Methods for preparing 5-(1-piperazinyl)-benzofuran-2-carboxamide and intermediate compounds

FIELD: organic chemistry, chemical technology, pharmacy.

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

EFFECT: improved preparing methods.

6 cl, 10 ex

 

The invention relates to a method for producing 5-(1-piperazinil)benzofuran-2-carboxamide, characterized in that

a) in one reactor conduct the reaction of 5-bromosalicylaldehyde first compound with the formula I

in which

L denotes Cl, Br, I or reactionsare esterified group HE and

R1represents alkyl containing from 1 to 6 carbon atoms or benzyl,

and then formamide, and get a 5-L-benzofuran-2-carboxamide (II)in which L represents Cl, Br, I or reactionsare esterified group HE,

(II) further subjected aminating with catalysts of transition metals, which conduct the reaction with R2-piperazine, in which R2represents H or aminosidine group, and get a connection with formula III

in which R2denotes H or aminosidine group,

and further, if R2≠N, R2otscheplaut,

or

b) conducting a reaction of the compound with formula IV

in which

L denotes Cl, Br, I or reactionsare esterified group HE,

R3denotes N or CH2R6,

R4and R5each, independently of one another, represent OR7, OR8, SR7or SR8,

R4and R5together represent an alternative, carbonyl, =S, =N-C(R7)2, =N-C(R8)2, =N-OH, =N-OR7, =N-N[(R7)2], =N-N[(R8)2] or-O-(CH2)n-O-,

R6denotes CN, COOH, COOR7or CONH2,

R7represents alkyl containing from 1 to 6 carbon atoms,

R8denotes phenyl which may be unsubstituted or mono - or bisamidines R7, OR7, SR7or Hal,

n denotes 2 or 3,

when aminating with catalysts of transition metals, with R2-piperazine, in which R2denotes H or aminosidine group,

and get a compound with the formula V

in which

R2denotes H or aminosidine group,

R3denotes N or CH2R6,

R4and R5each, independently of one another, represent, OR7, OR8, SR7or SR8,

R4and R5together represent an alternative, carbonyl, =S, =N-C(R7)2, =N-C(R8)2, =N-OH, -N-OR7, =N-N[(R7)2], =N-N[(R8)2] or-O-(CH2)n-O-,

R6denotes CN, COOH, COOR7or CONH2,

R7represents alkyl containing from 1 to 6 carbon atoms,

R8denotes phenyl which may be unsubstituted or is it any bisamidines R 7, OR7, SR7or Hal,

n denotes 2 or 3,

and then carry out the reaction in a single reactor of the first compound with the formula I

in which

L denotes Cl, Br, I or reactionsare esterified group HE and

R1represents alkyl containing from 1 to 6 carbon atoms, or benzyl, and then with formamide, and get a connection with formula III

in which R2denotes H or aminosidine group,

and then, if R2≠N, R2otscheplaut,

or

C) conducting the reaction of the compound with formula V

in which

R2means aminosidine group,

R3denotes N or CH2R6,

R4and R5each, independently of one another, denote OR7, OR8, SR7or SR8,

R4and R5together represent an alternative, carbonyl, =S, =N-C(R7)2, =N-C(R8)2, =N-OH, =N-OR7, =N-N[[R7)2], =N-N[(R8)2] or-O-(CH2)n-O-,

R6denotes CN, COOH, COOR7or CONH2,

R7represents alkyl containing from 1 to 6 carbon atoms,

R8denotes phenyl which may be unsubstituted or mono - or bisamidines R7, OR7, SR7or Hal,

n denotes 2 or 3,

with lorazeam the house, and get a connection with formula III,

in which R2means aminosidine group,

and then R2otscheplaut,

and/or the fact that 5-(1-piperazinil)benzofuran-2-carboxamide is converted into one of its salts by treatment with acid.

The invention relates also to compounds with the formula V

in which

R2denotes H or aminosidine group,

R3denotes N or CH2R6,

R4and R5each, independently of one another, represent, OR7, OR8, SR7or SR8,

R4and R5together represent an alternative, carbonyl, =S, =N-C(R7)2, =N-C{R8}2, =N-OH,=N-OR7, =N-N[(R7)2], =N-N[(R8)2] or-O-(CH2)n-O-,

R6denotes CN, COOH, COOR7or CONH2,

R7represents alkyl containing from 1 to 6 carbon atoms,

R8denotes phenyl which may be unsubstituted or mono - or bisamidines R7, OR7, SR7or Hal,

n denotes 2 or 3,

and their salts and solvate.

5-(1-piperazinil)benzofuran-2-carboxamide represents an important intermediate compound for the production of the active pharmaceutical ingredients. This is described, for example, in DE 19730989, WO 9857953, EP 738722, EP 736525, DE 4414113, DE 4333254 or DE 4101686.

<> Derivatives benzofuran as precursors are described, for example, in DE 19514567.

Methods of obtaining heterocyclic aromatic amines or arylamino, in which the catalysts are used transition metals, are known and described, for example, in EP 0802173.

The amination reaction such as described in a review article J.F.Martinez in Angew, Ch. Int. 37, 2046-2062. Other methods of obtaining tertiary arylamines using catalysts made from trialkylphosphine and palladium, are disclosed in JP 10-310561 (Kokai application), application No. 9-119477, or JP 11-80346 (Kokai application), application No. 9-245218.

Way catalytic get arylamino with catalysts of transition metals has been described S.L. Buchwald and others in the US 5576460. Another way of obtaining aromatic amines of chlorinated aromatic compounds in the presence of a palladium catalyst described in EP 0846676, J.F. Hartwig and others in J. Org. Chem. 1999, pp.5575-5580, or S.L. Buchwald and others in J.A.C.S. 1999, 121, 9550-9561.

In Tetrahedron Letters 39 (1998) 617-620, M. Nishiyama describes the synthesis of N-arylpiperazines from aryl halides and piperazine with catalysts of transition metals.

In studies of the synthesis of medicines described for example in DE 4333254 (EP 0648767), unexpectedly it was found that 5-(1-piperazinil)benzofuran-2-carboxamide you can get, at least with comparable or higher total output than in the prototype, being the m it should be noted, while there are significant advantages, the most significant of which are the simplicity of the reaction and, consequently, the ease of product selection.

Another consequence is the low consumption of solvent and energy.

If L in the compounds of formulas I, II or IV denotes reactionsare esterified group IT, then it should be, preferably, alkylsulfonates containing from 1 to 6 carbon atoms (preferably, methylsulfonylamino or triftormetilfullerenov), arylsulfonate containing 6-10 carbon atoms (preferably phenyl - or p-coolsolutionsgroup, and, in addition, 2-naphthalenesulfonate) or, alternatively, forcalifornia.

R1represents alkyl or benzyl. Alkyl in this case contains 1, 2, 3, 4, 5 or 6 carbon atoms, preferably 1, 2, 3 or 4 carbon atoms, especially preferably, for example, methyl or ethyl, in addition, propyl, isopropyl, and butyl, isobutyl, sec-butyl or tert-butyl.

In connection with formula I, L preferably denotes Cl, in addition, also Br.

R2denotes H or aminosidine group. Particularly preferably, R2represented aminosidine group.

The term "aminosidine group" is generally known and the relative is raised to groups which are suitable for protecting (blocking) amino group from chemical reactions but which are easy to remove after the desired chemical reaction carried out at other positions of the molecule. Typically, such groups are, in particular, Azimova, Aralova, oralmaxillofacial or Arakelova group. Because aminosidine group is removed after carrying out the desired reaction (or sequence of reactions), their type and size are not that significant; however, preferred are those which contain 1-20, in particular 1-8 carbon atoms. The term "allowa group" in the description of this method and these compounds should be understood in its broadest sense. It covers allowee groups derived from aliphatic, alifaticheskih, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl, aryloxyalkyl and especially alcoxycarbenium group. Examples atilovykh groups of this type are alkanoyl, such as acetyl, propionyl, butyryl; arcanery, such as phenylacetyl; aroly, such as benzoyl or tolyl; aryloxyalkanoic, such as phenoxyacetyl; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, BOC (tert-butoxycarbonyl), 2-iododeoxyuridine; arancelaria bodily, such as CBZ (carbobenzoxy), which is also referred to as "Z", 4-methoxybenzenesulfonyl, FMOC (9-fertilitycare); arylsulfonyl, such as Mtr (4-methoxy-2,3,6-trimethylphenylsulfonyl).

Particularly preferably, if R2represents benzyl or VOS.

Aminosidine group can be removed from connection with formula III, depending on the type of used protective group using, for example, strong acids, mainly using TFA (triperoxonane acid or perchloric acid, but also using other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids such as benzene - or p-toluensulfonate acid. Valid optional presence of an inert solvent, but it is not always necessary. Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as dimethylformamide, halogenated hydrocarbons such as dichloromethane, in addition, also alcohols, such as methanol, ethanol or isopropanol, and water. Also suitable are mixtures of the above solvents. TFA preferably in excess, without the addition of other solvents, and perchloric acid is used preferably in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. Temperature reactions are predominantly in the range of from about 0 to about 50°, preferably between 15 and 30°. Group VOS preferably otscheplaut using TFA in dichloromethane or using from 3 to 5N hydrochloric acid in dioxane at 15-30°.

Protective groups which can be removed by hydrogenolysis (for example, CBZ or benzyl)can be split, for example, by treatment with hydrogen in the presence of a catalyst (for example, a catalyst made of noble metals such as palladium, mainly on a substrate, such as graphite). Suitable for this purpose solvents are listed above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. In General, the hydrogenolysis is carried out at temperatures between 0 and 100° and pressures between about 1 and 200 bar, preferably at 20-30° and 1-10 bar.

R3preferably denotes N.

R3and R4preferably denote methoxy-, ethoxy-, propoxy - or fenoxaprop.

R4and R5together represent, in particular, the carbonyl.

In connection with formula IV Hal preferably denotes Br.

Connection with formula IV and V can on titsa also in the form of dimers, which can again be split into appropriate salicylaldehyde, in which L and R2take the above values:

R7denotes alkyl. In this case, the alkyl contains 1, 2, 3, 4, 5 or 6 carbon atoms, preferably 1, 2, 3 or 4 carbon atoms, particular preference is given, for example, stands or ethyl, and, in addition, propylene, isopropyl, and butila, isobutyl, sec-butile or tert-butile.

In the compounds of formulas IV and V,

=N-C(R7)2means preferably =N-C(CH3)2,

=N-C(R8)2means preferably =N-C(phenyl)2,

=N-OR7means preferably =N-och3,

=N-N[(R7)2] preferably denotes =N-N[(CH3)2],

=N-N[(R3)2] preferably denotes =N-N[(phenyl)2].

Compounds of formulas I and IV are either known or can be prepared by methods which are known in themselves and are described in the literature (for example, in the classic works, such as Houben-Weyl, Methods der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme Verlag, Stuttgart), and you can get them at reaction conditions which are known and are suitable for these reactions. You can also use variants of these reactions, which are in themselves known, but here in detail the e describes.

Method: option a)

The reaction of 5-bromosalicylaldehyde first connection with formula I, and then formamide is carried out in a single reactor in a suitable inert solvent with addition of a base.

Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol, onomatology or monotropy ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; NITRILES, such as acetonitrile; sulfoxidov, such as dimethylsulfoxide (DMSO); carbon disulfide; nitro compounds, such as nitromethane or nitrobenzene; you can also apply a mixture of these solvents with each other.

The time of reaction, depending on conditions, may range from a few minutes up to 14 days, and the reaction temperature is in the range from about 0° to 150°preferably between 60° 120°.

Most preferably, the time of reaction was in the range of from 4 to 20 hours, and the temperature is between 90 and 115°.

Suitable bases are the same, the connection, as, for example, carbonates of Na, K or Cs.

Then dorectory the reaction is carried out with formamide, preferably in the presence of organic bases, preferably the alkali metal alkoxide, such as, for example, tert-piperonyl Na, and its corresponding alcohol, and the result is 5-Hal-benzofuran-2-carboxamide (II). In (II), Hal denotes preferably Br.

The reaction is preferably carried out at temperatures from 0 to 60°.

Other ways of obtaining (II) are described, for example, in Bull. Soc. Chim. Fr., 1971; 4329, and O. Dann and others in Justus Liebigs Ann. Chem. 1975; 160-194. The above dorectory the reaction proceeds with the best output than those specified reaction.

For obtaining compounds of formula III, carried out the reaction of (II) with R2-piperazine in a suitable inert solvent, in the presence of base and catalyst of transition metal.

Suitable for use complexes of transition metals include PdCl2or Pd(OAc)2or other derivative Pd2+previously restored via, for example, the NaSH4or phosphines (this step can be omitted in case of excess of ligand R3P) or connection type Pd(O), such as, for example, Pd(DBA)2or Pd2(DBA)3(DBA = dibenzylideneacetone).

The palladium complexes of this series, you can add the corresponding complexes of ligands of Nickel or copper. In addition, the can is to apply such ligands, as salts of N,N-dailymalaria, according to the method described by J. Huang and others, Org. Lett. 1, 1999, 1307-1309.

In a number suitable for use with phosphine ligands or Aza/phosphine comprises Tris-ortho-tolylphosphino

tricyclohexylphosphine

1-(2-diphenylphosphino-1-naphthyl)isoquinoline (QUINAP)

1,8-bis(dimethylamino)naphthalene

Phe2P-CH2-PPhe2

In particular, also P(tert-butyl)3=P(t-Bu)3

1,1'-bis (diphenylphosphino)ferrocene (DPPF in the form of a complex DPPF×PdCl2)

2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (=BINAP)

(S)-debutts = 1-(2-di-tert-butylphosphine)-ethyldimethylamine

1-(N,N-dimethylamino)-1'-(dicyclohexylphosphino)-biphenyl -

1-(di-t-butylphosphino)biphenyl -

1,1'-bis(di-t-butylphosphino)biphenyl -

(t-Bu)2P-(CH2)n-P(t-Bu)2, n=1,2,3

(t-Bu)2P-(CH2)m-X-(CH2)n-P(t-Bu)2, m, n = 1,2,3; X = O.

...

or alternate

DBtPF = 1,1'-bis(di-tert-butylphosphino)ferrocene.

Examples of suitable solvents are hydrocarbons, such as benzene, toluene, xylene; chlorinated hydrocarbons, such as, for example, dichloromethane; ketones, such as acetone, butanone; ethers such as tetrahydrofuran (THF) or dioxane; NITRILES, such as acetonitrile, may be also suitable mixture of these solvents with each other.

Depending on the applied conditions, the time of reaction may ariyavamsa from a few minutes up to 14 days, while the reaction temperature is usually maintained in the range between 0° and 180°usually between 30° 130°.

Examples of suitable bases are alkoxides of alkali metals, such as, for example, Na tertbutoxide.

Method: option b)

The reaction of compounds of formula IV with R2-piperazine carried out under the conditions described above and Varian).

R4and R5can be converted into a carbonyl group. Subsequent dorectory the reaction of the compound with formula V with a compound of formula I and then formamide is also carried out under the above conditions. Remove R2if R2≠N, also produced under the above conditions.

Base with formula I or formula V can be converted in an associate salt with the acidic residue with acid, for example by reaction of equivalent amounts of base and acid in an inert solvent, such as ethanol, followed by evaporation. Particularly suitable for this reaction acids are those that yield physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalogenation acid, such as hydrochloric acid or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, the sylphs is a new acid, in addition, organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic oneonone or politonalnye carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, Pavlova acid, diethyloxalate acid, malonic acid, succinic acid, Pimenova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultancy acid, ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, p-toluensulfonate acid, naphtalene and desulfonema acid, laurylsarcosine acid. Salts with physiologically unacceptable acids, for example the picrate, can be used for identifying and/or purifying compounds of formula I.

Above and below, all temperatures are in °C. In the examples below, the term "conventional treatment" means that, if required, add water if necessary bring the pH to values from 2 to 10, depending on the composition of the final product, the product is extracted with ethyl acetate or dichloromethane, separated phases, the organic phase is dried over sodium sulfate and the issue is more, and the product purified by chromatography on silica gel and/or by crystallization.

Example 1

1) Synthesis of 5-bromobenzophenone-2-carboxamide

Carrying out the reaction with ethylbromoacetate: 200 g of 5-bromo-2-hydroxybenzaldehyde dissolved in 2000 ml of NMP under stirring, and added 144 g of potassium carbonate and 175 g of ethylbromoacetate. The mixture was stirred at 105° in nitrogen atmosphere for 15 hours. The obtained orange solution interspersed with crystals cooled to 25°add 135 g of formamide and stirred the mixture for 30 minutes. Further, within 15 minutes introduce 557 ml of sodium methoxide (30% in the Meon), without cooling. After 3 hours, there is a brownish solution interspersed with crystals. It poured into 6 liters of demineralized water (10°)and stirred the mixture for 30 minutes. The crystals are filtered with suction, washed with 1 liter of demineralized water, re-suspended in 4 liters of demineralized water, filtered off with suction and washed again in 1 liter of demineralized water.

The crystals are dried during the night, before the termination of weight change, under reduced pressure and 60°With (product weight: 113 g of light beige crystals; TPL 210-213°; CAS 35351-21-4).

Physical and spectroscopic characteristics correspond to the data published in: Rene; Royer; BSCFAS; Bull. So. Chim. Fr.; 1971; 4329, and Dann, O. and others; JLACBF; Justus Liebigs Ann. Chem.; GE; 1975; 160-194.

According to the same method can be obtained with comparable outputs 5-chlorobenzophenone-2-carboxamide (TPL 200-202°), 5-perbendaharaan-2-carboxamide and 5-identafone-2-carboxamide.

2) Synthesis of 5-(4-benzyl-1-piperazinil)benzofuran-2-carboxamide by aminirovaniya with catalysts of transition metals 5-bromobenzophenone-2-carboxamide using benzylpiperazine

To illustrate the conduct of synthesis used catalytic system Pd(OAc)2/P(t-Bu)3: 0,30 g R(t-Bu)3, 4.5 g of 5-bromobenzophenone-2-carboxamide, 4.9 g benzylpiperazine and 5.0 g Na t-OBu added to the suspension of 0.085 g of Pd acetate(II) in 150 ml of xylene after the latter was mixed for 15 minutes, and the mixture was kept at 125°C for 12-18 hours under a protective nitrogen gas. After cooling, the mixture was added to 500 ml of 2N hydrochloric acid, and three times to produce the extraction of the aqueous phase with the aid of 200 ml of ethyl acetate. The aqueous phase is brought to pH 10 using aqueous NaOH (20%) in the control of pH and temperature (20-25° (C), and obtained in the form of a solid phase 5-(4-benzyl-1-piperazinil)benzofuran-2-carboxamide is filtered off and crystallized, for example, from ethanol/water (product weight: 4.0 g/64%/TPL 277-279°).

3) Synthesis of 5-(1-piperazinil)benzofuran-2-carboxamide 5-(4-Ben the Il-1-piperazinil)benzofuran-2-carboxamide

The method of conducting hydrogenolysis:

5.0 g of 5-(4-benzyl-1-piperazinil)benzofuran-2-carboxamide is added to 300 ml of ethanol, and then injected into the system 9 g of palladium on charcoal (5%) and 5 g of SPLA (100%), and conduct dibenzylamine to end at 20-30°with hydrogen. In the filtration and removal of solvent under reduced pressure, followed by crystallization from alcohol or water and drying at 60°With under reduced pressure, you can select the product (3.1 g/85%/TPL 252-255°), by a spectroscope identical material, which is prepared by previously described methods, including, in DE 4101686 / revealed 23.07.92; DE 4333254 / revealed 6.04.95; EP 0648767 / published 19.04.95; EP 0738722 / published 23.10.96).

Example 2

1) Synthesis of 5-(4-tert-butoxycarbonyl-1-piperazinil) benzofuran-2-carboxamide from 5-bromobenzophenone-2-carboxamide

0.9 g of 5-bromobenzophenone-2-carboxamide, 1.1 g of the BOC-piperazine and 1.45 g Na t-OBu added to a suspension of 0.06 g of Pd(DBA)2and 0.25 g R(t-Bu)3in 40 ml of dimethyl ether of diethylene glycol, and the mixture is maintained at 120-130°C for 16 hours in an atmosphere of protective gas. After cooling, the mixture was added to water, the organic phase is diluted using 100 ml of MTBE and washed three times in 50 ml of water. The solvent is evaporated, and the product formed is a solid phase, filtered off and purified by crystallization from ethanol (product weight: 0.7 g/55%/TPL 210-213°).

The next stage of removal of the protective group BOC with hydrochloric acid and obtain 5-(1-piperazinil)benzofuran-2-carboxamide, which are presented below only in the form of the equations of the reactions can be carried out according to the methods described, for example, in T.W. GREENE and P.G.M. WUTS, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS.

Example 3

Synthesis of 5-(1-piperazinil)benzofuran-2-carboxamide from 5-bromobenzophenone-2-carboxamide

0.9 g of 5-bromobenzophenone-2-carboxamide, 0.97 g of piperazine and 2.20 g Na t-OBu added to a suspension of 0.06 g of Pd(DBA)2and 0.07 g of 1-(N,N-dimethylamino)-1'-(dicyclohexylphosphino)biphenyl in 50 ml of toluene, and the mixture is maintained at 120-130° for 16 in the protective gas atmosphere. After cooling, the reaction mixture was added to a mixture of 50 ml of water and 10 ml of 37% hydrochloric acid, then add 100 ml ethyl acetate and stirred the mixture for 20 minutes. Remove a small amount of undissolved product, and separating the organic phase. The aqueous phase is again washed by shaking in 50 ml of ethyl acetate and freed from residual solvent under reduced pressure, then purified with charcoal and filtered. Crystalline product precipitated from the filtrate at 20-22° using 20-25 ml of 32% rest the RA of sodium hydroxide. Then the product is filtered and dried (weight of product: 0.65 g/70%/TPL 252-255°).

Example 4

1) Synthesis of 5-(4-benzylpiperazine-1-yl)-2-hydroxybenzaldehyde

0.6 g of bis(dibenzylideneacetone)palladium and 0.16 g of tri-tert-butylphosphine add in a nitrogen atmosphere to 200 ml of toluene, and the resulting dark red solution was stirred at 20° within 20 minutes. Then add 10 g of 5-bromo-2-hydroxybenzaldehyde, 9.7 g of 1-benzylpiperazine and 7.2 g of tert-butoxide sodium. The mixture was stirred at 60° within 24 hours, then cooled, add 800 ml of water and twice extracted with the mixture using 500 ml of ethyl acetate. The combined organic phases are washed with 300 ml of water, then remove the solvent at 30° and under reduced pressure. The remaining dark orange oil (9.7 g) is purified by means of chromatography (300 g silica gel; MTB ether/heptane 5:1; 1.5 liters). Remains of 9.9 g of light yellow crystals (67%), TPL 101-103°; 296 MS (M+), 205, 119, 91 (100%).

2) Synthesis of ethyl 4-(4-benzylpiperazine-1-yl)-2-formylphenoxy

In nitrogen atmosphere, 0.5 g of 5-(4-benzylpiperazine-1-yl)-2-hydroxybenzaldehyde dissolved in 5 ml of NMP at 20°under stirring, then add 0.25 g of potassium carbonate and 0.2 ml of ethylbromoacetate. The mixture was stirred at 110° for 4 hours and cooled to 15°then to the mixture add recipients who have 30 ml of water and 30 ml of ethyl acetate, share phase, and the aqueous phase is extracted using 30 ml of ethyl acetate. Combine the organic phase, washed twice in their 30 ml of water and freed from solvent under reduced pressure. The remaining yellow oil (0.7 g) is subjected to chromatography on 10 g of silica gel (MTB ether/heptane 5:1), and obtain 0.45 g of product (70%; yellow oil, MS : 382 (M+), 296, 263, 199, 149, 119, 91 (100%).

Example 5

1) Synthesis of ethyl 5-(4-benzylpiperazine-1-yl)benzofuran-2-carboxylate

With stirring, 0.5 g of 5-(4-benzylpiperazine-1-yl)-2-hydroxybenzaldehyde add at 20° to 5 ml of NMP, and then to the solution was added 0.25 g of potassium carbonate and 0.2 ml of ethylbromoacetate. The mixture was stirred at 105° for 15 hours, then cooled to 25°. The received portion is added to 30 ml of water (10°) with stirring, and then the aqueous phase is shaken out three times with a 10° using 50 ml of ethyl acetate, the combined organic phases are washed them in 50 ml of water and freed from solvent under reduced pressure (1.2 g orange oil). Using column chromatography on 30 g of silica gel (MTB ether/heptane 5:1) gain of 0.43 g of light yellow crystals (71%), TPL 105-107°; 364 MS (M+), 268, 204, 146, 119, 91 (100%).

Samples of the corresponding hydrochloride (TPL 219-222°) can be obtained by dissolving in ethanol, followed by addition of aqueous 1N what olaney acid, allocation obtained solid phase and drying under reduced pressure.

Example 6

1) Synthesis of 5-(4-benzylpiperazine-1-yl)benzofuran-2-carboxamide

When mixing 500 mg of 5(4-benzylpiperazine-1-yl)-2-hydroxybenzaldehyde add at 20° in the atmosphere of nitrogen to 5 ml of NMP, and then to the solution was added 0.25 g of potassium carbonate and 0.2 ml of ethylbromoacetate. The mixture was stirred at 105° for 15 hours and cooled to 25°. Then to the mixture is added 0.2 ml of formamide and stirred for another 30 minutes. Next, at 25° within 15 minutes, add 1 ml of sodium methoxide (30% solution in methanol), and then the mixture was stirred at 25-30° for another 3 hours. Then the reaction mixture was poured into 30 ml of water (10°), thrice extracted the aqueous phase with 10° using 50 ml of ethyl acetate, the combined organic phases are washed them in 50 ml of water, and remove the solvent under reduced pressure (0.7 g orange oil). Produce recrystallization of the oil from 10 ml of toluene (375 mg of light yellow crystals; 66%), TPL 206-208°; MS 335 (M+), 244, 189, 146, 91 (100%).

After removal of the protective groups is obtained 5-(1-piperazinil)benzofuran-2-carboxamide.

Example 7

1) Synthesis of 5-(4-tert-butoxycarbonylmethyl-1-yl)-2-hydroxybenzaldehyde

of 0.58 g of bis(dibenzylideneacetone)Palladia 0.16 g three-tert-butylphosphine add in a nitrogen atmosphere to 200 ml of toluene, and the resulting solution, which becomes dark red, stirred at 20° within 30 minutes. Then add 10 g of 5-bromo-2-hydroxybenzaldehyde, 10.2 g of tert-butyl 1-piperidinecarboxylate and 7.2 g of tert-butoxide sodium. The mixture was stirred at 60° within 24 hours and cooled, then add 800 ml of water and twice extracted with the mixture using 500 ml of ethyl acetate. The combined organic phases are washed with 300 ml of water, then remove the solvent at 30° and under reduced pressure. The remaining dark orange oil (11 g) is purified by means of chromatography (300 g silica gel; MTB ether/heptane 5:1; 1-5 liters); remains of 7.8 g of light yellow crystals (51%), TPL 84-86°; MS 306 (M+), 250 (100%), 233, 176, 164.

2) Synthesis of ethyl 4-(4-tert-butoxycarbonylmethyl-1-yl)-2-formylphenoxy

In nitrogen atmosphere, 0.5 g of 5-(4-tert-butoxypropan-1-yl)-2-hydroxybenzaldehyde dissolved under stirring in 5 ml of NMP at 20°, then add 0.25 g of potassium carbonate and 0.2 ml of ethylbromoacetate. The mixture was stirred at 110° within 30 minutes and cooled to 25°. Then to the mixture is added 30 ml of water and 30 ml of ethyl acetate, and the separated phase, after which the aqueous phase is extracted using 30 ml of ethyl acetate. The combined organic phases are washed with 30 ml of water and then freed from solvent under reduced pressure. To the remaining suspension of crystals add 30 ml of toluene, 30 ml of water and 5 ml of 1N HCl, and then the toluene phase is removed under reduced pressure, the crystalline residue is separated and at 40° dried under reduced pressure (0,48 g; 75%), TPL 93-94°C; MS 392 (M+), 336 (100%), 250, 249, 57.

Example 8

1) Synthesis of ethyl 5-(4-tert-butoxycarbonylmethyl-1-yl)benzofuran-2-carboxylate

520 mg of 5-(4-tert-butoxycarbonylmethyl-1-yl)-2-hydroxybenzaldehyde add at 20° in nitrogen atmosphere with stirring to 5 ml of NMP, and then to the solution was added 0.25 g of potassium carbonate and 0.2 ml of ethylbromoacetate. The mixture was stirred at 105° for 3 hours, then cooled to 25°. The received portion is added to 30 ml of water (10°) with stirring, the aqueous phase is shaken out three times with a 10° using 30 ml of ethyl acetate, the organic phases are combined and washed first with 30 ml of saturated NaCl solution, then 30 ml of water and freed from solvent under reduced pressure (0.6 g orange oil with crystalline components). After chromatography on 30 g of silica gel (MTB ether/heptane 5:1) you can select 0.45 g of light-yellow crystals (70%), TPL 116-117°; MS 374 (M+), 318 (100%), 244, 232.

Example 9

1) Synthesis of 5-(4-tert-butoxycarbonylmethyl-1-yl)-benzofuran-2-carboxamide

At 20° 1.04 g of 5-(4-tert-butoxycarbonylmethyl-1-yl)-2-hydroxybenzaldehyde atmosphere nitrogen with stirring to 10 ml of NMP, then to the solution was added 0.5 g of potassium carbonate and 0.4 ml of ethylbromoacetate. The mixture was stirred at 120° for 5 hours and cooled to 25°. Then added to the mixture, 0.4 ml of formamide, and continue to mix for another 30 minutes. Then within 15 minutes, without cooling, add 1.9 ml of sodium methoxide (30% solution in methanol), and continue stirring for another hour at 25-30°. To this party add 30 ml of water and 30 ml of ethyl acetate, separate the phases, and the aqueous phase is extracted using 30 ml of ethyl acetate. The combined organic phases are washed in 30 ml of water, and remove the solvent under reduced pressure (1.1 g orange crystalline suspension). After crystallization using 20 ml of toluene remains 500 mg light beige crystals. The mother liquor is evaporated and the remaining oil is dissolved in 10 ml of toluene. After 3 hours at 0° formation of new light-beige crystals (identical with the first crystals; 70 mg). The total yield (0.57 g) is 49%, TPL 202-204°, MS : 345 (M+), 289 (100%), 272, 244, 215, 203.

After removal of the BOC group according to the already described method get 5-(1-piperazinil)benzofuran-2-carboxamide.

Example 10

1) Synthesis of 5-(4-tert-butoxycarbonylmethyl-1-yl)-benzofuran-2-carboxamide

5 ml of 1-methyl-2-pyrrolidone, 0.16 g of chloroacetamide and 0.25 g of potassium carbonate in 20°add with stirring is tmosphere nitrogen to 0.5 g of 5-(4-tert-butoxycarbonylmethyl-1-yl)-2-hydroentangled. The mixture was stirred at 60°C for 16 hours, cooled and filtered, and then remove the solvent under reduced pressure. The residue is placed in MTV broadcast, re-filtered and concentrated, then the residue is crystallized from toluene. The output of the selected product is about 0.34 g (60%).

2) Synthesis of 5-(4-benzylpiperazine-1-yl)benzofuran-2-carboxamide

10 ml of 1-methyl-2-pyrrolidone, 0.4 g of chloroacetamide and 0.8 g of potassium carbonate are added during 20°under stirring in nitrogen atmosphere to 1.0 g of 5-(4-benzylpiperazine-1-yl)-2-hydroxybenzaldehyde. The mixture was stirred at 60° for 16 hours, cooled, filtered, and then remove the solvent under reduced pressure. The residue is placed in MTV broadcast, re-filtered and concentrated, then the residue is crystallized from toluene. The output of the selected product is 0.73 g (65%).

1. The method of obtaining 5-(1-piperazinil)benzofuran-2-carboxamide, characterized in that in a single reactor conduct the reaction of 5-bromosalicylaldehyde first compound with the formula I

in which

L denotes Cl, Br, I or reactionsare esterified group HE,

R1represents alkyl containing from 1 to 6 carbon atoms or benzyl,

and then formamide, and get a 5-L-benzofuran-2-carboxamide (II), in L represents Cl, Br, I or reactionsare esterified group HE,

(II) further subjected aminating with catalysts of transition metals, which conduct the reaction with R2-piperazine, in which R2represents H or aminosidine group, and get a connection with formula III

in which R2denotes H or aminosidine group, and further, if R2≠N, R2otscheplaut,

and/or the fact that 5-(1-piperazinil)benzofuran-2-carboxamide is converted into one of its salts by treatment with acid.

2. The method of obtaining 5-(1-piperazinil)benzofuran-2-carboxamide, characterized in that conduct the reaction of the compound with formula IV

in which

L denotes Cl, Br, I or reactionsare esterified group HE,

R3denotes N or CH2R6,

R4and R5together are a carbonyl,

R6denotes CN, COOH, COOR7or CONH2,

R7represents alkyl containing from 1 to 6 carbon atoms,

when aminating with catalysts of transition metals, with R2-piperazine, in which R2denotes H or aminosidine group, and get a compound with the formula V

in which

R2denotes H or aminosidine group,

R3denotes N or CH2R6,

R4and R5together are a carbonyl,

R6denotes CN, COOH, COOR7or CONH2,

R7represents alkyl containing from 1 to 6 carbon atoms,

and then carry out the reaction in a single reactor of the first compound with the formula I

in which

L denotes Cl, Br, I or reactionsare esterified group HE,

R1represents alkyl containing from 1 to 6 carbon atoms, or benzyl,

and then with formamide, and get a connection with formula III

in which R2denotes H or aminosidine group,

and then, if R2≠N, R2otscheplaut,

and/or the fact that 5-(1-piperazinil)benzofuran-2-carboxamide is converted into one of its salts by treatment with acid.

3. The method of obtaining 5-(1-piperazinil)benzofuran-2-carboxamide, characterized in that conduct the reaction of the compound with formula V

in which

R2means aminosidine group,

R3denotes N or CH2R6,

p num="251"> R4and R5together are a carbonyl,

R6denotes CN, COOH, COOR7or CONH2,

R7represents alkyl containing from 1 to 6 carbon atoms,

with chloracetamide, and get a connection with formula III,

in which R2means aminosidine group,

and then R2otscheplaut,

and/or the fact that 5-(1-piperazinil)benzofuran-2-carboxamide is converted into one of its salts by treatment with acid.

4. The method according to claim 1 or 2, characterized in that the catalytic system with transition metal is Pd(SLA)2/P(tert-butyl)3.

5. The method according to claim 1 or 2, characterized in that in the reaction of 5-bromosalicylaldehyde or compounds of formula V with a compound of formula I in the solvent used N-organic.

6. The compounds of formula V

in which

R2denotes H or aminosidine group,

R3denotes N or CH2R6,

R4and R5together are a carbonyl,

R6denotes CN, COOH, COOR7or CONH2,

R7represents alkyl containing from 1 to 6 carbon atoms,

as well as their salts and solvate.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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

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

25 cl, 6 tbl

FIELD: organic chemistry, medicine, pharmacy.

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

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

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 2 tbl, 15 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

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

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

10 cl, 2 tbl, 4 dwg, 9 ex

FIELD: organic chemistry, pharmaceutical compositions.

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

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

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

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

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

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: color-forming compositions and recording material.

SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.

EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.

21 cl, 14 tbl, 153 ex

The invention relates to a method for producing a condensed 2-getreleasedate General formula

using the diamine of General formula

where A=

R=2-furyl, 2-thienyl, 2-(1-methyl)pyrrolyl, 3-(1-methyl)indolyl, and aldehydes in the presence of acetate or copper sulfate, characterized in that the interaction takes place by boiling in 50% acetic acid, followed by decomposition of the copper salt, the effect on its suspension in 50% acetic acid sodium thiosulfate in 100With

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to 1-methyl-5-alkylsulfonyl-, 1-methyl-5-alkylsulfonyl - 1-methyl-5-alkylthiomethyl pyrazolylborate and herbicide tool based on them

The invention relates to tricyclic condensed heterocyclic compounds of the formula I, X is, for example, CH, CH2, СНR (where R means a lower alkyl group or a substituted lower alkyl group) or CRR' (where R and R' have the values specified above for R); Y means, for example, CH, CH2or C=O; z means, for example, S, S=O=; U denotes C; R1-R4independent means, for example, a hydrogen atom, SR (where R has the above values), phenyl group, substituted phenyl group, follow group, thienyl group, benzofuran or benzothiazyl at least one element of R5and R8means, for example, HE and the rest of the elements of R5and R8independent means, for example, a hydrogen atom; and their optical isomers, conjugates, and pharmaceutically acceptable salts

The invention relates to an improved process for the preparation of 1-nitroso-4-methylpiperazine, which finds application in the chemistry of drugs as an intermediate product in the synthesis of 1-amino-4-methylpiperazine and 1-methylpiperazine used for modern drugs: rifampicin, azaleptinum, triftazin, pefloksatsina, tetrazine and other drugs

FIELD: organic chemistry, chemical technology, pharmacy.

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

EFFECT: improved preparing methods.

6 cl, 10 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula I where A represents an optionally substituted aryl or heteroaryl, B - a benzene or thiophene cycle, C - a benzene or aliphatic hydrocarbon cycle, while values of other radicals are disclosed in the description. The compound according to the present invention, and the based pharmaceutical compositions exhibit a strong antagonistic effect in relation to GnRH receptor that makes them applicable for treatment of GnRH-related diseases, particularly prostate cancer, benign prostatic hyperplasia, breast cancer, endometriosis and/or uterine fibroid tumour.

EFFECT: improved clinical effectiveness.

11 cl, 70 tbl, 765 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel sterically hindered phenols which are intermediate compounds for the further functionalisation of 2,6-diisobornyl phenol,

,

where the isobornyl fragments have the configuration (1S, 2R, 4R, 1'R, 2'S, 4'S), where the isobornyl fragments have the configuration (1S, 2R, 4R, 1'S, 2'R, 4'R) and (1R, 2S, 4S 1'R, 2'S, 4'S), R1 is a formyl group or a group of general formula II -(CH2)nNX2, where X is a C1-C8 alkyl radical, straight or branched, cyclohexyl-, morpholine-, piperidine-, benzyl-, salsolidine, salsoline, N-benzyl-1-phenylethylamine, n=1-10.

EFFECT: high output.

2 cl, 2 ex

FIELD: color-forming compositions and recording material.

SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.

EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.

21 cl, 14 tbl, 153 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: organic chemistry, pharmaceutical compositions.

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

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

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: organic chemistry, medicine, oncology, pharmacy.

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

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

10 cl, 2 tbl, 4 dwg, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 2 tbl, 15 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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

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

25 cl, 6 tbl

FIELD: organic chemistry, chemical technology, pharmacy.

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

EFFECT: improved preparing methods.

6 cl, 10 ex

Up!