography (SiO260, CH2Cl2/EtOH 9+1).

TPL 247°C.

IR (ATR): 1602, 1298 (SO2), 1145 (SO2), 1006, 953, 827, 775, 701 cm-1.

1H-NMR (DMSO-d6): δ (ppm)is 3.21 (s, 3H, CH3), of 4.54 (s, 2H, CH2), 7,31-7,58 (m, 7H, 4-Pyr and Ph), of 7.70 (d, 2H, 8,3 Hz, 4-MeSO2-Ph), to $ 7.91 (d, 2H, 8,3 Hz, 4-MeSO2-Ph), 8,45-8,59 (m, 2H, 4-Pyr), 12,87(users, 1H, exchangeable, NH).

Example 17

4-{5-(4-Forfinal)-2-[2-(4-methanesulfonyl)ethylsulfanyl]-1H-imidazol-4-yl}pyridine (17A)

Using the General method As specified in the title compound was obtained from1A(0.25 g; 0.9 mmol) and12A(0,22 g; 1.1 mmol) with the addition of Na2CO3(1 portion at the tip of a spatula) and a catalytic amount of NaI, after the reaction for 50 hours and the separation column chromatography (SiO260, CH2Cl2/EtOH 9+1).

TPL 177°C.

IR (ATR): 1221 (C-F), 1032 (S=O) cm-1.

1H-NMR (DMSO-d6): δ (ppm)a 2.71 (s, 3H, CH3), 3,06-3,13 (m, 2H,CH 2), 3,42-to 3.49 (m, 2H, CH2), 7,25-the 7.65 (m, 10H, 4-Pyr, 4-F-Ph and 4-MeS(O)-Ph), 8,40-8,58 (m, 2H, 4-Pyr),12,80(users, 1H, exchangeable, NH).

4-{5-(4-Forfinal)-2-[2-(4-methanesulfonyl)propylsulfonyl]-1H-imidazol-4-yl}pyridine (17b)

Using the General method As specified in the title compound was obtained from1A(0.25 g; 0.9 mmol) and12b(0,22 g; 1.0 mmol) with the addition of Na2CO3(1 portion at the tip of a spatula) and a catalytic amount of NaI, after the reaction for 40 hours, and separation column chromatography (SiO260, CH2Cl2/EtOH 9+1).

TPL 142°C.

IR (ATR): 1222 (C-F), 1043 (S=O) cm-1.

1H-NMR (DMSO-d6): δ (ppm)1,95-of 2.09 (m, 2H, CH2), a 2.71 (s, 3H, CH3), 2,82 (t, 2H, 7.4 Hz, CH2)and 3.15 (t, 2H, 7.0 Hz, CH2), 7,25 to 7.62 (m, 10H, 4-Pyr, 4-F-Ph and 4-MeS(O)-Ph), 8,46-8,49 (m, 2H, 4-Pyr),12,86(users, 1H, exchangeable, NH).

4-[2-Benzylmethyl-5-(4-forfinal)-1H-imidazol-4-yl]pyridine (17c)

Using the General method As specified in the title compound was obtained from1A(0.28 g; 1.0 mmol) and 1-chloromethylbenzene (0,13 g; 1.0 mmol) after the reaction for 6 hours, and rubbing with Meon. TPL 223°C.

IR (ATR): 1233 cm-1(C-F).

1H-NMR (DMSO-d6): δ (ppm)to 4.41 (s, 2H, CH2), 7.23 percent-7,51 (m, 11H, 4-Pyr, 4-F-Ph and Bz), 8,44-of 8.47 (m, 2H, 4-Pyr), 12,82(users, 1H, exchangeable, NH).

4-[5-(4-Forfinal)-2-penicillanic-1H-they are the azole-4-yl]pyridine ( 17d)

Using the General method As specified in the title compound was obtained from1A(0.5 g, 1.9 mmol) and 2-chloroethylene (0.28 g; 2.0 mmol) with the addition of Na2CO3(1 portion at the tip of a spatula) and a catalytic amount of NaIafter the reaction for 70 hours and trituration with EtOH. TPL 257°C.

IR (ATR): 1223 cm-1(C-F).

1H-NMR (DMSO-d6): δ (ppm)to 2.99 (t, 2H, 7.4 Hz, CH2), 3,40 (t, 2H, 7.5 Hz, CH2), 7,17-7,53 (m, 11H, 4-Pyr, 4-F-Ph and Bz), 8,44-8,46 (m, 2H, 4-Pyr), NH not visible.

4-[5-(4-Forfinal)-2-(3-phenylpropylamine)-1H-imidazol-4-yl]pyridine (E)

Using the General method As specified in the title compound was obtained from1A(0.5 g, 1.9 mmol) and 3-chloropropanol (0.28 g; 2.0 mmol) with the addition of Na2CO3(1 portion at the tip of a spatula) and a catalytic amount of NaIafter the reaction for 70 hours and trituration with EtOH. TPL 183°C.

IR (ATR): 1226 cm-1(C-F).

1H-NMR (DMSO-d6): δ (ppm)1,90-2,04 (m, 2H, CH2), of 2.72 (t, 2H, 7.4 Hz, CH2), of 3.12 (t, 2H, 7.0 Hz, CH2), 7,18-7,51 (m, 11H, 4-Pyr, 4-F-Ph and Bz)of 8.37-8,44 (m, 2H, 4-Pyr), 12,82(users, 1H, exchangeable, NH).

4-[5-(4-Forfinal)-4-pyridin-4-yl-1H-imidazol-2-ylsulphonyl]acetonitrile (17f)

Using the General method As specified in the title compound was obtained from1A(1.1 g; 4.0 mmol) and chloroacetonitrile (0,30 g; 4,0 shall mol) after conducting the reaction for 18 hours, and the purification column chromatography (SiO 260, ethyl acetate).

TPL 219°C.

IR (ATR): 2243 (CN), 1226 cm-1(C-F).

1H-NMR (DMSO-d6): δ (ppm)4,32 (s, 2H, CH2), 7,34-EUR 7.57 (m, 6H, 4-Pyr and 4-F-Ph), 8,50-charged 8.52 (m, 2H, 4-Pyr), 13,20(users, 1H, exchangeable, NH).

4-[5-(4-Forfinal)-2-(naphthalene-1-elmersolver)-1H-imidazol-4-yl]pyridine (17g)

Using the General method As specified in the title compound was obtained from1A(0.28 g; 1.0 mmol) and 1-chloromethylketone (0.18 g; 1.0 mmol) after conducting the reaction for 6.5 hours, and the purification column chromatography (SiO260, ethyl acetate). TPL 364°C.

IR (ATR): 1225 cm-1(C-F).

1H-NMR (DMSO-d6): δ (ppm)the 4.90 (s, 2H, CH2), 7,25 to 7.62 (m, 10H, 4-Pyr, 4-F-Phenyl and naphthyl), 7,80-7,98 (m, 2H, naphthyl), 8,20-8,23 (m, 1H, naphthyl), 8,48-charged 8.52 (m, 2H, 4-Pyr), 12(users, 1H, exchangeable, NH).

4-[2-2-Cyclohexanesulfonyl-5-(4-forfinal)-1H-imidazol-4-yl]pyridine (17h)

Using the General method As specified in the title compound was obtained from1A(0.25 g; 0.9 mmol) and 1-chloromethylketone (0.18 g; 1.0 mmol) with the addition of Na2CO3(1 portion at the tip of a spatula) and a catalytic amount of NaIafter the reaction for 47 hours and trituration with EtOH. TPL 235°C.

IR (ATR): 2922, 2852 (C-Hex), 1222 cm-1(C-F).

1H-NMR (DMSO-d6): δ (ppm)0,95-of 1.23 (m, 5H, cyclo-Hex)and 1.51-of 1.85 (m, 6H, cyclo-Hex)to 3.06 (d, 2H, 6,7 Hz, CH2), 722-7,51 (m, 6H, 4-Pyr and 4-F-Ph), 8,43-to 8.45 (m, 2H, 4-Pyr), 12,76(users, 1H, exchangeable, NH).

4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine (17i)

Using the General method As specified in the title compound was obtained from1A(0,41 g; 1.5 mmol) and iodotope bromide (0.27 g; 1.9 mmol) after conducting the reaction for 8 hours and trituration with EtOH. TPL 263°C.

IR (ATR): 1226 cm-1(C-F).

1H-NMR (DMSO-d6): δ (ppm)2,61 (s, 3H, CH3), 7,22-7,51 (m, 6H, 4-Pyr and 4-F-Ph), 8,42-to 8.45 (m, 2H, 4-Pyr), NH not visible.

4-[5-(4-Forfinal)-2-(2-methylsulfonylbenzoyl)-1H-imidazol-4-yl]pyridine (17j)

Using the General method As specified in the title compound was obtained from1A(0.28 g; 1.0 mmol) and 1-chloromethyl-2-methylsulfonylbenzoyl (0.17 g; 1.0 mmol) after conducting the reaction for 5.5 hours, and the purification column chromatography (SiO260, ethyl acetate). TPL 223°C.

IR (ATR): 1228 cm-1(C-F).

1H-NMR (CD3OD): δ (ppm)of 2.51 (s, 3H, CH3), of 4.44 (s, 2H, CH2), 7,13-of 7.48 (m, 10H, 4-Pyr, 4-F-Ph and 2-MeS-Ph), 8,43-8,46 (m, 2H, 4-Pyr).

4-[5-(4-Forfinal)-2-(2-methanesulfonylaminoethyl)-1H-imidazol-4-yl]pyridine (17k)

Using the General method As specified in the title compound was obtained from1A(0.28 g; 1.0 mmol) and 1-chloromethyl-2-methysulfonylmethane (0.18 g; 1.0 mmol) after carrying out the reaction for 4 hours and recrystallization from CME and methanol/ethyl acetate (1+1). TPL 205°C.

IR (KBr): 1213 (C-F), 1033 cm-1(S=O).

1H-NMR (CD3OD): δ (ppm)2,87 (s, 3H, CH3), 4,50 (d, 1H, 13,6 Hz, CH2), to 4.62 (d, 1H, 13,6 Hz, CH2), 7,24-7,33 (m, 2H, 4-F-Ph), 7,47 to 7.62 (m, 5H, 4-F-Ph, C4-A/C5-A/C6-H 2-MeS(O)-Ph), to 7.95 (d, 1H, 7.2 Hz, C3-H 2-MeS(O)-Ph), 7,99-8,03 (m, 2H, 4-Pyr), 8,55-8,58 (m, 2H, 4-Pyr).

4-[5-(4-Forfinal)-2-(3-methylsulfonylbenzoyl)-1H-imidazol-4-yl]pyridine (17l)

Using the General method As specified in the title compound was obtained from 1A (1.1 g; 4.1 mmol) and 1-chloromethyl-3-methylsulfonylbenzoyl (0.7 g; 4.1 mmol) after conducting the reaction for 11 hours and recrystallization from EtOH. TPL 218°C.

IR (KBr): 1225 cm-1(C-F).

1H-NMR (DMSO-d6): δ (ppm)is 2.40 (s, 3H, CH3), to 4.46 (s, 2H, CH2), 7,16-the 7.43 (m, 6H, 4-F-Ph and 3-MeS-Ph), 7,56-7,63 (m, 2H, 4-F-Ph), of 7.90-to 7.93 (m, 2H, 4-Pyr), 8,66-8,69 (m, 2H, 4-Pyr), NH not visible.

4-[5-(4-Forfinal)-2-(3-methanesulfonylaminoethyl)-1H-imidazol-4-yl]pyridine (17m)

A solution of N2About2(0,13 ml; 1.3 mmol) of 35%concentration) was added dropwise to a suspension of17l(0.50 g; 1.2 mmol) in glacial acetic acid (7 ml). The reaction mixture was stirred at room temperature for 20,5 hours, diluted with H2O (5 ml), brought to pH 9 using ammonia water 25%concentration and was extracted with ethyl acetate (3×). The combined organic extract was washed with saturated races is a thief NaCl (3× ) and dried over Na2SO4. The oily crude product obtained after removal of solvent, rubbed with a mixture of diethyl ether/ethyl acetate (1+1) and semi-solid residue was purified column chromatography (RP-18, MeOH). TPL 171°C.

IR (KBr): 1228 (C-F), 1019 cm-1(S=O).

1H-NMR (CD3OD): δ (ppm)to 2.67 (s, 3H, CH3), 4,37 (s, 2H, CH2), 7,13-7,21 (m, 2H, 4-F-Ph), 7,37-7,58 (m, 8H, 4-Pyr, 4-F-Ph and 3-MeS(O)-Ph), 8,40-8,43 (m, 2H, 4-Pyr).

Example 18

2-[5-(4-Forfinal)-4-pyridin-4-yl-1H-imidazol-2-ylsulphonyl]phenol (18a)

Using the General method (23 hours, room temperature) specified in the title compound was obtained from1A(0.20 g; 0.7 mmol) and 2-hydroxymethylene (0.10 g; 0.8 mmol) after trituration with EtOH. TPL 200°C (decomposition).

IR (ATR): 1266 (HE bend), 1222 (C-F), 1005 (C-O)

1H-NMR (DMSO-d6): δ (ppm)4,37 (s, 2H, CH2), 6,70-6,85 (m, 2H, 2-HO-Ph), 7,05-7,14 (m, 1H, 2-HO-Ph), 7.23 percent-7,53 (m, 7H, 4-Pyr, 4-F-Ph 2-HO-Ph), 8,46-8,49 (m, 2H, 4-Pyr), 9,95 (users, 1H, exchangeable, OH), 12,81(users, 1H, exchangeable, NH).

3-[5-(4-Forfinal)-4-pyridin-4-yl-1H-imidazol-2-ylsulphonyl]phenol (18b)

Using the General method (9 hours, heated at the boil under reflux) specified in the title compound was obtained from1A(0.20 g; 0.7 mmol) and 3-hydroxymethylene (0.10 g; 0.8 mmol) after purification column chromatography (SiO260, CH2 Cl2/EtOH 9+1)

TPL 230°

IR (ATR): 1287 (HE bend), 1241 (C-F), 1007 cm-1(C-O)

1H-NMR (DMSO-d6): δ (ppm)4,34 (s, 2H, CH2), of 6.65 (DD, 1H, 1,4/8,0 Hz, 3-HO-Ph C4-H), 6,79-PC 6.82 (m, 2H, 3-HO-Ph C2-A/C6-H), 7,07-to 7.15 (m, 1H, 3-HO-Ph C5-H), 7,27-7,53 (m, 6H, 4-Pyr and 4-F-Ph), to 9.45 (s, 1H, exchangeable, OH), 12,83(users, 1H, exchangeable, NH).

4-[5-(4-Forfinal)-4-pyridin-4-yl-1H-imidazol-2-ylsulphonyl]phenol (18c)

Using the General method (14 hours, room temperature) specified in the title compound was obtained from1A(0.20 g; 0.7 mmol) and 3-hydroxymethylene (0.10 g; 0.8 mmol) after purification column chromatography (SiO260, CH2Cl2/EtOH 9+1)

TPL 250°C (decomposition)

IR (ATR): 1271 (HE bend), 1232 (C-F), 1004 cm-1(C-O)

1H-NMR (DMSO-d6): δ (ppm)4,32 (s, 2H, CH2), 6,69 (d, 2H, 7.5 Hz, 4-HO-Ph), 7,19 (d, 2H, 7.9 Hz, 4-HO-Ph), 7,27-7,51 (m, 6H, 4-Pyr and 4-F-Ph), 8,43 are 8.53 (m, 2H, 4-Pyr), 9,41 (s, 1H, exchangeable, OH), 12,79(users, 1H, exchangeable, NH).

2-[5-(4-Forfinal)-4-pyridin-4-yl-1H-imidazol-2-ylsulphonyl]-4-methylsulfinylphenyl (18d)

Using the General method (1 hour, room temperature) specified in the title compound was obtained from1A(0.50 g; 2.9 mmol) and8A(0.50 g; 2.9 mmol) after trituration with Meon. TPL 243°

IR (KBr): 1275 (HE bend), 1230 (C-F), 1005 cm-1(C-O)

1H-NMR (DMF-d7): δ (ppm) of 2.36 (s, 3H, CH3), to 4.46 (s, 2H, CH2), of 6.90 (d, 1H, 8,4 Hz, 2-HO-Ph C3(H)7,13 (DD, 1H, 2,3/8,3 Hz, 2-HO-Ph C4-H), 7,27-7,35 (m, 3H, 4-F-Ph 2-HO-Ph C6(H)7,51-7,53 (m, 2H, 4-Pyr), 7,58-the 7.65 (m, 2H, 4-F-Ph), charged 8.52-8,55 (m, 2H, 4-Pyr), 10,30-10,70 (users, 1H, exchangeable, NH), IT is not visible.

4-Chloro-2-[5-(4-forfinal)-4-pyridin-4-yl-1H-imidazol-2-ylsulphonyl]-6-methylsulfinylphenyl (18E)

Using the General method (1.5 hours, 75° (C) specified in the title compound was obtained from1A(0,80 g; 3.0 mmol) and8b(0,60 g; 3.0 mmol) after trituration with Meon. TPL 220°C (decomposition)

IR (KBr): 1259 (HE bend), 1225 (C-F), 1007 cm-1(C-O)

1H-NMR (DMSO-d6): δ (ppm)of 2.34 (s, 3H, CH3), to 4.38 (s, 2H, CH2), 6,97 (d, 1H, 2,3 Hz, 3-Cl-Ph C2-H), 7,17 (d, 1H, 2,3 Hz, 3-Cl-Ph C4-H), 7.23 percent-7,51 (m, 6H, 4-Pyr and 4-F-Ph), 8,48-of 8.50 (m, 2H, 4-Pyr), 12,74 (users, 1H, exchangeable, NH), IT is not visible.

4-[5-(4-Forfinal)-4-pyridin-4-yl-1H-imidazol-2-ylsulphonyl]-4-methylsulfinylphenyl (18f)

Using the General method (2 hours, room temperature) specified in the title compound was obtained from1A(0.20 g; 0.7 mmol) and8s(0.14 g; 0.8 mmol) after trituration with Meon. TPL 230°C (decomposition)

IR (KBr): 1227 (C-F), 1019 cm-1(C-O)

1H-NMR (CD3OD): δ (ppm)of 2.21 (s, 3H, CH3), to 4.17 (s, 2H, CH2), 6,69 (d, 1H, 8.0 Hz, 4-HO-Ph C3-H), 6.90 to-7,01 (m, 2H, 4-HO-Ph C2-A/C6-H), 7,12-7,21 (m, 2H, 4-F-Ph), 7,32-7,53 (m, 4H, 4-Pyr and 4-F-Ph), 8,39-8,43 (m, 2H, 4-Pyr)

2-[5-(4-Forfinal)-4-pyridin-4-yl-1H-imidazol-2-ylsulphonyl]-4-methanesulfonate (18g)

Using the General method (1 hour, room temperature) specified in the title compound was obtained from1A(0.27 g; 1.0 mmol) and8A(0.17 g; 1.0 mmol) with a solution of N2About235%concentration after recrystallization from a mixture of toluene/THF (1+1). TPL 216°

IR (KBr): 1278 (HE bend), 1232 (C-F), 1031 (S=O), 1003 cm-1(C-O)

1H-NMR (CD3OD): δ (ppm)2,60 (s, 3H, CH3), to 4.33 (s, 2H, CH2), of 6.96 (d, 1H, 8.2 Hz, 2-HO-Ph C3-H), 7,11-7,21 (m, 2H, 4-F-Ph), 7,41-7,47 (m, 6H, 4-Pyr, 4-F-Ph 2-HO-Ph C4-A/C6(H)8,39-8,42 (m, 2H, 4-Pyr).

4-Chloro-2-[5-(4-forfinal)-4-pyridin-4-yl-1H-imidazol-2-ylsulphonyl]-6-methanesulfonamido (18h)

Using the General method (1.5 hours, 75° (C) specified in the title compound was obtained from1A(0.27 g; 1.0 mmol) and8b(0.21 g; 1.0 mmol) with a solution of N2About235%concentration after purification column chromatography (SiO260, acetone). TPL 175°C (decomposition)

IR (KBr): 1265 (HE bend), 1236 (C-F), 1051 (S=O), 1005 cm-1(C-O)

1H-NMR (CD3OD): δ (ppm)of 2.72 (s, 3H, CH3), 4,39 (s, 2H, CH2), 7,14-of 7.23 (m, 2H, 4-F-Ph), 7,39 (d, 1H, 2.6 Hz, 3-Cl-Ph C2-H), 7,42-7,49 (m, 6H, 4-Pyr, 4-F-Ph 3-Cl-Ph C4(H)8,43-8,46 (m, 2H, 4-Pyr).

Example 19

4-[5-(4-Forfinal)-4-pyridin-4-yl-1H-imidazol-2-ylsulphonyl the Teal]-2-methansulfonate ( 19)

Using the General method (2.5 hours, room temperature) specified in the title compound was obtained from1A(0.27 g; 1.0 mmol) and8s(0.14 g; 0.8 mmol) with a solution of N2About235%concentration after trituration with acetone.

TPL 185°C (decomposition)

IR (KBr): 1296 (HE bend), 1230 (C-F), 1062 (S=O), 1013 cm-1(C-O)

1H-NMR (CD3OD): δ (ppm)2,70 (s, 3H, CH3), 4,28 (s, 2H, CH2), is 6.78 (d, 1H, 8,3 Hz, 4-HO-Ph C3-H), 7,12-7,21 (m, 2H, 4-F-Ph), 7,28 (DD, 1H, 2,2/8,3 Hz, 4-HO-Ph C2-H), 7,39-7,46 (m, 5H, 4-Pyr, 4-F-Ph and 4-HO-Ph C6(H)to 8.40 (m, 2H, 4-Pyr).

Example 20

4-Fluoro-N-methoxy-N-methylbenzamide (20)

A suspension of 4-fermenting acid (20 g, 143 mmol) in chloride tionale (130 g; 1.1 mol) was stirred at the boil under reflux for 6 hours; intensive gas development, a clear solution after about 10 minutes, deepening the color from yellow to orange. Excess chloride tiomila was removed by distillation (first atmospheric pressure/40°With, then diaphragm vacuum pump/40°). Distillation of the residue 4-perbenzoate drove away with the use of membrane vacuum pump at 90°With over a short column. The reaction product crystallized during storage in the refrigerator (n20D1,5315; TPL 9°s; output 20g/89%). Fresh air triethylamine (29 ml) was added to a suspension hydroch oride N,O-dimethylhydroxylamine (9.0 g; 92 mmol) in CH2Cl2(75 ml). The reaction mixture was stirred at room temperature for 2 hours and then cooled to -10°C. When cooled to the initial loading for 6 minutes, was added dropwise 4-perbenzoate (13.5 g; 85 mmol). Upon completion of addition, the cooling was removed and the reaction mixture was stirred at room temperature for 1.5 hours. Light brown suspension was poured into H2O (100 ml). The organic phase was removed and the aqueous phase was extracted with diethyl ether (2×). The combined extract was washed with saturated solution of NaCl, dried over Na2SO4and concentrated. The oily brown residue crystallized upon cooling and rubbing. The crude product was dried using an oil pump (residual triethylamine) and was introduced in the reaction without additional purification.

1H-NMR (CDCl3): δ (ppm)3,37 (s, 3H, NCH3), of 3.54 (s, 3H, OCH3),? 7.04 baby mortality-7,13 (m, 2H, 4-F-Ph), 7,71 for 7.78 (m, 2H, 4-F-Ph).

Example 21

2-(2-Chloropyridin-4-yl)-1-(4-forfinal)alanon (21A)

In dvuhgolosy flask dried by heating and purging with argon, was added dropwise n-BuLi (solution 15%concentration in n-hexane, 45 ml, 104 mmol) cooled to -85°With the solution Diisopropylamine (15 ml, 106 mmol) in absdf (150 ml), the temperature was raised to -50°C. At the end D. is bauleni light yellow solution was stirred at -85° C for 55 min At -85°With the original mixture was added a solution of 2-chloro-4-methylpyridine (2-chloro-γ-picoline, 8.6 g; 68 mmol) in abs. THF (75 ml); the temperature was raised to -50°With original color changed to purple. Upon completion of addition, the reaction mixture was stirred at -85°C for 1 hour and for 3 minutes at this temperature was added a solution of20(12.4 g; 68 mmol) in abs. THF (75 ml); the temperature was raised to -60°C. the Reaction mixture representing a purple suspension was stirred at -85°C for 1 hour and then, within 1 hour, heated to 0°C. the Mixture was poured into saturated NaCl (300 ml), on top of which was in ethyl acetate (300 ml). The organic phase was removed and the aqueous phase was extracted with ethyl acetate (2×250 ml), with light yellow foamy residue of 1,3-bis-(2-chloropyridin-4-yl)-2-(4-forfinal)propan-2-ol was separated at the phase boundary. The combined organic extract was washed with saturated solution of NaCl, dried over Na2SO4and concentrated. The oily residue was placed in a small amount of tert-butyl methyl ether and kept at 4°With during the night. The crystals were filtered off and dried.

1H-NMR (CDCl3): δ (ppm)4.26 deaths (s, 2H, CH2), 7,11-7,26 (m, 4H, C3-A/C5-H 2-Cl-Pyr and 4-F-Ph), 7,99-of 8.06 (m, 2H, 4-F-Ph), 8,35 (DD, 1H, 0,6/5,1 Hz, C6/sup> -H 2-Cl-Pyr).

1-(4-Forfinal)-2-(2-herperidin-4-yl)alanon (21b)

21bwas obtained from 2-fluoro-4-methylpyridine (13,9 g; 125 mmol) using the method described for the synthesis of21A.

1H-NMR (CDCl3): δ (ppm)4,32 (s, 2H, CH2), 6,85-6,86 (m, 1H, C3-H 2-F-Pyr), 7,08-7,19 (m, 3H, C5-H 2-F-Pyr and 4-F-Ph), 8,00-8,07 (m, 2H, 4-F-Ph), 8,18 (d, 1H, 5.1 Hz, C6-H 2-F-Pyr).

2-(2-Bromopyridin-4-yl)-1-(4-forfinal)alanon (21c)

Swas obtained from 2-bromo-4-methylpyridine (9.6 g; 56 mmol) using the method described for the synthesis of21A.

1H-NMR (CDCl3): δ (ppm)of 4.35 (s, 2H, CH2), 7,17-7,37 (m, 3H, 2-Br-Pyr and 4-F-Ph), to 7.50 (s, 1H, C3-H 2-Br-Pyr), 8.07-a of 8.15 (m, 2H, 4-F-Ph), 8,42 (d, 1H, 5.1 Hz, C6-H 2-Br-Pyr).

Example 22

1-(2-Chloropyridin-4-yl)-2-(4-forfinal)ethane-1,2-dione-1-oxime (22A)

Under stirring and cooling in a water bath (about 10° (C) a solution of NaNO2(0,85 g; 12.3 mmol) in N2About (10 ml) was added dropwise over 2.5 minutes to a solution of21A(3.0 g; 12 mmol) in glacial acetic acid. Upon completion of addition, the reaction mixture was stirred at room temperature for 0.5 hours, was added N2O (60 ml) and stirring at room temperature was continued for 3 hours. Light beige precipitate was filtered, washed with water and dried under reduced pressure over CaCl2.

1H-NMR (DMSO-d6): δ (ppm) 7,34-7,52 (m, 4H, C3-A/C5-H 2-Cl-Pyr and 4-F-Ph), to 7.93-of 8.00 (m, 2H, 4-F-Ph), of 8.47 (d, 1H, 5,2 Hz, C6-H 2-Cl-Pyr), 12,71 (users, 1H, exchangeable, OH).

1-(2-Herperidin-4-yl)-2-(4-forfinal)ethane-1,2-dione-1-oxime (22b)

22breceived from21b(10.0 g; 43 mmol) using the method described for the synthesis of22A.

1H-NMR (DMSO-d6): δ (ppm)7,19-7,20 (m, 1H, C3-H 2-F-Pyr), 7,35-7,47 (m, 3H, C5-H 2-F-Pyr and 4-F-Ph), to $ 7.91-7,98 (m, 2H, 4-F-Ph), 8,29 (d, 1H, 5.3 Hz, C6-H 2-F-Pyr), 12,69 (users, 1H, exchangeable, OH).

1-(4-Forfinal)-2-(2-isopropoxypyridine-4-yl)-2)ethane-1,2-dione-1-oxime (22p)

Solution22b(200 mg; from 0.76 mmol) in a saturated HCl in isopropanol (15 ml) was stirred at the boil under reflux for 2.5 hours. The solution was concentrated and yellowish-white residue triturated with a small amount of ethanol, filtered and dried.

1H-NMR (DMSO-d6): δ (ppm)to 1.24 (d, 6H, 6.2 Hz, 2×CH3), 5,15 at 5.27 (m, 1H, Metin-H), is 6.54 (s, 1H, C3-H 2-ISO-O-Pyr), was 7.08 (DD, 1H, 1,2/a 5.3 Hz, C5-H 2-ISO-O-Pyr), was 7.36-7,49 (m, 2H, 4-F-Ph), 7,88-of 7.97 (m, 2H, 4-F-Ph), 8,19 (d, 1H, 5.4 Hz, C6-H 2-ISO-O-Pyr), to 12.44 (users, 1H, exchangeable, OH).

1-(2-Bromopyridin-4-yl)-2-(4-forfinal)ethane-1,2-dione-1-oxime (22d)

22dreceived fromS(5.0 g; 17 mmol) using the method described for the synthesis of22A.

1H-NMR (DMSO-d6): δ (ppm)7,40-of 7.48 (m, 3H, C3-H 2-Br-Pyr and 4-F-Ph), the 7.65 (d, 1H, 0.8 Hz, C5H 2-Br-Pyr), 7,93 shed 8.01 (m, 2H, 4-F-Ph), to 8.45 (d, 1H, 5,2 Hz, C6-H 2-Br-Pyr), 12,72 (users, 1H, exchangeable, OH).

Example 23

Hydrochloride of 2-amino-2-(2-chloropyridin-4-yl)-1-(4-forfinal)ethanone (23a)

With gentle heating22A(1.5 g; to 45.4 mmol) was dissolved in methanol (15 ml). The solution was cooled to room temperature, was added HCl-containing methanol and the mixture was transferred into dvuhgolosy flask. Was injected into the flask with an initial mixture of 10% Pd-C (15 mg). The reaction flask was evacuated using an oil pump, and then typed N2through capillary for gas inlet (4×). At room temperature the suspension was shaken in a closed three-neck flask in an atmosphere of H2(240 beats per minute) up until the starting material had not ceased to be detected according to thin-layer chromatography (6 hours). The suspension was filtered and the catalyst washed with a large quantity of methanol. The combined filtrate was concentrated and the solid amorphous residue mustard dried using an oil pump. The crude product was used without further purification in the next reaction stage.

1H-NMR (DMSO-d6): δ (ppm)6,53 (users, 1H, Metin-N), 7,35-7,45 (m, 2H, 4-F-Ph), to 7.59 (DD, 1H, 1,5/5,2 Hz, With5-H, 2-Cl-Pyr), a 7.85 (d, 1H, 0.9 Hz, With3-H, 2-Cl-Pyr), 8,17-of 8.25 (m, 2H, 4-F-Ph), 8,49 (d, 1H, 4,9 Hz, With6-H, 2-Cl-Pyr), was 9.33 (users, 3H, exchangeable, NH3Ȋ +).

Hydrochloride of 2-amino-2-(2-herperidin-4-yl)-1-(4-forfinal)ethanone (23b)

With gentle heating 22b(5.0 g; 19 mmol) was dissolved in HCl-containing isopropanol (IsOH/IsOH, saturated HCl, 1+1, 60 ml). The yellowish solution was cooled to room temperature and transferred in dvuhgolosy flask (100 ml). The reaction flask was evacuated using an oil pump, and then typed N2through capillary for gas inlet (4×). At room temperature the suspension was shaken in a closed three-neck flask in an atmosphere of H2(240 beats per minute) up until the starting material had not ceased to be detected according to thin-layer chromatography (6.5 hours). The catalyst was filtered. The residue after filtration was washed by a large amount of methanol (about 800 ml). The combined filtrates were concentrated and the solid amorphous residue was dried on an oil pump. The crude product was used without further purification in the next reaction stage.

1H-NMR (DMSO-d6): δ (ppm)6,58 (users, 1H, Metin-N), 7,33-7,41 (m, 2H, 4-F-Ph), 7,54 (m, 2H, C3-A/C5-H 2-F-Pyr), 8,14-of 8.25 (m, 2H, 4-F-Ph), 8,30 (d, 1H, 5.5 Hz, C6-H 2-F-Pyr),9,40 (users, 3H, exchangeable, NH3+).

Hydrochloride of 2-amino-1-(4-forfinal)-2-(2-isopropoxypyridine-4-yl)ethanone (23C)

23Creceived from22p(2.0 g; 7.6 mmol) and the use of the method, described for the synthesis of23a.

1H-NMR (DMSO-d6): δ (ppm)of 1.23 (d, 6N, 5,6 Hz, 2×CH3), 5,09 with 5.22 (m, 1H, Metin-H, CH(CH3)2), 6,38-6,41 (users, 1H, Metin-N, CH-NH3+), 7,00-was 7.08 (m, 2H, 2-ISO-O-Pyr), 7,33-7,46 (m, 2H, 4-f-Ph), 8,14-8,23 (m, 3H, 2-ISO-O-Pyr and 4-F-Ph), of 9.21 (users, 3H, exchangeable, NH3+).

Hydrochloride of 2-amino-1-(4-forfinal)-2-(2-methoxypyridine-4-yl)ethanone (23d)

23dobtained when processing the22b(7.5 g; 29 mmol) under the conditions described for the synthesis of23a.

1H-NMR (DMSO-d6): δ (ppm)a 3.83 (s, 3H, CH3), 6,44 (users, 1H, Metin-N), 7,13-7,16 (m, 2H, C3-A/C5-H 2-MeO-Pyr), 7,34-7,46 (m, 2H, 4-F-Ph), 8,16 is 8.25 (m, 3H, C6-H 2-MeO-Pyr and 4-F-Ph), 9,29 (users, 3H, exchangeable, NH3+).

Hydrochloride of 2-amino-1-(4-forfinal)-2-pyridine-4-ratanana (23rd)

23rdobtained when processing the22p(4.0 g; 12.4 mmol) under the conditions described for the synthesis of23b.

1H-NMR (DMSO-d6): δ (ppm)6,78 (users, 1H, Metin-N), 7,32-7,38 (m, 2H, 4-F-Ph), 8.07-a 8,13 (m, 2H, 4-Pyr), 8,17-of 8.27 (m, 2H, 4-F-Ph), 8,92-8,95 (m, 2H, 4-Pyr),9,43 (users, 3H, exchangeable, NH3+).

Hydrochloride of 2-amino-2-(2-bromopyridin-4-yl)-1-(4-forfinal)ethanone (23f)

Solution22d(1.8 g; 5.6 mmol) in absolute ethanol (30 ml) was cooled to -10°and was added concentrated sulfuric acid (1.3 ml). When cooled to the initial mixture was added is gradually zinc dust (1.1 g). The reaction mixture was stirred at -10°C for 30 minutes and then heated to room temperature. Gray-green suspension was filtered and the white balance (ZnSO4) were washed in a large amount of ethanol. United yellow filtrate was concentrated and the solid yellow residue was dried using an oil pump.

1H-NMR (DMSO-d6): δ (ppm)6,39 (users, 1H, Metin-N), 7,35-7,44 (m, 2H, 4-F-Ph), 7,56 (DD, 1H, 1,4/5,1 Hz, C5-H 2-Br-Pyr), to $ 7.91 (s, 1H, C3-H2-Br-Pyr), 8,12-8,19 (m, 2H, 4-F-Ph), 8,46 (d, 1H, 5.1 Hz, C6-H2-Br-Pyr),8,94 (users, 3H, exchangeable, NH3+).

Example 24

4-(2-Chloropyridin-4-yl)-5-(4-forfinal)-1,3-dihydroimidazole-2-tion (24A)

With gentle heating23a(2.9 g; approximately 9.6 mmol) was dissolved in absolute DMF (75 ml). In a clear orange-red solution was injected into the potassium thiocyanate (1.9 grams; and 19.6 mmol), was immediately observed opalescence and color became lighter. The reaction mixture was stirred at the boil under reflux for 1.5 hours. The suspension was cooled to room temperature and during cooling of H2About was diluted dropwise N2About (140 ml). The yellow precipitate was filtered, washed with N2O and dried under reduced pressure over CaCl2.

1H-NMR (DMSO-d6): δ (ppm)7,12-7,52 (m, 6H, C3-A/C5-H 2-Cl-Pyr and 4-F-Ph), and 8.7 (d, 1H, 5,2 Hz, C6-H 2-Cl-Pyr), 12,82 (users, 2H, exchangeable, 2×NH).

4-(4-Forfinal)-5-(2-herperidin-4-yl)-1,3-dihydroimidazole-2-tion (24b)

24breceived from23b(6,1 g; 20 mmol) using the method described for the synthesis of24A.

1H-NMR (DMSO-d6): δ (ppm)7,12-7,16 (m, 2H, C3-A/C5-H 2-F-Pyr), 7,28-7,27 (m, 2H, 4-F-Ph), 7,46-of 7.55 (m, 2H, 4-F-Ph), 8,13 (d, 1H, 5.1 Hz, C6-H 2-F-Pyr),12,85 (users, 2H, exchangeable, 2×NH).

4-(4-Forfinal)-5-(2-isopropoxypyridine-4-yl)-1,3-dihydroimidazole-2-tion (24C)

24Creceived from23C(2.5 g; 7.6 mmol) using the method described for the synthesis of24A.

1H-NMR (DMSO-d6): δ (ppm)to 1.24 (d, 6H, 6.2 Hz, 2×CH3), 5,10-5,19 (m, 1H, Metin-H), 6,69-6,76 (m, 2H, 2-ISO-O-Pyr), 7,24-to 7.32 (m, 2H, 4-F-Ph), 7,42-7,49 (m, 2H, 4-F-Ph), 8,02 (d, 1H, 5.5 Hz, C6-H 2-ISO-O-Pyr), 12,68 (users, 2H, exchangeable, 2×NH).

4-(4-Forfinal)-5-(2-methoxypyridine-4-yl)-1,3-dihydroimidazole-2-tion (24d)

The potassium thiocyanate (2 g, of 20.6 mmol) was injected into the solution23d(3.2 g; the 10.8 mmol) in hydrochloric acid 10%concentration (50 ml). The reaction mixture was stirred at the boil under reflux for 30 minutes. The orange solution was cooled and neutralized using a solution of NaHCO310%concentration. The precipitate was filtered off, washed with N2O and dried under reduced pressure over CaCl2. The crude product is to grow the Ali with ethanol and insoluble components were filtered off. When storing24dprecipitated from ethanol filtrate.

1H-NMR (DMSO-d6): δ (ppm)3,81 (s, 3H, OCH3), 6,79-PC 6.82 (m, 2H, C3-A/C5-H2-MeO-Pyr), 7,26-to 7.50 (m, 4H, 4-F-Ph), of 8.06 (d, 1H, 5.3 Hz, C6-H 2-MeO-Pyr), 12,65 (users, 2H, exchangeable, 2×NH).

Example 25

2-Chloro-4-[5-(4-forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine (25A)

Using the General method As specified in the title compound was obtained from24A(0.5 g, 1.6 mmol) and iodotope bromide (0.35 g; 2.5 mmol) after reaction for 12 hours, and the purification column chromatography (Al2O3CH2Cl2/ethyl acetate 1+1). TPL 236°C.

IR (ATR): 3126, 3057, 2929, 1591, 1529, 1499, 1389, 1231 (C-F), 1159, 996, 976, 844, 780 cm-1.

1H-NMR (DMSO-d6): δ (ppm)2,62 (s, 1H, CH3), 7,27 was 7.36 (m, 3H, 2-Cl-Pyr and 4-F-Ph), 7,45-of 7.55 (m, 3H, 2-Cl-Pyr and 4-F-Ph), 8,24 (d, 1H, 5.1 Hz, C6-H 2-Cl-Pyr), 12,85(users, 1H, exchangeable, NH).

2-Fluoro-4-[5-(4-forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine (25b)

Using the General method As specified in the title compound was obtained from24b(1.4 g; 9.9 mmol) and iodotope bromide (1.4 g; 9.9 mmol) after conducting the reaction for 40 hours. The crude product is boiled with a mixture of CH2Cl2/ethyl acetate (1+1). The combined organic extract was decolorized using Al2O3and received after concentrated the I of the filtrate the residue is triturated with a small amount of EtOH. TPL 224°C.

IR (ATR): 3073, 1609, 1497, 1421, 1234 (C-F), 1159, 1002, 883, 851, 833, 815 cm-1.

1H-NMR (DMSO-d6): δ (ppm)2,62 (s, 3H, CH3), was 7.08 (s, 1H, C3-H 2-F-Pyr), 7,26-7,35 (m, 3H, C5-H 2-F-Pyr and 4-F-Ph), 7,46-rate of 7.54 (m, 2H, 4-F-Ph), 8,08 (d, 1H, 5.3 Hz, C6-H 2-F-Pyr), 12,85(users, 1H, exchangeable, NH).

4-[5-(4-Forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]-2-isopropoxypyridine (25s)

NaH (55-65%; 1.0 g; approximately 23 mmol) was injected into the solution24C(4.0 g; of 13.8 mmol) in absolute THF (60 ml). This initial mixture was stirred at room temperature for 5 minutes and was added dropwise a solution of iodotope bromide (2.2 g; 17.3 mmol) in absolute THF (5 ml) under cooling H2O. the Reaction mixture was stirred at room temperature for 1 hour. Transparent brown solution was concentrated and the residue was placed in N2O. the Aqueous solution was neutralized with hydrochloric acid 10%concentration and was extracted with ethyl acetate (2×). The combined organic extract was washed with saturated solution of NaCl, dried over Na2SO4and concentrated. Semi-solid residue was extracted with boiling tert-butylmethylamine ether (2×) and filtered. Transparent ethereal filtrate was concentrated and the solid residue triturated with a small amount of tert-butyl methyl ether, filtered and dried. Additional kolichestvennogo product was obtained by separation of the mother liquor column chromatography (SiO 260, CH2Cl2/ethyl acetate 1+1). TPL 141°C.

IR (ATR): 2928, 1610, 1544, 1509, 1412, 1314, 1222 (C-F), 1104, 1005, 954, 865, 843, 816 cm-1.

1H-NMR (DMSO-d6): δ (ppm)of 1.28 (d, 6H, 6,1 Hz, 2×CH3), 2,63 (s, 3H, SCH3), 5,08-5,14 (m, 1H, Metin-H)6,76 (s, 1H, C3-H 2-ISO-O-Pyr), to 6.88 (DD, 1H, 1,4/a 5.4 Hz, C5-H 2-ISO-O-Pyr), 7,10-7,19 (m, 2H, 4-F-Ph), 7,40-7,47 (m, 2H, 4-F-Ph), 7,95 (DD, 1H, 0,7/a 5.4 Hz, C6-H 2-ISO-O-Pyr).

4-[5-(4-Forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]-2-methoxypyridine (25d)

Solution24d(1.0 g; 3.3 mmol) and iodotope bromide (5.6 g; 39 mmol) in methanol (50 ml) was stirred at the boil under reflux for 3 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated and the residue was placed in ethanol. Insoluble components were filtered off and the filtrate was concentrated. The residue was placed in CH2Cl2/EtOH (9+1). Insoluble components were filtered off and the filtrate was divided by column chromatography (SiO260, CH2Cl2/EtOH, 9+1). TPL 158°C.

IR (ATR): 1618, 1608, 1497, 1391, 1222 (C-F), 1212, 1036, 835, 825 cm-1.

1H-NMR (DMSO-d6): δ (ppm)to 2.67 (s, 3H, SCH3), 3,90 (s, 3H, OCH3), 6,87-6,89 (m, 1H, C3-H 2-MeO-Pyr), 6,98 (DD, 1H, 1,5/5,5 Hz, C5-H2-MeO-Pyr), 7,16-7,24 (m, 2H, 4-F-Ph), 7,46-7,53 (m, 2H, 4-F-Ph), 8,03 (DD, 1H, 0,7/5,5 Hz, C6-H 2-MeO-Pyr).

4-[5-(4-Forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]-1H-pyridine-2-he (25th)

When processing23d(8.8 g;31 mmol) of potassium thiocyanate in boiling DMF same way, described for24A,25th,was obtained as the sole product of the reaction. TPL 314°C (decomposition). After cyclization, leading to 1,3-dihydroimidazole, a methyl group from metaxylene Deputy goes to the nucleophilic sulfur atom thione with education, first, 2-methylsulfanyl-3H-imidazole and, secondly, 2-hydroxypyridine/1H-pyridine-2-it.

IR (ATR): 1634 (pyridone (I), 1610, 1557 (pyridone (II), 1493, 1220 (C-F), 968, 837, 800 cm-1.

1H-NMR (DMSO-d6): δ (ppm)2,61 (c, 3H, SCH3), 6,16 (users, 1H,3Mr. pyridone), 6,34 (s, 1H, WITH5Mr. pyridone), 7,25-7,33 (m, 3H),6-pyridone and 4-F-Ph), 7,46-7,53 (m, 2H, 4-F-Ph), 11,38(users, 1H, exchanged, pyridone-NH), 12,71 (users, 1H, exchanged, imidazole-NH).

Benzyl-{4-[5-(4-forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine-2-yl}amine (25f)

Using the General method mentioned in the title compound was obtained from25b(0.2 g, 0.7 mmol) and benzylamine (0.8 g; 7.5 mmol) after carrying out the reaction for 5 hours at a temperature of 160°and separating column chromatography (Al2O3CH2Cl2/ethyl acetate 1+1). TPL 152°C (decomposition).

IR (ATR): 3234 (NH), 3006, 2916, 1601, 1583, 1501, 1451, 1432, 1353, 1225 (C-F), 1074, 844, 813, 729, 695 cm-1.

H-NMR (CD3OD): δ (ppm) at 2.59 (s, 3H, CH3), 4,37 (s, 2H, CH2), 6,56-6,59 (m, 2H, C3-A/C5-H 2-amino-Pyr),? 7.04 baby mortality-7,44 (m, 9H, Ph and 4-F-Ph), 7,83 (d, 1H, 5.6 G is, C6-H 2-amino-Pyr).

{4-[5-(4-Forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine-2-yl}-(4-methoxybenzyl)Amin (25g)

Using the General method mentioned in the title compound was obtained from25b(0,44 g; 1.5 mmol) and 4-methoxybenzylamine (2.0 g; 14.6 mmol) after conducting the reaction for 7 hours at a temperature of 160°and separating column chromatography (SiO2CH2Cl2/EtOH 9+1). TPL 207°C.

IR (ATR): 1598, 1558, 1510, 1244, 1217 (C-F), 846, 812 cm-1.

1H-NMR (CD3OD): δ (ppm) 2,61 (s, 3H, SCH3in ), 3.75 (s, 3H, OCH3), 4,30 (s, 2H, CH2), 6,56-6,59 (m, 2H, C3-A/C5-H 2-amino-Pyr), for 6.81-7,30 (m, 6H, 4-MeO-Ph 4-F-Ph), 7,39-7,46 (m, 2H, 4-F-Ph), to 7.84 (d, 1H, 6,0 Hz, C6-H 2-amino-Pyr).

{4-[5-(4-Forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine-2-yl}-(4-methylbenzyl)Amin (25h)

Using the General method mentioned in the title compound was obtained from25b(0.2 g, 0.7 mmol) and 4-methylbenzylamine of 0.85 g; 7.0 mmol) after the reaction for 6 hours at 160°and separating column chromatography (SiO2CH2Cl2/EtOH 9+1). TPL 185°C.

IR (ATR): 1600, 1559, 1502, 1427, 1218 (C-F), 844, 809 cm-1.

1H-NMR (CD3OD): δ (ppm) to 2.29 (s, 3H, CH3), 2,60 (s, 3H, SCH3), 4,32 (s, 2H, CH2), 6,57-6,60 (m, 2H, C3-A/C5-H 2-amino-Pyr), 7,05 is 7.50 (m, 8H, 4-Me-Ph 4-F-Ph), 7,83 (d, 1H, 5.3 Hz, C6-H2-amino-Pyr).

(4-Chlorbenzyl)-{4-[5-(4-forfinal)--methylsulfanyl-3H-imidazol-4-yl]pyridine-2-yl}amine ( 25i)

Using the General method mentioned in the title compound was obtained from25b(0.2 g, 0.7 mmol) and 4-chlorobenzylamino (1.0 g; 7.0 mmol) after conducting the reaction for 5.5 hours at boiling under reflux and separation column chromatography (SiO2CH2Cl2/EtOH 9+1). TPL 195°C.

IR (ATR): 3409, 1597, 1549, 1502, 1489, 1422, 1218 (C-F), 843, 814, 793 cm-1.

H-NMR (CD3OD): δ (ppm) 2,60 (s, 3H, SCH3), to 4.38 (s, 2H, CH2), 6,57-6,60 (m, 2H, C3-A/C5-H 2-amino-Pyr), 7,05-7,14 (m, 2H, 4-F-Ph), 7,22-7,30 (m, 4H, 4-Cl-Ph), 7,38 was 7.45 (m, 2H, 4-F-Ph), 7,83 (d, 1H, 5.7 Hz, C6-H 2-amino-Pyr).

(3,4-Dichlorobenzyl)-{4-[5-(4-forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine-2-yl}amine (25j)

Using the General method mentioned in the title compound was obtained from25b(0.2 g, 0.7 mmol) and 3,4-dichloraniline (1.2 g; 6.8 mmol) after conducting the reaction for a period of 7.5 hours at 160°and separating column chromatography (SiO2CH2Cl2/EtOH 9+1). TPL 212°C.

IR (ATR): 3409, 1600, 1552, 1509, 1490, 1424, 1225 (C-F), 842, 827, 813 cm-1.

1H-NMR (CD3OD): δ (ppm) 2,60 (s, 3H, SCH3), 4,39 (s, 2H, CH2), 6,56-6,62 (m, 2H, C3-A/C5-H 2-amino-Pyr), 7,06 is 7.50 (m, 7H, 3,4-di-Cl-Ph 4-F-Ph), to 7.84 (d, 1H, 5.5 Hz, C6-H 2-amino-Pyr).

{4-[5-(4-Forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine-2-yl}phenylamine (25k)

Using the General method specified in sagola the COC connection received from 25b(0.2 g, 0.7 mmol) and aniline (0.65 g; 7.0 mmol) after the reaction for 6 hours at the boil under reflux and separation column chromatography (SiO2CH2Cl2/EtOH 9+1). TPL 228°C.

IR (ATR): 3031, 1610, 1590, 1561, 1504, 1433, 1265, 1225 (C-F), 839, 827, 749, 695 cm-1.

1H-NMR (DMSO-d6): δ (ppm) 2,62 (s, 3H, CH3), 5,95-6,13 (m, 2H, WITH3-A/C5-H2-amino-Pyr), 6,68-of 7.60 (m, N, Ph 4-F-Ph), 7,97 shed 8.01 (m, 1H,6-N, 2-amino-Pyr), 8,99 (users, 1H, exchanged, aniline-NH), 12,68 (users, 1H, exchanged, imidazole-NH).

{4-[5-(4-Forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine-2-yl}phenethylamine (25l)

Using the General method mentioned in the title compound was obtained from25b(0.2 g, 0.7 mmol) and 2-phenethylamine (0,85 g; 7.0 mmol) after conducting the reaction for 5.5 hours at 160°and separating column chromatography (SiO2CH2Cl2/EtOH 9+1). TPL 99°C.

IR (ATR): 3409, 1604, 1546, 1504, 1220 (C-F), 838, 813, 698 cm-1.

1H-NMR (CD3OD): δ (ppm) 2,61 (s, 3H, SCH3), of 2.81 (t, 2H, 7,7 Hz, NCH2), to 3.41 (t, 2H, 7,7 Hz, CH2Ph), 6,55-to 6.57 (m, 2H, C3-A/C5-H 2-amino-Pyr), 7,08-7,26 (m, 7H, Ph, and 4-F-Ph), 7,42-7,49 (m, 2H, 4-F-Ph), of 7.82 (d, 1H, 6,1 Hz, C6-H 2-amino-Pyr).

(RS)-{4-[5-(4-Forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine-2-yl}-(1-phenylethyl)amine (25m)

Using the General method specified in the header of connection produces and from 25b(0.2 g, 0.7 mmol) and (RS)-1-phenethylamine (0,80 g; 6.6 mmol) after conducting the reaction for 7 hours at 160°and separating column chromatography (SiO2CH2Cl2/EtOH 9+1). TPL 117-119°C.

IR (ATR): 2926, 1607, 1547, 1502, 1434, 1221 (C-F), 1157, 838, 814, 699 cm-1.

1H-NMR (DMSO-d6): δ (ppm) of 1.37 (d, 3H), 5.5 Hz, CH3), 2,58 (s, 3H, SCH3), 4,82-to 5.03 (m, 1H, Metin-N), 6,39-7.74 (m, N, Ph, 2-amino-Pyr and 4-F-Ph), 12,57 (users, 1H, exchangeable, NH).

(R)-{4-[5-(4-Forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine-2-yl}-(1-phenylethyl)amine (25n)

Using the General method mentioned in the title compound was obtained from25b(0.2 g, 0.7 mmol) and (R)-1-phenethylamine (0,80 g; 6.6 mmol) after conducting the reaction for 7 hours at 170°and separating column chromatography (SiO2CH2Cl2/ethyl acetate 1+1). TPL 117-119°C.

IR (ATR): 2926, 1607, 1547, 1502, 1434, 1221 (C-F), 1157, 838, 814, 699 cm-1.

1H-NMR (CD3OD): δ (ppm) of 1.44 (d, 3H, 6.9 Hz, CH3), at 2.59 (s, 3H, SCH3), 4,62-4,69 (m, 1H, Metin-H), 6,47-to 6.57 (m, 2H, C3-A/C5-H2-amino-Pyr), 7,05-7,42 (m, 9H, Ph and 4-F-Ph), 7,80 (d, 1H, 5.5 Hz, C6-H 2-amino-Pyr).

(S)-{4-[5-(4-Forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine-2-yl}-(1-phenylethyl)amine (25 ° )

Using the General method mentioned in the title compound was obtained from25b(0.2 g, 0.7 mmol) and (S)-1-phenethylamine (0,80 g; 6.6 mmol) after re who work for 13 hours at 170° With and separation column chromatography (SiO2CH2Cl2/ethyl acetate 1+1). TPL 117-119°C.

IR (ATR): 2926, 1607, 1547, 1502, 1434, 1221 (C-F), 1157, 838, 814, 699 cm-1.

1H-NMR (CD3OD): δ (ppm) of 1.44 (d, 3H, 6.9 Hz, CH3), at 2.59 (s, 3H, SCH3), 4,62-4,69 (m, 1H, Metin-H), 6,47-to 6.57 (m, 2H, C3-A/C5-H2-amino-Pyr), 7,05-7,42 (m, 9H, Ph and 4-F-Ph), 7,80 (DD, 1H, 0,5/5,5 Hz, C6-H 2-amino-Pyr).

Benzyl-{4-[5-(4-forfinal)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine-2-yl}methylamine (25R)

Using the General method mentioned in the title compound was obtained from25b(0.2 g, 0.7 mmol) and N-methylbenzylamine of 0.85 g; 7.0 mmol) after conducting the reaction for 7 hours at 180°and two divisions column chromatography (SiO2CH2Cl2/ethyl acetate 1+1). TPL 79°C.

IR (ATR): 2924, 1601, 1494, 1407, 1219 (C-F), 837, 810, 730, 696 cm-1.

1H-NMR (CD3OD): δ (ppm) 2,60 (s, 3H, SCH3), of 2.97 (s, 3H, NCH3), with 4.64 (s, 2H, CH2), 6,64 of 6.66 (m, 2H, C3-A/C5-H 2-amino-Pyr), 7,02 was 7.45 (m, 9H, Ph and 4-F-Ph), of 7.96 (d, 1H, 5.0 Hz, C6-H 2-amino-Pyr).

The compounds listed below in table 2, were obtained using the above method

Table 2

{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}naphthalen-2-yl-methylamine
Approx.MethodNameStructure
25q(4-Forfinal)-{4-[5-(4-forfinal)-2-m is tilsley-1H-imidazol-4-yl]pyridine-2-yl}Amin
25r(4-Chlorophenyl)-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
25s{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-m-tolylamino
25tC(2,4-Differenl)-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
25u(2,4-Dichlorophenyl)-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
25v{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-(1-phenylpropyl)Amin
25wC(3,3-Diphenylpropyl)-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
25x{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}naphthalen-1-yl-methylamine
25y

Example 26

4-[2-Benzylmethyl-5-(4-forfinal)-3H-imidazol-4-yl]-2-chloropyridine (26a)

Using the General method As specified in the title compound was obtained from24A(0.3 g; 1.0 mmol) and benzyl chloride (0.12 g; 1.0 mmol) after the reaction for 6 hours and the separation column chromatography (SiO260, CH2Cl2/EtOH 9+1). TPL 223°C.

IR (ATR): 2939, 1591, 1530, 1505, 1233 (C-F), 997, 838, 782, 700 cm-1.

1H-NMR (DMSO-d6): δ (ppm)4,43 (s, 2H, CH2), 7,27-7,47 (m, 11H, 2-Cl-Pyr, Ph 4-F-Ph), compared to 8.26 (d, 1H, 5,2 Hz, C6-H 2-Cl-Pyr), 12,94(users, 1H, exchangeable, NH).

4-[2-Benzylmethyl-5-(4-forfinal)-3H-imidazol-4-yl]-2-herperidin (26b)

Using the General method As specified in the title compound was obtained from24b(5,1 g; 17.6 mmol) and benzyl bromide (9,2 g; 54 mmol) after conducting the reaction for 1.5 hours and the separation column chromatography (Al2O3CH2Cl2/ethyl acetate 1+1). TPL 174°C.

IR (ATR): 3028, 2948, 1611, 1496, 1413, 1228 (C-F), 1203, 1003, 879, 838, 698 cm-1.

1H-NMR (DMSO-d6): δ (ppm)4,43 (s, 2H, CH2), 7,11 (s, 1H, C3-H 2-F-Pyr), 7,25-7,51 (m, 10H, C5-H 2-F-Pyr, Ph 4-F-Ph), 8,10 (d, 1H, 5.3 Hz, C6-H 2-F-Pyr), 12,93(users, 1H, exchange learning the method, NH).

Benzyl-{4-[2-benzylmethyl-5-(4-forfinal)-3H-imidazol-4-yl]pyridine-2-yl}amine (26C)

Using the General method mentioned in the title compound was obtained from26b(0.2 g; of 0.53 mmol) and benzylamine (0,60 g; 5.6 mmol) after the reaction for 6 hours at 180°and separating column chromatography (SiO260, CH2Cl2/ethyl acetate 1+1). TPL 185°C.

IR (ATR): 3407 (NH), 3025, 2855, 2713, 1599, 1550, 1489, 1356, 1220 (C-F), 1155, 840, 814, 693 cm-1.

1H-NMR (CD3OD): δ (ppm) is 4.21 (s, 2H, NCH2), to 4.38 (s, 2H, SCH2), 6,52-6,55 (m, 2H, C3-A/C5-H 2-amino-Pyr), 7,03-7,38 (m, 9H, Ph and 4-F-Ph), 7,83 (d, 1H, 5.7 Hz, C6-H 2-amino-Pyr).

(RS)-{4-[2-Benzylmethyl-5-(4-forfinal)-3H-imidazol-4-yl]pyridine-2-yl}-(1-phenylethyl)amine (26d)

Using the General method mentioned in the title compound was obtained from26b(0.2 g; of 0.53 mmol) and (RS)-1-phenethylamine (0.65 g; 5.4 mmol) after conducting the reaction for 15 hours at 150°and separating column chromatography (SiO260, CH2Cl2/ethyl acetate 1+1). TPL 145°C.

IR (ATR): 3028, 1606, 1546, 1494, 1450, 1221 (C-F), 1157, 837, 813, 697 cm-1.

1H-NMR (CD3OD): δ (ppm) of 1.44 (d, 3H, 6,8 Hz, CH3), 4,22 (s, 2H, CH2), 6,44-is 6.54 (m, 2H, C3-A/C5-H 2-amino-Pyr),? 7.04 baby mortality-to 7.35 (m, 9H, Ph and 4-F-Ph), 7,80 (d, 1H, 5.4 Hz, C6-H 2-amino-Pyr).

{4-[2-Benzylmethyl-5-(4-forfinal)-3H-imidazol-4-yl]pyridine-2-yl}-(4-methoxime the ZIL)Amin ( 26th)

Using the General method mentioned in the title compound was obtained from 26a (0.2 g, 0.5 mmol) and 4-methoxybenzylamine (2.0 g; 14.6 mmol) after conducting the reaction for 22 hours at boiling under reflux and separation column chromatography (Al2O3CH2Cl2/ethyl acetate 1+1). TPL 196-200°C.

IR (ATR): 1605, 1574, 1507, 1245, 1225 (C-F), 843, 814, 698 cm-1.

1H-NMR (DMSO-d6): δ (ppm) 4,29 (s, 2H, isomers "And"+"", NCH2), 4,35 (s, 2H, "A" + "B", SCH2), to 6.43-6,47 (m, 1H "AND" + 2N "IN", WITH5Mr. "A" and C3-/S5Mr. "B", 2-amino-Pyr), of 6.65 (s, 1H "AND"3-H 2-amino-Pyr), 6,80-6,84 (m, 2H "AND"+"", 4-MeO-Ph), 7,14-7,51 (m, 11N "A" + "B", 4-MeO-Ph Ph 4-F-Ph), 7,79 (d, 1H"", 5,4 Hz, With6-N, 2-amino-Pyr), to $ 7.91 (d, 1H,"", 5,4 Hz, With6-N, 2-amino-Pyr), 12,67 (users, 1H, exchanged, imidazole-NH), amino-NH not visible.

4-[2-Benzylmethyl-5-(4-forfinal)-3H-imidazol-4-yl]-2-methoxypyridine (26f)

Suspension25A(0.1 g; 0.25 mmol) in methanol solution NaOCH3(30%, 2 ml) was diluted with methanol (5 ml) and was stirred at the boil under reflux for 13 hours. The reaction mixture was diluted with H2Oh and the aqueous solution was extracted (CH2Cl2) (3×). The combined organic extract was washed with saturated solution of NaCl, dried over Na2SO4and concentrated. The oily residue was purified column is cromatografia (SiO 260, CH2Cl2/ethyl acetate 1+1).

1H-NMR (CDCl3): δ (ppm) 3,91 (s, 3H, OCH3), the 4.29 (s, 2H, CH2), 6,91-to 6.95 (m, 1H, 2-MeO-Pyr), 7,02-7,11 (m, 2H, 4-F-Ph), 7,27-7,38 (m, 7H, Ph, and 4-F-Ph), with 8.05 (d, 1H, 5.4 Hz, C6-H 2-MeO-Pyr), NH not visible.

Example 27

2-Chloro-4-[5-(4-forfinal)-2-(4-methanesulfonylaminoethyl)-3H-imidazol-4-yl]pyridine (27A)

NaH (55-65%; 0.1 g; approximately 2 mmol) was injected into the solution24A(0.31 g; 1.0 mmol) in absolute THF (15 ml). The initial mixture was stirred at room temperature for 5 minutes and was added 4-methylsulfonylbenzoyl (3, 0,19 g; 1.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. Yellow-brown solution was diluted with N2O and neutralized with citric acid 10%concentration. THF was removed and the aqueous solution was extracted with ethyl acetate (2×). The combined organic extract was washed with saturated solution of NaCl (2×), dried over Na2SO4and concentrated. The solid residue was purified column chromatography (SiO260, CH2Cl2/EtOH 9,5+0,5). TPL 179°C.

IR (ATR): 3049, 1592, 1505, 1374, 1224 (C-F), 1086, 1030 (S=O), 1014, 989, 839, 816,781 cm-1(C-Cl).

1H-NMR (DMSO-d6): δ (ppm)a 2.71 (s, 3H, CH3), 4,48 (s, 2H, CH2), 7,25-8,24 (m, 10H, 2-Cl-Pyr, 4-MeS(0)-Ph 4-F-Ph), compared to 8.26 (d, 1H, 5.3 Hz, C6-H 2-Cl-Pyr), 12,94(users, 1H, exchangeable, NH).

2-Fluoro-4-[5-(4-forfinal)-2-(4-means huniversity)-3H-imidazol-4-yl]pyridine ( 27b)

Using the General method As specified in the title compound was obtained from24b(4,2 g; 14.5 mmol) and3(4.1 g; 22 mmol) after carrying out the reaction for 2 hours and the separation column chromatography (1. Al2O3CH2Cl2/ethyl acetate 1+1; 2. SiO260, CH2Cl2/EtOH 9+1). TPL 150°C.

IR (ATR): 3061, 1610, 1506, 1408, 1227 (C-F), 1030 (S=O), 1016, 995, 978, 882, 839, 815 cm-1.

1H-NMR (DMSO-d6): δ (ppm) a 2.71 (s, 3H, CH3), of 4.49 (s, 2H, CH2), 7,10 (s, 1H, C3-H2-F-Pyr), 7,30-7,37 (m, 3H, C5-H 2-F-Pyr and 4-F-Ph), 7,47-to 7.67 (m, 6H, 4-F-Ph and 4-MeS(O)-Ph), 8,11 (d, 1H, 4.8 Hz, C6-H 2-F-Pyr), 12,95(users, 1H, exchangeable, NH).

Benzyl-{4-[5-(4-forfinal)-2-(4-methanesulfonylaminoethyl)-3H-imidazol-4-yl]pyridine-2-yl}amine (27)

Using the General method mentioned in the title compound was obtained from27b(0.3 g; of 0.68 mmol) and benzylamine (0.75 g; 7.0 mmol) after conducting the reaction for 7 hours at 170°and separating column chromatography (SiO260, CH2Cl2/EtOH 19+1). TPL 149°C.

IR (ATR): 3238, 3064, 1600, 1558, 1514, 1495, 1227 (C-F), 1034 (S=O), 1006, 982, 839, 814 cm-1.

1H-NMR (CD3OD): δ (ppm) 2,70 (s, 3H, CH3), is 4.21 (s, 2H, NCH2), 4,32 (s, 2H, SCH2), 6,51-6,55 (m, 2H, C3-A/C5-H 2-amino-Pyr), 7,03-7,42 (m, 13H, Ph, 4-MeS(O)-Ph 4-F-Ph), of 7.82 (d, 1H, 5.5 Hz, C6-H 2-amino-Pyr).

(RS)-{4-[5-(4-forfinal)-2-(4-methanesulfonylaminoethyl)-3H-imide is evil-4-yl]pyridine-2-yl}-(1-phenylethyl)amine ( 27d)

Using the General method mentioned in the title compound was obtained from27b(0.3 g; of 0.68 mmol) and (RS)-1-phenethylamine (0,85 g; 7.0 mmol) after conducting the reaction for 10 hours at 170°and separating column chromatography (SiO260, CH2Cl2/EtOH 9+1). TPL 193°C.

IR (ATR): 2967, 1606, 1547, 1502, 1221 (C-F), 1085, 1031 (S=O), 1014, 838, 814, 670 cm-1.

1H-NMR (CD3OD): δ (ppm) of 1.45 (d, 3H, 6,8 Hz, CH3), to 2.67 (s, 3H, S(O)CH3), 4,28 (s, 2H, CH2), 4,62-to 4.73 (m, 1H, Metin-H), 6.42 per-6,53 (m, 2H, C3-A/C5-H 2-amino-Pyr), 7,09-7,44 (m, 9H, Ph and 4-F-Ph), 8,21 (d, 1H, 5.0 Hz, C6-H 2-F-Pyr).

Compounds obtained by the method presented below in table 3 (but connection # 31 was obtained by the method (D)

Table 3.

Data1H NMR
Example No.R31H-NMR spectrum
Solventδ (ppm)
28DMSO-d6at 2.59 (s, 3H, -SCH3), 4,59 (t, 2H, J=4,74 Hz, >N-CH2-), 6,46-of 6.71 (m, 2H, C3-/C5-H 2-amino-Pyr), 6,91-6,94 (m, 2H, thiophene), 7,07 (t, 1H, exchangeable, J=4,7 Hz, Pyr-NH-), 7,16-of 7.23 (m, 1H, thiophene), 7,28-7,35 (m, 2H, 4-F-Phe), 7,41-to 7.50 (m, 2H, 4-F-Phe), 7,82-of 7.96 (m, 1H, C6-H 2-amino-Pyr), 12,1 (s, 1H, exchanged, imidazole-NH)
29DMSO-d62,60 (s, 3H, -SCH3), to 4.41 (d, 2H, J=5,74 Hz, >N-CH2-), 6,17 (d, 1H, J=3.12 Hz, C3-H furan), 6,34-6,37 (m, 1H, C4-H furan), 6,46-of 6.49 (m, 1H, C5-H 2-amino-Pyr), of 6.65 (s, 1H, C3-H 2-amino-Pyr), to 6.95 (t, 1H, J=6,00 Hz, Pyr-NH-), 7,18-7,27 (m, 2H, 4-F-Phe), 7,44-of 7.55 (m, 3H, C5-H furan and 4-F-Phe), 7,88 (d, 1H, J=4,70 Hz, C6-H 2-amino-Pyr), br12.62 (s, 1H, imidazole-NH)
30DMSO-d61,47-of 1.53 (m, 1H, C3-H tetrahydrofuran), a 1.75-of 1.88 (m, 3H, C3-/C5-H tetrahydrofuran), at 2.59 (s, 3H, -SCH3), 3,20 of 3.28 (m, 2H, >N-CH2-), 3,55-3,61 (m, 1H, C5-H tetrahydrofuran), 3,69 is 3.76 (m, 1H, C5-H tetrahydrofuran), 3,89-3,93 (m, 1H, Metin-H tetrahydrofurfurylamine), 6,39 of 6.68 (m, 3H, C3-/C5-H 2-amino-Pyr and Pyr-NH- (1H exchangeable)), 7,15-7,31 (m, 2H, 4-F-Phe), 7,41-to 7.50 (m, 2H, 4-F-Phe), 7,76-a 7.92 (m, 1H, C6-H 2-amino-Pyr), to 12.58 (s, 1H, exchanged, imidazole-NH)
31CD3ODof 2.6 (s, 3H, -SCH3), of 4.54 (s, 2H, >N-CH2-), 6,60 (d, 2H, J=4,16 Hz, C3-/C5-H 2-amino-Pyr), 7.03 is for 7.12 (m, 2H, 4-F-Phe), 7,27-7,44 (m, 4H, C3-/C5-H 2-(aminomethyl)pyridine and 4-F-Phe), 7,71-7,80 (m, 1H, C4-H 2-(aminomethyl)pyridine), to 7.84 (d, 1H, J=6,04 Hz, C6-H 2-amino-Pyr), 8,43-8,46 (m, 1H, C6-H 2-(aminomethyl)pyridine)
32CD3OD2,60 (s, 3H, -SCH3), 4,48 (s, 2H, >N-CH2-), 6,59-6,62 (m, 2H, C3-/C5-H 2-amino-Pyr), 7,06-7,14 (m, 2H, 4-F-Phe), 7,34 was 7.45 (m, 3H 4-F-Phe and C5-H 3-(aminomethyl)pyridine), 7,73-7, 78 (m, 1H, C4-H 3-(aminomethyl)pyridine), to 7.84 (d, 1H, J=6,18 Hz, C6-H 2-amino-Pyr), of 8.37-to 8.40 (m, 1H, C6-H 3-(aminomethyl)pyridine), 8,44-to 8.45 (m, 1H, C2-H 3-(aminomethyl)pyridine)
33DMSO-d6to 0.78 to 0.92 (m, 2H, cyclohexane), 1,10-1,22 (m, 3H, cyclohexane), 1,42-of 1.45 (m, 1H, Metin-H, cyclohexylethylamine), 1,64 is 1.70 (d, 5H, J=10,49 Hz, cyclohexane), at 2.59 (s, 3H, -SCH3), 2,93-to 3.02 (m, 2H, >N-CH2-), 6,39-6,60 (m, 3H, Sz-/C5-H 2-amino-Pyr and Pyr-NH-, (1H exchangeable)), 7,12-7,31 (m, 2H, 4-F-Phe), 7,40-7,53 (m, 2H, 4-F-Phe), 7,76-to $ 7.91 (m, 1H, C6-H 2-amino-Pyr), 12,60 (s, 1H, exchanged, imidazole-NH)
CD3ODof 0.93 (t, 2H, J=11,05 Hz, cyclohexane), 1,17 of 1.28 (m, 3H, cyclohexane), 1,40-1,49 (m, 1H, Metin-H, cyclohexane), a 1.75 (d, 5H, J=11,47 Hz, cyclohexane), 2,62 (s, 3H, -SCH3), 2,96-to 2.99 (m, 2H, >NH-CH2-), is 6.54 (d, 2H, J=5,10 Hz, C3-/C5-H 2-amino-Pyr), 7,14 (t, 2H, J=8,77 Hz, 4-F-Phe), 7,43-to 7.50 (m, 2H, 4-F-Phe), 7,80 (d, 1H, J=5,52 Hz, C6-H 2-amino-Pyr)
34CD3ODa 1.75-to 1.86 (m, 1H, C3-H 1-aminoindan), 2,45 of $ 2.53 (m, 1H, C3-H 1-aminoindan), 2,61 (s, 3H, -SCH3), 2,82-32,96 (m, 2H, C2-H, 1-aminoindan in), 5.25 (t, 1H, J-7,29 Hz, Metin-H 1-aminoindan), 6,56-6,59 (m, 1H, C5-H 2-amino-Pyr), to 6.67 (s, 1H, C3-H 2-amino-Pyr), 7,07-7,25 (m, 6H, C4/C5/C6/C7-H 1-aminoindan and 4-F-Phe), 7,42-7,49 (m, 2H, 4-F-Phe), 7,84-7,87 (m, 1H, C6-H 2-amino-Pyr)
35CD3OD2,62 (s, 3H, -SCH3), totaling 3.04 (t,2H, J-7,02 Hz, -CH2 - 2-(2-thienyl)ethylamine)), 3,47 (t, 2H, J=? 7.04 baby mortality Hz, >N-CH2 - 2-(2-thienyl)ethylamine)), 6,56-6,59 (m, 2H, C3-/C5-H 2-amino-Pyr), 6,83-6,85 (m, 1H, C3-H, thiophene), 6,89-6,94 (m, 1H, C4-H, thiophene), 7,09-7,20 (m, 3H, 4-F-Phe and C5-H of the thiophene), 7,43-to 7.50 (m, 2H, 4-F-Phe), to 7.84 (d, 1H, J=6,12 Hz, C6-H 2-amino-Pyr)
36CD3ODof 2.58 (s, 3H, -SCH3), 3,00-3,03 (m, 2H, -CH2 - 1,2-diphenylethylamine), to 4.73 (t, 1H, J=7,20 Hz, Metin-H, 1,2-diphenylethylamine), 6,40 (s, 1H, C3-H 2-amino-Pyr), 6,55 (d, 1H, J=5,44 Hz, C5-H 2-amino-Pyr), 7,05-7,40 (m, 14H, 4-F-Phe and Ar-H 1,2-diphenylethylamine), to 7.77 (d, 1H, J=5,44 Hz, C6-H 2-amino-Pyr)

Example 37A

Cyclohexyl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}amine (37A)

2-Fluoro-4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine (1.2 g, 4 mmol), which was weighed in odnogolosy flask with a capacity of 25 ml, purged with argon, suspended in cyclohexylamine (of 3.97 g, 0.04 mol), was introduced protective atmosphere of argon and then heated at boiling amine under reflux on an oil bath at a temperature of 160°C for 48 hours. The brown suspension was left to cool to room temperature. Then added 30 ml Na-citrate (10%citric acid solution, pH 5 with concentrated NaOH) and the mixture was stirred for 10 minutes and was extracted twice with 30 ml of ethyl acetate.

The combined organic phases are again ek who was tragically twice in each case 30 ml Na-citrate (10%solution of citric acid, pH 5 with concentrated NaOH), and then 30 ml NaHCO3and was extracted once with saturated solution of NaCl. The organic phase was dried over Na2SO4and concentrated using a rotary evaporator, the residue was led out of 10 ml.

The recrystallization was carried out from a mixture of isopropanol/water (approximately 5 ml iPrOH heat and leave to cool and slowly add about 5 ml of distilled water). Output: 0,76 g (49,7%), purity (by HPLC) 96,6%.

In this way we obtain the compounds of formula I, shown below in table 4.

Table 4
Approx.MethodNameStructure
37b4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]-2-methoxypyridine
SCyclohexyl-{4-[5-(4-forfinal)-2-isopropylphenyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
37dCyclohexyl-{4-[5-(4-forfinal)-2-(2,2,2-cryptonemiales)-1H-imidazol-4-yl]pyridine-2-yl}Amin
ECyclohexyl-{4-[5-(2,4-dif is arvanil)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
37fCyclohexyl-{4-[5-(2,4-differenl)-2-ethylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
37gCyclohexyl-{4-[5-(2,4-differenl)-2-isopropylphenyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
37hCyclohexyl-{4-[5-(2,4-differenl)-2-(2,2,2-cryptonemiales)-1H-imidazol-4-yl]pyridine-2-yl}Amin
37i indigenousCyclohexyl-{4-[2-methylsulfanyl-5-(3-triptoreline)-1H-imidazol-4-yl]pyridine-2-yl}Amin
37jCyclohexyl-{4-[2-ethylsulfanyl-5-(3-triptoreline)-1H-imidazol-4-yl]pyridine-2-yl}Amin

The compounds shown below in table 5 were obtained using the above method.

td align="center"> /tr>
Table 5
Approx.MethodNameStructure
38G4-[5-(4-Forfinal)-2-METI is effect-free remedy 1H-imidazol-4-yl]pyridine-2-ylamine
39Methyl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
40Ethyl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
41Isopropyl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
42Methoxyethyl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
43N,N-Dimethylaminoethyl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
44Hydroxypropyl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
45N'-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-N,N-diphenylethane-1,2-diamine
46NCinnam is l-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
47Cyclopropyl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
48Cyclopropylmethyl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
49Cycloheptyl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
50Bicyclo[2.2.1]hept-2-yl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
51Adamant-1-yl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
52Adamant-2-yl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
53{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-(tetrahydrofuran-3-yl)Amin
54N {4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-(tetrahydropyran-4-yl)Amin
55(1-Ethylpyrrolidin-2-ylmethyl)-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
56{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-(2-piperidine-1-retil)Amin
57{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-(2-morpholine-4-retil)Amin
58{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-(1-methylpiperidin-4-yl)Amin
59{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-[2-(4-methylpiperazin-1-yl)ethyl]amine
60{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-(1-naphthalene-2-retil)Amin
61N2.2-Diphenylether-{4-[5-(4-forfinal)-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
62NBiphenyl-2-ylmethyl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
63N{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-(3-phenylpropyl)Amin
64{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}indan-2-Alamein
65{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-(1,2,3,4-tetrahydronaphthalen-1-yl)Amin
66{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-(1,2,3,4-tetrahydronaphthalen-2-yl)Amin
67{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}quinoline-2-ylmethylamino
68{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}pyridine-4-ylmethylamino
69{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}quinoline-4-ylmethylamino
70N[1-(5-Chlorothiophene-2-yl)ethyl]-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
71{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}thiophene-3-ylmethylamino
72Benzo[b]thiophene-2-ylmethyl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
73Benzofuran-2-ylmethyl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
74N(1-Benzofuran-2-retil)-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
75(2,3-Dihydrobenzofuran-2-ylmethyl)-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
76{4-[5-(4-f is arvanil)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}oxazol-2-ylmethylamino
77Benzoxazol-2-ylmethyl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
782-({4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-ylamino}methyl)-4-isopropylamino-5-ol
79N-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-N'-(2-methylsulfinylphenyl)formamidine
80N-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-N'-(1-methyl-2-methylsulfinylpropyl)formamidine
81N-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-N'-(2-methylsulfinylphenyl)formamidine
82{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-(2-methylthiazole-5-ylmethyl)Amin
83{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-(2-metallia the ol-4-ylmethyl)Amin
84{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-[2-(2-methylenedianiline)ethyl]amine
85In2-Bromo-4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine
86G2 Azido-4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine
87D2 Ethoxy-4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine
884-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]-2-p-collectibility
892-(2,6-Dichlorophenoxy)-4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine
90D2-Benzyloxy-4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine
91D4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]-2-Fe is ethoxypyridine
92D2 Cyclohexyloxy-4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine
934-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]-2-(tetrahydrofuran-3-yloxy)pyridine
94D6-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yloxy}hexahydrofuro[3.2-b]furan-3-ol
954-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]-2-(tetrahydrofuran-2-ylethoxy)pyridine
964-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]-2-(tetrahydropyran-2-ylethoxy)pyridine
972-(Benzofuran-2-ylethoxy)-4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine
984-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]-2-(furan-2-ylethoxy)pyridine
994-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]-2-(thiophene-2-ylethoxy)pyridine
1004-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]-2-(5-chlorothiophene-2-ylethoxy)pyridine
1014-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]-2-(thiophene-3-ylethoxy)pyridine
1024-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]-2-(thiazol-2-ylethoxy)pyridine
103Bicyclo[2.21]hept-2-yl-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Amin
1043-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yloxy}-1-azabicyclo[2.2.2]Octan
1054-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]-2-methylsulfinylphenyl
1062-Benzazolyl-4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]Piri is John
1074-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]-2-phenylalaninamide
1082-Ethylsulfanyl-4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine
1092-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-ylsulphonyl}ethanol-
110C3-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-ylsulphonyl}propan-1-ol
110AEN-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}formamide
111EN-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}benzamide
112E4-Chloro-N-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}benzamide
113EN-{4-[5-(4-Forfinal)-2-metals hanil-1H-imidazol-4-yl]pyridine-2-yl}-3-methylbenzamide
114EN-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-3-cryptomelane
115FN-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-2-phenylacetamide
116F{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}amide cyclohexanecarbonyl acid
117F2-Cyclohexyl-N-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}ndimethylacetamide
118F2-(4-Chlorophenyl)-N-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}ndimethylacetamide
119FN-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-2-(4-methoxyphenyl)ndimethylacetamide
120F2-(4-Forfinal)-N-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}ndimethylacetamide
121F2-(2-Forfinal)-N-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}ndimethylacetamide
122FN-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-3-phenylpropionamide
123FN-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-3-phenylacrylate
124FBenzyl ester {4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}carbamino acid
125F1-Benzoyl-3-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}urea
126EN-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}ndimethylacetamide
127F2,2,2-Cryptor-N-{4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}ndimethylacetamide
128FN-{4-[5-(4-Forfinal)-2-matilal panel-1H-imidazol-4-yl]pyridine-2-yl}-2-methoxyacetate
129FN-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-2-(methylpentylamino)ndimethylacetamide
130FCyclohexyloxy ester {4-[5-(4-forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}carbamino acid
131{4-[5-(2,4-Differenl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Isopropylamine
132{4-[5-(2,4-Differenl)-2-ethylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}Isopropylamine
133{4-[5-(2,4-Differenl)-2-isopropylphenyl-1H-imidazol-4-yl]pyridine-2-yl}Isopropylamine
134FIsopropyl-{4-[2-methylsulfanyl-5-(3-triptoreline)-1H-imidazol-4-yl]pyridine-2-yl}Amin
135F{4-[2-Ethylsulfanyl-5-(3-triptoreline)-1H-imidazol-4-yl]pyridine-2-yl}Isopropylamine
136F{4-[5-(2,4-Differenl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}-(2-methoxyethyl)Amin
137F{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl}urea
138FN-{4-[5-(4-Forfinal)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine-2-yl-2-(4-isobutylphenyl)propionate

1. 2-Tizanidine imidazole derivative of the formula I

where R1represents aryl, which is substituted by a halogen atom or halogen-C1-C6-alkyl;

R2selected from the group including

a) aryl-C1-C4-alkyl, and

b) C1-C6-alkyl;

R3selected from the group including

a) NR4R10;

b) NR7COR10;

c) OR10;

d) NH2;

R4represents H,

R5and R6that may be the same or different, represent H, halogen, HE, C1-C6-alkoxy, C1-C6-alkyl or halogen-C1-C6-alkyl;

R7not only is em a R 4;

R10has one of the following values:

(a) a-b

b)

c)

d)

e)

f) C1-C6-alkyl, which is substituted by 2 phenyl groups;

But it represents a linear or branched C1-C6-alkylen;

In selected from the group including

a) N

b)

c)

d)

e)

f) OS1-C6-alkyl;

g) OH;

Well is a 3-10-membered nonaromatic, mono-, bi - or tricyclic carbocycle, which may or may not be condensed with a benzene ring;

Ar represents a 5 - or 6-membered aromatic heterocycle, which has 1 heteroatom selected from the group consisting of O, S and N, and which may be condensed with a benzene ring;

Het represents a 5 - or 6-membered nonaromatic a heterocycle, which has 1 heteroatom, which is About, which may be condensed with a benzene ring;

m is 0, 1 or 2;

or its optical isomers or Phys is logicheskie acceptable salt.

2. The compound according to claim 1 of formula I,

where R1represents aryl, which is substituted by a halogen atom;

R2selected from the group including

a) aryl-C1-C4-alkyl, and

b) C1-C6-alkyl;

R3selected from the group including

a)NR4Rl0;

b) NR7COR10; and

C) C1-C6-alkoxy;

R4represents H;

R10represents a

R5and R6that may be the same or different, represent H, halogen, C1-C6-alkoxy or C1-C6-alkyl;

R7represents N;

But it represents a linear or branched C1-C6-alkylen, and

m is 0, 1 or 2,

or an optical isomer or a physiologically acceptable salt.

3. The compound according to claim 1 or 2 formula Ia

where R1, R2, R3and m are as defined in claim 1.

4. The compound according to claim 1 or 2, where R3represents a

where A, R5and R6are as defined in claim 1.

5. The compound according to claim 1 of formula I, where R10is one, not only is the R below radicals

a)

where Ar represents a 5 - or 6-membered aromatic heterocycle, which contains a heteroatom selected from the group comprising N, O and S; And is a C1-C3-alkylene, and R5and R6represent N;

b)

where Het represents a 5 - or 6-membered nonaromatic a heterocycle, which contains About heteroatom; And represents a C1-C3-alkylene, and R5and R6represent N;

C)

where a represents a C1-C3-alkylene, and R5and R6represent H, and Well represents cyclopentyl or cyclohexyl;

d) cyclopentyl or cyclohexyl;

e) phenyl-C1-C6-alkyl, and the alkyl radical can have an optional phenyl substituent; and

f)2-C6-alkyl, which is substituted by phenyl.

6. The compound according to claim 1 of formula I, where R3represents NR7COR10; where R10selected from the group comprising phenyl and C2-C6-alkyl, which is substituted by phenyl.

7. The compound according to any one of the preceding paragraphs, where a represents a C1-C2-alkylen.

8. The compound according to any one of the preceding paragraphs, where a represents the FDS is th ethylene.

9. The compound according to any one of the preceding paragraphs, where R5and R6represent N.

10. The compound according to any one of the preceding paragraphs, where R1represents a halogen-substituted phenyl or phenyl substituted CF3.

11. The compound according to any one of the preceding paragraphs, where R2represents benzyl or C1-C6-alkyl.

12. Pharmaceutical composition having inhibitory activity against the release of cytokines, which includes an effective amount of at least one compound according to any one of claims 1 to 11, together with one or more pharmaceutically acceptable carriers and/or auxiliary additives.

13. The use of at least one compound according to any one of claims 1 to 11 when receiving the pharmaceutical composition having inhibitory activity against the release of cytokines.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of phtalazine with general formula (I) , in which R represents a methyl or difluromethyl group; R1 represents phenyl or oxazolyl or thiophenyl, chemically bonded to a phtalazine ring through a carbon-carbon bond. Both phenyl and the above mentioned heterocycle are substituted with a carboxylic group, and optionally with a second functional group, chosen from methoxy-, nitro-, N-acetylamino-, N-metanesulphonylamino- group. The invention also relates to pharmaceutical salts of such derivatives. The given compounds with general formula (I) are inhibitors of phosphodiesterase.

EFFECT: objective of the invention is also the method of obtaining compounds with general formula (I) and pharmaceutical compositions for treating allergies and antiphlogistic diseases based on the given compounds.

9 cl, 9 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to a new method of obtaining derivatives of N-phenyl-2-pyrimidineamine (2-anilinopyrimidine) with general formula (I), which have a wide spectrum of biological effects and can be used mainly, for treating various types of tumours, leucaemia, cerebral ischemia, vascular stenosis and other diseases. In general formula (I) , R1 represents a pyridyl or its oxide bonded to a carbon atom, which can be substituted with a low alkyl or alkoxy, each of R2 and R3 independently represents hydrogen, branched of unbranched low alkyl, phenyl, unsubstituted of substituted with a haloid, R4 represents hydrogen, unbranched or branched low alkyl, R5 represents hydrogen, low alkyl, possibly substituted with halogen atoms. Other representations of radical are given in the formula of invention. The method involves the following stages: A) reaction of urea, mainly in a basic medium with N,N-dialkyamino-1-(3-pyridyl)-2-propene-1-ono with general formula II: with obtaining of the corresponding dihydropyrimidinone with general formula (III) B) oxidation of compound (III) by proton oxidation, with obtaining of the corresponding hydroxypyrimidine with formula IV , C) activation of the hydroxy group in the obtained compound IV , for example, treatment using sulphohalide R'SC2Hal or anhydride R'(SO2)2O, with obtaining of a compound with general formula V , where R' represents aryl of low alkyl, D) reaction of the obtained compound V with the corresponding aromatic amino compound with formula VI , with obtaining of compound with formula (I) and subsequent possible conversion of the obtained compounds to other compounds with general formula (I).

EFFECT: method allows for excluding use of toxic compounds and simplifies the process.

13 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) or their pharmaceutically acceptable salts, where R1 and R2 are H or Me; R3 is H, hydroxy or (1-4C)alkoxi; R4 is H, OH, (1-4C)alkoxi; R5 is OH, (1-4C)alkoxi or R7; provided the R4 is H, then R5 differs from OH or (1-4C)alkoxi; R6 is (2-5C)heteroaryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, bromine or chlorine; (6C)aryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, (1-4)C-alkoxi, bromine, chlorine, phenyl or (1-4C) (di)alkylamino; (3-8C)cycloalkyl, (2-6C)heterocycloalkyl or (1-6C)-alkyl; R7 is amino, (di)(1-4C)alkylamino, (6C)arylcarbonylamino, (2-5C)heteroarylcarbonylamino, (2-5C)heteroaryl-carbonylokxi, R8-(2-4C)alkoxi, R9-methylamino or R9-methoxi; R8 is amino, (1-4C)alkoxi, (di)(1-4C)-alkylamino, (2-6C)-heterocycloalkyl, (2-6C)heterocycloalkylcarbonylamino or (1-4C)-alkoxicarbonylamino; and R9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl. The invention also relates to the pharmaceutical composition which contains the said derivatives, and to the application of the derivatives in fertility modulating.

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

15 cl, 51 dwg

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of quinoline with general formula Ia or Ib their stereoisomers and pharmaceutical salts, where X represents oxygen or sulphur, Z-CH2, Y-NO2, -C(O)OR5, -NR5SO2R5, -SO2R5 (for Ia) and -NO2 or -C(O)OR5 (for Ib). Description is also given of the method of obtaining Ia and Ib compounds, pharmaceutical compositions based on them, and their use when making medicinal preparations.

EFFECT: compounds can be used for treating lesions, related to inhibition of migration of magrophage, for example, during treatment of septic shock or arthritis.

175 cl, 16 tbl, 22 ex, 16 dwg

FIELD: chemistry.

SUBSTANCE: invention pertains to new 2,4-substituted indole with formula: I, its pharmaceutically accepted salt, where R1 represents phenyl, optionally substituted with one or two substitutes, chosen from a group, consisting of a halogen, C1-12alkyl, halogen C1-12alkyl, or represents thienyl; R2 represents residue of a saturated ring, consisting of six ring atoms, one or two of which are nitrogen atoms, and the others are carbon atoms, optionally substituted with one or two C1-12alkyls; R represents H, C1-12alkyl; R4 represents H; p represents 1 or 2; n represents 0,1 or 2. The compounds have antagonistic activity to the "5-ГТ6" receptor, which allows to use in pharmaceutical mixtures.

EFFECT: use in pharmaceutical mixtures.

10 cl, 7 dwg, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidinium of the general formula (I): possessing antagonistic effect with respect to muscarinic receptors M3 wherein B means phenyl or thienyl group; each radical among R1, R2 and R means independently hydrogen, fluorine, chlorine atom or hydroxyl; n means a whole number from 0 to 1; A means group chosen from groups -CH2 and -O-; m means a whole number from 0 to 6; R means (C1-C8)-alkyl; X- represents a pharmaceutically acceptable anion of mono- or multibasic acid, and involving all separate stereoisomers and their mixtures. Also, invention relates to methods for synthesis of such compounds, pharmaceutical compositions containing such compounds and to their using in therapy as antagonists of muscarinic receptors M3.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

17 cl, 51 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I): wherein R1 means quinolinyl possibly substituted with (C1-C5)-alkoxy-group, isoquinolinyl, quinoxalinyl, pyridinyl, pyrazinyl, benzyl possibly substituted with halogen atom, naphthalinyl, thiophenyl, furanyl, cinnolyl, phenylvinyl, quinolylvinyl or 4-oxo-4H-chromenyl possibly substituted with halogen atom, (C1-C5)-alkyl or (C1-C5)-alkoxy-group; R2, R5, R8 and R11 mean hydrogen atom; R3 and R4 mean halogen atom, (C1-C5)-alkoxy-group; R6 and R7 mean hydrogen atom (H) or (C1-C5)-alkyl or form in common radical -CH2-CH2-; R9 and R10 mean (C1-C5)-alkoxy-group; m and n mean a whole number from 0 to 4 independently; X means -CH2- or sulfur atom (S). Also, invention describes their pharmaceutically acceptable salts, a method for their preparing and pharmaceutical composition based on thereof. Proposed compounds are inhibitors of P-glycoprotein, enhance bioavailability of anti-cancer drug and can be used in medicine.

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

7 cl, 3 tbl, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (IA): or the formula (IB): wherein B means hydrogen atom or lower alkyl; A means an unsubstituted or substituted cyclic group chosen from compounds of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) and (k) wherein R1-R4 mean independently of one another hydrogen atom, halogen atom, -CF3, -CHF2, -C(CH3)F2, (C3-C6)-cycloalkyl, lower alkoxy-group, lower alkyl, -OCF3 or phenyl; R5-R10 means independently of one another hydrogen atom, halogen atom, lower alkoxy-group, lower alkyl or -CHF2; R11-R16 mean independently of one another hydrogen atom, halogen atom, alkoxy-group or lower alkyl; R17 means halogen atom or -CHF2; R18-R20 mean independently of one another hydrogen atom, lower alkoxy-group or lower alkyl, and to their pharmaceutically acceptable acid-additive salts. Also, invention relates to a medicinal agent possessing the selective effect of blockers of NMDA receptors of subtype 2B. Invention provides synthesis of novel biologically active compounds and medicinal agents based on thereof.

EFFECT: valuable medicinal properties of compounds and drugs.

6 cl, 180 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: tricyclic bonds are substituted with heterocyclic ones, which have the formula (I), or its pharmaceutically acceptable salt or solvate in which: n denotes 0-2; Q denotes , R1 denotes H, R2 represents H or alkyl with 1-6 carbon atoms, R3 represents H, hydroxy-group, -NR22R23, Het denotes mono- or bycyclic heteroaryl group from 5 - 10 atoms, containing from 1 to 9 carbon atoms and 1 heteroatom N, where Het bonds with B through the cyclic carbon atom, and the group Het has a substitute W. W consists of from 1 to 4 substitutes, independently selected from the group containing H, halogen, R21-aryl and P21-heteroaryl, R4 and R5 are independently selected from the group containing H and alkyl with 1 - 6 carbon atoms, R7, R8, R10 and R11 denote R1, R9 represent H, B represents -(CH2)n3-. cis- or trans -(CH2)n4CR12=CR12a(CH2)n5 or -(CH2)n4C=C(CH2)n5, where n3 denotes 0-5, n4 and n5 independently denote 0-2, and R12 and R12a denote H, X represents -O-, Y represents =O, each R13 is independently selected from the group containing H, alkyl with 1-6 carbon atoms, -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16, and -(CH2)n6C(O)NR28R29, where n6 denotes 0, each R14 is independently selected from the group containing H, alkyl with 1-6 carbon atoms, -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16 and -(CH2)n6C(O)NR28R29, where n6 denotes 0, where, at least one of R13 and R14 is chosen from the group containing -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16 and -(CH2)n6C(O)NR28R29, where n6 denotes 0, R16 represents an alkyl with 1-6 carbon atoms, R16b represents H, an alkyl with 1-6 carbonatoms, (an alkoxy with 1-6 carbon atoms)-(an alkyl with 1 - 6 carbon atoms)-, R22-O-C(O)-(an alkyl with 1 - 6 carbon atoms)-, a cycloalkyl with 3-6 carbon atoms, R21 represents from 1 to 3 substitutes, which are independently selected from a group comprising of H, -CN, -CF3, halogen, alkyl with 1 - 6 carbon atoms, -OH, alkoxy- group with 1 - 6 carbon atoms, -C(O)NR25R26 and -SR13, R22 represents H or an alkyl with 1-6 carbon atoms, R23 represents H, R25 and R26 are independently selected from a group comprising of H and an alkyl with 1 - 6 carbon atoms, and R28 and R29 are independently selected from a group comprising of H, an alkyl with 1 - 6 carbon atoms, heteroaryl, heterocyclil and also a pharmaceutical composition, containing these bonds.

EFFECT: application for getting medication for the treatment of diseases related to thrombosis, atherosclerosis, restenosis, hypertension, sternocardia, arrythmia, cardiac insufficiency and cancer, the way of administering is specified in the bonds Also therapy in combination with other cardiovascular agents is allowed.

23 cl, 7 tbl, 92 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compound with the formula (1): where R1 is C1-C12 alkyl group, which can have the substitute, or C2-C12 alkenyl group, which can have the substitute represented with the C6-C14 aryl group, which can be substituted with the halogen atoms; each of R2 and R3 represent the hydrogen atom, alkyl group, hydroxyalkyl group, dihydroxyalkyl group, or R2 and R3 form with the adjacent nitrogen atoms the 5-membered, 6-membered, or 7-membered nitrogen-containing saturated heterocyclic group, which can be substituted with the alkyl group; (the dotted line means the possible double bind), or its salt, as well as to the pharmaceutical composition containing the said compound, and to its application as a pharmaceuticals and to the treatment method.

EFFECT: invented compound demonstrates inhibiting activity against the tumor necrosis factor production (TNF-α) and improved absorbability after oral administration.

16 cl, 1 tbl, 18 dwg, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I) possessing inhibitory effect on production of interleukin-12 (IL-12) wherein R1 represents group of the formula , aryl or heteroaryl; each among R2 and R4 represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy group; R3 represents Rc, alkenyl, -ORc, -OC(O)Rc, -SRc, -NRcCORd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcSO2Rd, -CORc, -C(O)ORc or -C(O)NRcRd; R5 represents hydrogen atom (H); n = 0, 1, 2, 3, 4, 5 or 6; X represents oxygen atom (O) or -NRc; Y represents a covalent bond. -CH2, O or -NRc; Z represents nitrogen atom (N); one of values U and V represents N and another represents -CRc; W represents O, sulfur atom (S) or -S(O)2 wherein each radical among Ra and Rb represents independently H, (C1-C6)-alkyl, aryl or heteroaryl; each radical among Rc and Rd represents independently H, (C1-C6)-alkyl, phenyl, heteroaryl, cyclyl, heterocyclyl or (C1-C6)-alkylcarbonyl wherein term "aryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring; term "heteroaryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring that comprises at least one heteroatom, such as O, N or S as a part of cyclic system and wherein other atoms mean carbon; term "cyclyl" and "heterocyclyl" relate to partially or completely saturated monocyclic or bicyclic system comprising from 4 to 14 carbons in rings wherein heterocyclic ring comprises one or some heteroatoms (for example, O, N or S) as part of cyclic system and wherein other atoms mean carbon, and under condition that when X represents -NH, Y represents a covalent bond, n = 0, and R3 represents H or CH3 then R1 doesn't mean thiazolyl or pyrimidinyl. Also, invention relates to a pharmaceutical composition and a method for treatment of disorder associated with hyperproduction of interleukin-12.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

49 cl, 43 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds, namely, to N-substituted derivatives of piperidine of the formula (I): or their pharmaceutically acceptable salts, amides, esters wherein values R1, R, R3, m, X, n, W, Ar1 and Ar2 are disclosed in the invention claim. Also, invention relates to methods for inhibition of activity and methods for inhibition of activation of monoamine receptors. Methods involve contacting monoamine receptors or system comprising monoamine receptors with the effective amount of one or some compounds of the formula (I). Except for, invention relates to using compounds of the formula (I) in treatment of psychotic diseases.

EFFECT: valuable medicinal properties of compounds.

35 cl, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel benzofuran derivatives comprising group of carbamoyl type of the formula [1]: wherein cycle Z represents group of the formula or A represents a simple bond or group of the formula -NH-; Y represents lower alkylene group, cycloalkanediyl group, phenyl group or piperidyl group; R4 and R5 are similar or different, and each represents hydrogen atom, unsubstituted lower alkyl group, lower alkyl group substituted with amino group optionally substituted with 1-2 lower alkyl groups, lower alkyl group substituted with hydroxyl group, lower alkyl group substituted with lower alkoxy group, or lower alkyl group substituted with pyridyl group; or R4 and R5 represent tetrahydropyranyl; or R4 and R are bound by ends to form in common with adjacent nitrogen atom and represent pyrrolidinyl group, morpholinyl group, pyrrolidinyl group substituted with (hydroxy)(lower alkyl) group, pyrrolidinyl group substituted with hydroxyl group, thiomorpholinyl group, piperidinyl group, piperdinyl group substituted with hydroxyl group, piperazinyl group substituted with (hydroxy)(lower alkyl) group, piperidinyl group substituted with (hydroxy)(lower alkyl) group, piperazinyl group substituted with lower alkyl group, pyrrolidinyl group substituted with lower alkoxycarbonylamino group, piperidinyl group substituted with amino group optionally substituted with 1-2 lower alkyl groups, or piperidinyl group substituted with lower alkoxycarbonyl group; R1 represents hydrogen atom, halogen atom or lower alkyl group; cycle B of the formula: represents benzene cycle optionally substituted with one or two groups chosen independently from halogen atom, optionally substituted lower alkyl group, hydroxy group, lower alkoxy group optionally substituted with alkoxycarbonyl group or amino group; carbonyl group optionally substituted with lower alkoxy group, hydroxyl group, amino group optionally substituted with 1-2 alkyl groups, morpholinyl or pyrrolidyl group; optionally substituted amino group; R3 represents hydrogen atom or lower alkyl group. Also, invention relates to it's a pharmaceutically acceptable salt that are useful as Fxa inhibitors. Also, invention relates to a pharmaceutical composition based on these compounds and their using in treatment of thrombosis.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

18 cl, 22 tbl, 143 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I): wherein R1 means quinolinyl possibly substituted with (C1-C5)-alkoxy-group, isoquinolinyl, quinoxalinyl, pyridinyl, pyrazinyl, benzyl possibly substituted with halogen atom, naphthalinyl, thiophenyl, furanyl, cinnolyl, phenylvinyl, quinolylvinyl or 4-oxo-4H-chromenyl possibly substituted with halogen atom, (C1-C5)-alkyl or (C1-C5)-alkoxy-group; R2, R5, R8 and R11 mean hydrogen atom; R3 and R4 mean halogen atom, (C1-C5)-alkoxy-group; R6 and R7 mean hydrogen atom (H) or (C1-C5)-alkyl or form in common radical -CH2-CH2-; R9 and R10 mean (C1-C5)-alkoxy-group; m and n mean a whole number from 0 to 4 independently; X means -CH2- or sulfur atom (S). Also, invention describes their pharmaceutically acceptable salts, a method for their preparing and pharmaceutical composition based on thereof. Proposed compounds are inhibitors of P-glycoprotein, enhance bioavailability of anti-cancer drug and can be used in medicine.

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

7 cl, 3 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

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