Imidazole derivatives

 

(57) Abstract:

Usage: in medicine as inhibitors of the action of the hormone angiotensin. The inventive products - imidazole derivatives f-ly I, where R1-COOH, or R2- H-C3H7or H-C4H9, R3- Cl,CF3C2F5C6H5or COOH, R4- COOH, CHO, or CH2OH , provided that when R4-CH2OH , R3-C2F5and R2-H-C3H7b) when R3- COOH, R4also is COOH, C) when R2-H-C3H7, R3-C2F5and R4- COOH, R1- is the group of Reagent 1: compound f-crystals 2, where R2- has the specified values, R5-Cl, CF3C2F5C6H5or COO( C1-C4-alkyl), R6-COO(C1-C4) - alkyl), CH2OH or CHO Reagent 2: compound f-crystals 3, where X is halogen, p-toluensulfonate or methylsulfonate, R7-COO(C1-C4) -alkyl), CN, or reaction Conditions: in the midst of a solvent in the presence of a base at a temperature from 20C to the boiling point of the solvent. 10 table.

The invention relates to new imidazole derivative of General formula I

where R1-COOH Il is C6H5or COOH;

R4-COOH, CHO, or CH2HE, provided that

a) when R4-CH2OH, R3-C2F5and R2-n-C3H7,

b) when R3-COOH, R4also is COOH,

b) when R2-n-C3H7, R3-C2F5and R4-COOH, R1is a group which inhibit the action of the hormone angiotensin and can be used in medicine.

It is known that N-substituted imidazole derivatives can be obtained by the reaction of alkylation (I).

Known compound of the formula II, which is a structural analogue of the compounds I,

which also has activity as an antagonist of the angiotensin receptor and protivogipertonicheskoe activity.

The aim of the invention is to provide new derivatives of imidazole, which has a higher biological activity than structural analogue using a known method of alkylation of imidazoles.

The new imidazole derivatives of the formula I are obtained by the interaction of the imidazole derivative of the formula III:

where R2adopt these values,

R5-Cl, CF3C2F5C6H5
where X is halogen, n toluensulfonate or methylsulfonate,

R7-COO (C1-C4-alkyl), CN, or C(C6H5)3in a solvent in the presence of a base for 1-10 hours at a temperature of 20aboutC to the boiling point of the solvent in the case when R5, R6or R7ester group, it deesterification and produce the target product or in the case when R6-CH2OH, it is subjected to oxidation to obtain the target product, where R4-CHO or COOH, or in the case when R6-SNO possible after alkylation with a derivative of formula IV to recover it with obtaining the target product, where R6-CH2OH, or when R7-CN, he is transferred to the target connection, where R1or in the case when R7_ he is transferred to the target connection, where R1-

P R I m e R 1. Section a:

Obtaining methyl-4'-methylbiphenyl-3-carboxylate.

To a stirred solution of 25.2 g of methyl-3-iodobenzoate and 21.0 g of 4-iodotoluene at 180-190aboutC in an atmosphere of nitrogen is added to 30.3 g of copper powder portions over 1 h When it was added approximately one third of the powder, the reaction begins and the temperature spontaneously rises to 240aboutC. a Mixture of additional hours. Mixture is allowed to cool to room temperature and filtered, using benzene as solvent, the resulting filtrate was concentrated in vacuo to obtain the crude product.

Chromatography on a column of silica gel (elution with 50-100% benzene/hexane) followed by distillation of 7.60 g of methyl-4' -methylbiphenyl-3-carboxylate (so Kip. 114-115aboutWith/of 0.025 Torr) as a colourless oil: NMR (200 MHz, CDCl3), : 8,27 (Shir.with. 1H), to 7.99 (d, 1H), to 7.77 (d, 1H), 7,50 (t, 1H), 7,39 (A2IN2, 4H), of 3.94 (s, 3H), 2,41 (s, 3H).

Section C.

Obtaining methyl-4' -bromomethylbiphenyl-3-carboxylate.

The solution 7,31 g methyl-4' -methylbiphenyl-3-carboxylate, 5.75 g of N-bromosuccinimide, 0.125 g azo(visitorville) and 500 ml of carbon tetrachloride is refluxed for 3 hours After cooling to room temperature the resulting suspension it is filtered, and then concentrated in vacuo, get to 9.90 g of crude methyl-4' -bromomethylbiphenyl-3-carboxylate, which was used in subsequent reactions without further purification.

NMR (200 MHz, CDCl3): 8,28 (c, 1H), with 8.05 (d, 1H), 7,79 (d, 1H), to 7.67-of 7.48 (m, 5H), 4,55 (s, 2H), 3,98 (s, 3H).

The following bromomethylbiphenyl intermediate products obtained when in)

7,79 (d, 1H), 7,56-7,24 (m, 7H), 4,51 (s, 2H), 1,25 (s, N).

Section WITH:

Obtaining 1-[(3' -carbomethoxybiphenyl-4-ID)methyl]-2-butyl-4-chloro-5-oximate - imidazole.

To a suspension of 1.43 g of sodium methoxide in 20 ml of dimethylformamide at 25aboutTo add a solution of 5.00 g of 2-butyl-4(5)-chloro-5(4)-oximetronidazole in 15 ml of DMF. The resulting mixture was stirred at 25aboutC for 0.25 h, then to this mixture was added dropwise a solution to 9.90 g of methyl-4' -bromomethylbiphenyl-3-carboxylate in 15 ml of DMF. Finally, the reaction mixture is stirred at 40aboutC for 4 h After cooling to 25aboutThe solvent is removed in vacuum. The residue is dissolved in ethyl acetate and the solution washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product contains two stereoisomer, moving faster when TLC is a more potent isomer. Column chromatography on silica gel (eluate 10-25% ethyl acetate (benzene) causes of 3.85 g of 1-[(3' -carbomethoxybiphenyl-4-yl)-methyl]-2-BU - Tyl-4-chloro-5-oximetronidazole (so pl. 162-163aboutC).

Stereoisomer with higher Rf: NMR (200 MHz, CDCl3), 8,24 (s, 1H), 8,03 (d, 1H), 7,76 (d, 1H), 7,52 (t, 1H), 7,33 (A2IN2, 4H), at 5.27 (s, 2H), to 4.52 (d, 2H), 3,93 (S, 3H), 2,60 (t, 2H),biphenyl-4-yl)methyl]-2-butyl-5-oxymethylene - ash.

Smesi of 1.00 g of 10% palladium on coal and 1.00 g of 1-[(3' -carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-oxymethylene - dazole in 20 ml of methanol is stirred at 25aboutC for 5 min Hydrogen is bubbled into the solution and the mixture is stirred in an atmosphere of H2(g) (1 ATM.) at 25aboutWith over 3.5 hours the Mixture filmout and the resulting solution was concentrated in vacuo. Column chromatography (eluate: 0-5% methanol (chloroform) leads to 0.33 g of 1-[(3-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-5-hydroxy-methylimidazole.

NMR (200 MHz, DMSO-d6) to 8.20 (s, 1H), 7,98 (d, 2H), 7,65 (t, 1H), 7,41 (A2M2, 4H), to 6.80 (s, 1H), and 5.30 (s, 2H), 5,12 (t, 1H), 4,37 (d, 2H), 3,90 (s, 3H), 2,52 (t, 2H) and 1.51 (quintet, 2H), 1.27mm (sextet, 2H), 0,80 (t, 3H).

The following intermediate products are shown below in table. 1, obtained according to the methods described in example 1.

P R I m e R 4. Part A.

Obtaining 1-[(3' -carbomethoxybiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-methoxymethyl - imidazole.

A solution of 5.00 g of 1-[(3' -carbomethoxybiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-oxime-elimidate and 1 ml of concentrated sulfuric acid in 200 ml of methanol is refluxed for 20 hours, After cooling the solvent is removed in vacuo and the residue poured into saturated the s phase is washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. After chromatography was carried out on a column of silica gel (elution: 0-20% ethyl acetate (benzene) to obtain 5.35 g of 1-[(3' -carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethyl-imidazole.

NMR (200 MHz, CDCl3), compared to 8.26 (t, 1H), 8,03 (l, t, 1H), 7,76 (d of t, 1H), 7,51 (t, 1H). 7,33 (A2M2, 4H), 5,20 (s, 2H), or 4.31 (s, 2H), of 3.94 (s, 3H), of 3.27 (s, 3H), 259 (t, 2H), by 1.68 (Quint, 2H), 1,34 (Sextus. 2N), of 0.87 (t, 3H).

The following intermediates obtained using the above methods.

The characteristics of the intermediate compounds are given in table. 2.

P R I m e R 7 (a known compound). Part A.

Obtain 4' -methylbiphenyl-2-carboxylic acid.

Methyl-4' -methylbiphenyl-2-carboxylate (10.0 g, a 44.2 mmol, 1 EQ) in 0.5 n KOH in methanol (265,5 ml, 133 mmol, 3 EQ.) and water (50 ml) are mixed and refluxed in an atmosphere of N2. After 5 h the solvent is removed in vacuo and water is added (200 ml ) and ethyl acetate (200 ml). The aqueous layer was acidified with concentrated hydrochloric acid to pH 3 and the layers separated. The aqueous phase is extracted with ethyl acetate (CH ml), organic layers combined, dried (MgSO4) and the solvent is distilled in vacuum, obtaining 8,71 g J=7 Hz), 7,40 (t, 1H, J=Hz), 7,25 (s, 4H), of 2.36 (s, 3H).

Calculated With 79,23; N 5,70.

WITH14H12ABOUT2:

Found, 79,22; N 5,47.

Part of the Century.

Obtain 4' -methyl-2-cyanobiphenyl.

4' -Methylbiphenyl-2-carboxylic acid (8,71 g, 41 mmol, 1 EQ.) and thionyl chloride (30,0 ml, 411 mmol, 10 EQ) are mixed and refluxed for 2 hours, the Excess thionyl chloride is distilled off in vacuum and the residue is dissolved in toluene. The toluene is removed by rotary evaporation and the technique of evaporation of toluene again, to make sure that all the thionyl chloride is removed. The crude acid chloride is then added slowly to a cold (aboutC) concentrated NH4OH (50 ml) so that the temperature remained below 15aboutC. After stirring for 15 minutes, add water (100 ml) and the precipitated solid. This substance is put together, well washed with water and dried in high vacuum over P2ABOUT5in a desiccator over night, getting 7,45 g of a white solid substance, so pl. 126,0-128,5aboutC.

NMR (200 MHz, DMCO-d6) 7,65-7,14 (m, 10H), 2,32 (s, 3H).

Calculated With 79,59; N. Of 6.20; N 6,63.

WITH14H13NO

Found, 79,29; N 6,09; N 6,52.

The above amide (7,45 g, 35 mmol, what lorid removed using the same methodology as described above. The residue is washed with a small amount of hexane, which is partially solubilities product, but also removes the impurity, receiving only 6.64 g of a white solid.

So pl. 44,0-47,0aboutC.

NMR (200 MHz, DMCO-d6) to 7.95 (d, 1H, J=8 Hz), 7,78 (t, 1H, J=7 Hz), 7,69-7,32 (m, 6N), 2,39 (s, 3H).

Calculated C 87,01; N 5,74.

WITH14H11N

Found, 86,44; N 5,88.

Part C.

Obtain 4'-methyl bromide-2-candidemia.

4' -Methyl-2-sandifer (5,59 g) bromilow in the benzyl position according to the method of example 1, part b, using benzoyl peroxide as initiator. The product is recrystallized from ether, receiving of 4.7 g of the product, so pl. 114,5-120,0about.

NMR (200 MHz, CDCl3) 7,82-7,37 (m, 8H), 4,50 (s, 2H).

Calculated With 61,79; N 3,70; N 5,15.

WITH14H10BrN.

Found, 62,15; N. Of 3.45; N 4,98.

Part D.

Getting 2-n-butyl-4-chloro-1-(2' -sandifer-4-yl/methyl)-5-(oxymethyl)-imida - ash.

4'-methyl bromide-2-sandifer (4.6 g) alkylate 2-n-butyl-4-chloro-5-(oxymethyl)imidazole by well-known methods.

Part A.

Processing and instant chromatography in 1:1 hexane (ethyl acetate on sisala from acetonitrile gives of 1.57 g of analytically pure product, so pl. 153,5-155,5aboutC.

NMR (200 MHz, CDCl3) 7,82-the 7.43 (m, 6), 7,12 (D. 2, J=8 Hz), 5,32 (s, 2), to 4.52 (s, 2), 2,62 (t, 2 J=7 Hz), 1.70 to (t t,2, J 7.7 Hz), 1.39 in (t, 2, J=7,7 Hz) of 0.90 (t, 3, J=7 Hz).

Calculated With 69,56; N. Of 5.84; N, 11,0.

WITH22H22lN3O

Found, 69,45; N. Of 5.89; N 10,79.

Part E.

Getting 2-n-butyl-4-chloro-5-oxymethyl-1-[(2' -(1H-tetrazol-5-yl)diphenyl-4-yl)methyl] imidazole. 2-n-butyl-4-chloro-1-(2' -sandifer-4-yl)methyl]-5-(oxymethyl) imidazole (11,93 g) in turn describes the product according to the method described in example 8, part C. the Product was then purified instant chromatography in 100% ethyl acetate to 100% ethanol on silica gel, getting the ceiling of 5.60 g of light yellow solid. By recrystallization from acetonitrile get 4,36 g of light yellow crystals, which melt at a wide temperature range. The crystals are placed in 100 ml of hot acetonitrile. The solid that did not dissolve, filter, receiving 1.04 g of product as light yellow solid substance, so pl. 183,5-184,5aboutC. After cooling the mother liquor gives in addition to 1.03 g of the product as a pale yellow solid, so pl. 179,0-180,0aboutC.

NMR (200 MHz, DMCO-d6) 7,75-of 7.48 (m, 4H), 7,07 (d, 2H, J=9 Hz),? 7.04 baby mortality (d, 2H, J=9 Hz), of 5.24 (s, 2H), 5,24 UB>22
H23ClN6O,

With 62,48; N 5,48, Cl Scored 8.38.

Found for solids that do not dissolve in 100 ml of acetonitrile, 62,73; N. Of 5.50; Cl compared to 8.26.

Found for solids withdrawn from the mother liquor, With 62,40; N 5,23; Cl 8,35.

P R I m e R 8.

Part A.

Getting 2-n-butyl-4-chloro-5-chloromethyl-1-[(2'-sandifer-4-yl)methyl] imida evil. HCl salt.

2-n-Butyl-4-chloro-5-oxymethyl-1-[(2'-TSI - antivenin-4-yl)-methyl]imidazole (15,00 g, or 39.3 mmol, 1 EQ.) converted into chloride. The reaction time is 5 o'clock

The crude solid product is washed with ether until the disappearance of the yellow color. Solid white powdery product is then dried in a high vacuum, the output 10,02 g, so pl. to 152.0-154,0aboutC.

NMR (200 MHz, CDCl3) a 7.85-7,46 (m, 6N), 7,20 (d, 2H, J=10 Hz), vs. 5.47 (s, 2H), 4,50 (s, 2H), 3,06 (t, 2H, J=7 Hz), 1,82 (so t, 2H, J=7,7 Hz), 1,45 (t, 2H, J=7,7 Hz) to 0.94 (t, 3H, J=7 Hz). Mass calculated for C22H21CL2N3, 397,1113.

Found 397, 1105.

Part of the Century.

Getting 2-n-butyl-4-chloro-1-[(2'-sandifer-4-yl)methyl]-5-(methoxymethyl them - dazole.

2-n-Butyl-4-chloro-5-chloromethyl-1-[(2'-TSI - antivenin-4-yl)-methyl]imidazole. HCl salt (5,00 g, 11.5 mmol, 1 EQ), sodium methoxide (1,37 g, to 25.3 mmol, 2.2 EQ. ) and methanol (1 water (200 ml). The layers are separated and the aqueous layer was extracted with ethyl acetate (CH ml). The organic layers are dried (MgSO4), the solvent is removed in vacuo and the residue instantly chromatographic on silica gel in 1:1 hexane/ethyl acetate, getting 4,08 g of a clear light yellow oil.

NMR (200 MHz, CDCl3) 7,82-the 7.43 (m, 6), 7,10 (d, 2H, J=7 Hz), 5,23 (s, 2H), 4,32 (s, 2H), 3,30 (s, 3H), 2,60 (t, 2H, J=7 Hz), to 1.70 (t of t, 2H, J=7,7 Hz) to 1.38 (t, 2H, J=7,7 Hz) to 0.89 (t, 3H, J=7 Hz).

Calculated With 68,11; N 6,54; Cl 9,58.

WITH23H24ClN3O

Found, 68,70; N 6,11; Cl 9,51.

Mass calculated for C23H24ClN3O, 393, 1607.

Found: 393,1616.

Part C.

Getting 2-n-butyl-4-chloro-5-methoxymethyl-1-[(2'-(1H-tetrazol-5-yl)diphenyl-4-methyl]their data

2-n-Butyl-4-chloro-1-[2'-sandifer-4 - yl-(methyl)-5-methoxymethyl]imidazole (3.9 g, 10 mmol, 1 EQ.) sodium azide (1,95 g, 30 mmol, 3 EQ).

Ammonium chloride (1.60 g, 30 mmol, 3 EQ.) mixed and stirred in DMF (150 ml) in a round bottom flask connected with a reflux condenser, in an atmosphere of N2. Then use an oil bath with a temperature controller in order to carry out the reaction at 100aboutC for 2 days, after which the temperature was raised to 120aboutC for 6 d the Reaction mixture is heated again for another 5 days at 120aboutC. the Reaction mixture is cooled, the inorganic salts filtered off and the filtered solvent is removed in vacuum. To the residue add water (200 ml) and ethyl acetate (200 ml) and the layers separated. The aqueous layer was extracted with ethyl acetate -(CH ml), organic layers combine together, dried (MgSO4) and the solvent is removed in vacuum, obtaining a dark yellow oil. Fast chromatography in 100% ethyl acetate receive of 3.54 g of a white glass.

NMR (200 MHz, CDCl3) 7,83 (d, 1H, J=7 Hz), to 7.59 (t, 1H, J=7 Hz), to 7.50 (t, 1H, J=7 Hz), 7,39 (d, 1H, J=7 Hz), 7,03 (d, 2H, J=8 Hz), 6.73 x (d, 2H, J= 8 Hz), to 5.08 (s, 2H), 4,12 (s, 2H), 3,18 (s, 3H), 2,32 (t, 2H, J=7 Hz), 1,52 (t of t, 2H, J=7,7 Hz), 1.28 (in t, 2H, J=7,7 Hz), or 0.83 (t, 3H, J=7 Hz). Mass calculated for C23H25ClN6O: 436,1178.

Found: 436,1750.

P R I m e R 9. Part A.

Obtaining 1-[(2'-tert-butoxycarbonyl-diphenyl-4-yl)methyl]-2-butyl-4-iodine-5-(2-IU - toxicokinetics]-imidazole.

The solution to 5.56 ml (n-utility)hexane and 80 ml of tetrahydrofuran at 0aboutWith added dropwise to 1.15 ml of tert-butanol. To the solution was added 3.28 g of 1-[(2-tert-butoxycarbonylmethyl-4-yl) methyl]-2-butyl-5-oxymethyl-4-itimidate - La followed by the addition of 1.15 ml of 2-methoxyethoxymethyl. The resulting solution was stirred Pym sodium sulfate, filter and concentrate. Chromatographytandem on columns get 2,61 g of 1-(2' -tert-butoxycarbonylmethyl-4-yl-methyl)] 2-butyl-4-iodine-5-(2-methoxyethoxymethyl)imidazole.

NMR (200 MHz, CDCl3) : for 7.78 (d, 1H), 7,43 (m, 2H), 7,28 (m, 3H), 6,98 (d, 2H), 5,26 (s, 2H), 4,69 (s, 2H), of 4.45 (s, 2H), 368 (m, 2H), only 3.57 (m, 2H), 3,37 (s, 3H), 2,58 (t, 2H), rate of 1.67 (Quint, 2H), 1,34 (Sextus, 2H), 1.26 in (C, N), of 0.87 (t, 3H).

Part of the Century.

Obtaining 1-[(2' -tert-butoxycarbonylmethyl-4-yl)-methyl]-2-butyl-5-(2-methoxy - ethoxyethoxy)-4-trifloromethyl - dazole.

To a suspension of 22.4 g of cadmium powder in 50 ml of dimethylformamide at 25aboutWith added dropwise at 8.60 ml bromargyrite.

The resulting mixture was stirred at 25aboutC for 2 h and then filtered through a filter Slence with an average pore size under nitrogen pressure, getting a dark brown solution of triptoreline reagent.

To a mixture of 15 ml of the specified solution and 20 ml of triamide hexamethylphosphoric acid at 0aboutWith the type of 2.10 g of copper bromide (1), and then adding 2,61 g of 1-[(2' -tert-butoxycarbonylmethyl-4-yl)methyl]-2-butyl-4-iodine-5-(2-methoxyethoxymethyl simetal) of imidazole in 5 ml of dimethylformamide. The reaction mixture was stirred at 70-75aboutC for 6 hours After the basics washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Chromatographytandem on columns (elution: ethyl acetate/hexane) to obtain 2.30 g of 1-[(2'-tert-butoxycarbonylmethyl-4-yl-methyl] -2-butyl-5-(2-methoxyethoxide oxymethyl)-4-Cryptor-methylimidazole.

NMR (200 MHz, CDCl3) 7,79 (d, 1H), 7,46 (m, 2H), 7,28 (m, 3H), of 7.00 (d, 2H), 5,28 (s, 2H), 4,71 (s, 2H), 4,58 (s, 2H), 3,66 (m, 2H), 3,54 (m, 2H), 3,38 (s, 3H), 2,62 (t, 2H), 1,70 (Quint, 2H), 1,36 (Sextus. 2H), 1.27mm (s, 3H), from 0.88 (t, 3H).

Part C.

Obtaining 1-[(2'-carboxyphenyl-4-yl)-methyl] -2-butyl-5-oxymethyl-4-crypto-methylamide ash

A solution of 2.30 g of 1-[(2' -tert-butoxycarbonylmethyl-4-yl)-methyl]-2-butyl-5-(2-method xiatotelex.html)-5-cryptomate - imidazole in 200 ml of 1.5 M aqueous terraforming acid/ acetonitrile was stirred at 25aboutC for 18 h, then the mixture is poured into water. The resulting aqueous solution was adjusted to pH 3 using a saturated solution of sodium bicarbonate and then extracted with chloroform. Combined organic phases are washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Chromatographytandem on columns (elution: methanol/chloroform) get to 1.38 g of 1-[(2' -carboxyphenyl-4-yl)methyl] -2-butyl-5-oxymethyl-4 - triptorelin), are 5.36 (s, 2H), 4,51 (s, 2H), has 2.56 (t, 2H), and 1.56 (Quint, 2H), 1,30 (Sextus. 2H), or 0.83 (t, 3H).

P R I m e R 10. Part A.

Getting eloxierarbeiten-4-yl-methyl-2-butyl-5-)2-methods xiaoxin etoc

To 20 ml of triptoreline reagent obtained in example 9, part b, add 2,80 g of copper bromide (1) and the resulting solution was stirred at 25aboutC for 14 hours At this stage, add 20 ml of triamide hexamethylphosphoric acid, and then adding 1,90 g of 1-[(2' -tert-butoxycarbonylmethyl-4-yl)-methyl] -2-butyl-4-iodine-5-(2-methoxyethoxyethoxy - methyl)-imidazole in 5 ml of dimethylformamide. Then the reaction mixture was stirred at 70-75aboutC for 6 hours After cooling, the mixture is diluted with water and then extracted with methylene chloride. Combined organic phases are washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Chromatography on columns (elution: ethyl acetate:benzene) get 1,71 g of 1-[2' tertbutoxycarbonyl-4-yl)methyl]-2-butyl-5-(2-methoxy-ethoxyethoxy Il)desola.

NMR (200 MHz, CDCl3) : to 7.77 (d, 1H), 7,55-7,35 (m, 2H), 7,27 (m, 3H), 6,97 (d, 2H), 5,28 (s, 2H), 4,69 (s, 2H), 4,55 (s, 2H), 3,65 (m, 2H), 3,53 (m, 2H), 3.33 and (s, 3H), 2.63 in (t, 2H), by 1.68 (Quint. 2H), 1,35 (Sextus. 2H), 1.26 in (C, N), of 0.87 (t, 3H).

This connection receive in accordance with the method described in example 9, part C. From 1,71 g of 1-[(2' -tert-butoxycarbonylmethyl-4-yl)methyl]2-butyl-5-(2-methoxyethoxide - oxymethyl)-4-pentafluorothiophenol get to 0.72 g of 1-[(2' -carboxyphenyl-4-yl)methyl] -2-butyl-5-oxymethyl-4-pentaho - recriminate (so pl. 190-191aboutC).

NMR (200 MHz, DMCO-d6) : 7,72 (d, 1H), to 7.61-7,42 (m, 2H), 7,34 (m, 3H), 7,11 (d, 2H), 5,50 (Sch.with. 2N), of 5.39 (s, 2H), 4,50 (s, 2H), 2, 55 (t, 2H), 1,50 (Quint, 2H), 1,25 (Sextus. 2H), 0,80 (t, 3H).

P R I m e R 11.

Part A.

Getting 2-butyl-1-[(2' -sandifer-4-yl)-methyl]5-oxymethyl-4-trifloromethyl - imidazole.

This connection receive in accordance with the method described in example 9, part a-N-2-butyl-1-[(2-sandifer-4-yl)-methyl]-5-oxymethyl-4-itimidate get 2-butyl-1-[(2-sandifer-4-yl)-methyl]-5-OK - dimetil-4-cryptomaterial (so to 136.5 square-137,5aboutC).

NMR (200 MHz, CDCl3) : 7,76 (d, 1H), to 7.64 (t, 1H), 7,56-7,42(m, 4H), was 7.08 (d, 2H), 5,33 (s, 2H) and 4.65 (d, 2H), the 3.65 (t, 2H), 1,97 (sh.T. 1H), 1.69 in (Quint. 2H), 1,38 (Sextus. 2N), of 0.89 (t, 3H).

Part of the Century.

Getting 2-butyl-5-oxymethyl-4-trifluoromethyl-1-[(2' -(triphenylmethanol-5-yl)diphenyl-4-yl)-methyl]imidazole.

A solution of 6.45 g of 2-butyl-1-[(2' -sandifer-4-yl)-methyl]-5-oxymethyl-4-tripto the 8 hours of reaction add portions 1.00 g trimethylaniline. After a total of 64 h of reaction at 115-120aboutThe mixture is cooled to 80aboutWith and filtered, obtaining 10,22 g white solid.

To a suspension of this solid in 60 ml of methylene chloride and 10 ml of THF at 25aboutWith added dropwise over several minutes of 1.65 ml of 10 N. aqueous sodium hydroxide solution and the mixture is stirred at 25aboutC for 15 minutes Then to the reaction mixture add 4,60 g triphenylmethylchloride and the resulting mixture was stirred at 25aboutC for 2 hours In the end, the mixture was poured into water and then extracted with methylene chloride. Combined organic phases are washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. By recrystallization of the crude product from a mixture of toluene/hexane get to 7.59 g of 2-butyl-5-oxymethyl-4-trifluoromethyl-1-[(2'- (triphenylmethanol-5-yl)diphenyl-4 - yl)methyl]imidazole.

NMR (200 MHz, CDCl3) : to 7.93 (d of d, 1H) 7,46 (m, 2H), 7,35-was 7.08 (m, N), of 6.90 (d, 6N), of 6.71 (d, 2H), 5,13 (s, 2H), 4,39 (d, 2H), 2,53 (t, 2H), and 1.63 (Quint, 2H), 1,30 (Sextus. 2H) to 0.85 (t, 3H).

Part C.

Getting 2-butyl-5-oxymethyl-1-[(2' -(1H-tetrazol-5-yl)diphenyl-4-yl)methyl]-4-three - pharmatramadol.

The solution 4,06 g of 2-butyl-5-oxymethyl-4-tertrahydrofuran stirred at 25aboutC for 2 h and then poured into water containing an excess of sodium hydroxide. The aqueous solution was washed with diethyl ether, adjusted to pH 3 with 10% hydrochloric acid, and then extracted with chloroform. Combined extracts in chloroform, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The chromatography was carried out on columns (elution: 10% methanol/chloroform) gives 2,04 g of 2-butyl-5-oxymethyl-1-[(2' -(1H-tetrazol-5-yl)diphenyl-4-yl)methyl]-4-cryptomaterial in the form of an amorphous solid.

NMR (200 MHz, DMCO-d6) : 7.68 per-7,47 (m, 4H), 7,02 (A2IN24H), 5,43 (sh.with. 1H), 5,27 (s, 2H), of 4.44 (s, 2H), 2,47 (t, 2H), 1,47 (Quint. 2H), 1,22 (Sextus. 2H), 0,77 (so 3H).

In table. 3 shows the connection 1, which receive according to the methods of examples 7-11.

P R I m e R 24. Obtaining 1-[(2' -carboxyphenyl-4-yl)methyl]-2-butyl-4-chlorine - Gasol-5-carboxaldehyde.

A mixture of 1.46 g of 1-[(2' -carboxyphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-oxymethylene - dazole and 7.30 g of activated manganese dioxide in 40 ml of tetrahydrofuran was stirred at 25aboutC for 5 days. The mixture is filtered through Celite and the filtrate concentrated in vacuo. The chromatography was carried out on a column of silica gel (elution: 2-Tyl]-2-butyl-4-chloroimidazo-5-carboxaldehyde (so pl. 154-158aboutWith/decomp).

NMR (200 MHz, DMCO-d6) : 1 2,85 (sh.with. 1H), made up 9.77 (s, 1H), to 7.77 (d, 1H), 7.62mm (t, 1H), 7,50 (t, 1H), 7,40 (d, 1H), 7,26 (A2IN2, 4H), 5,67 (s, 2H), 2,70 (t, 2H), and 1.56 (Quint. 2H), 1.28 (in Sextus. 2H), or 0.83 (t, 3H).

P R I m e R 25. Obtain methyl 1-[(2' -carboxyphenyl-4-yl)methyl]-2-butyl-4 - chloroimidazo-5-carboxylate.

To a mixture of 1.45 g of 1-[(2' -carboxyphenyl-4-yl)-methyl]-2-butyl-4-chloroimidazo-5-ka-roccalbegna and of 0.91 g of sodium cyanide in 20 ml of methanol at 25aboutWith the type of 0.32 ml of acetic acid followed by the addition of 7.25 g of manganese dioxide. The resulting mixture was stirred at 25aboutC for 40 h, the Reaction mixture was filtered through Celite and the filtrate is diluted with water. The aqueous solution was adjusted to pH 3 using hydrochloric acid and extracted with methylene chloride. Combined organic phases are washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product is recrystallized from sulphuric ether, receiving of 0.90 g of methyl-[(2' -carboxyphenyl-4-yl)methyl]-2-butyl-4-chloroimidazo-5-ka-rboxylic (so pl. 154-155aboutC).

NMR (200 MHz, DMCO-d6) : was 12.75 (W.with. 1H), 7,73 (d: 1H), 7,58 (t, 1H), 7,46 (i.e 1H). 7,34 (m, 3H), 7,07 (d, 2H), 5,63 (s, 2H), of 3.78 (s, 3H), to 2.67 (t, 2H), and 1.56 (Quint, 2H), 1,29 (Sextus. 2H), or 0.83 (t, 3H).

is caldereta.

A mixture of 2.06 g of 1-[(2' -carbomethoxybiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-oxime-elimidate and is 3.08 g of activated manganese dioxide in 20 ml of methylene chloride at 25aboutWith is stirred for 40 hours, the Reaction mixture was filtered through Celiteand the filtrate concentrated in vacuo. The chromatography was carried out on columns (elution: ethyl acetate/benzene) network of 1.15 g of 1-[(2' -carbomethoxybiphenyl-4-yl)methyl]2-butyl-4-chlorine - imidazol-5-carboxaldehyde.

NMR (200 MHz, CDCl3) : 9,76 (s, 1H), 7,83 (d, d, 1H), 7,52 (t, d, 1H), 7,40 (t of d, 1H), 7,31 (d of d, 1H), 7,17 (A2IN2, 4H), to 5.58 (s, 2H), 3,63 (s, 3H), to 2.67 (t, 2H), 1,70 (Quint, 2H), 1,38 (Sextus. 2N), of 0.90 (t, 3H).

In table. 4 presents the compound I, which receive according to the methods of examples 24-26.

P R I m e R 36. Part A.

Obtain 2-propyl-4-chloroimidazo-5-carboxaldehyde.

This example illustrates predpochtitelnye method of obtaining compounds of example 17.

To a solution of 2-propyl-4-chloro-5-hydroxymethylimidazole (obtained according to U.S. patent N 4355040) so pl. 110,5-114aboutWith, of 32.0 g (0,18 mol) in dichloromethane (1 l) was added activated manganese dioxide (207 g of 2.38 mol, 13 EQ. ). The resulting mixture was stirred for 4-18 h at room temperature and then the and the filtrate was concentrated in vacuum with the receipt of 24.7 g of pale yellow solid. By recrystallization from ethyl acetate received 16.6 g (53%) of pure product, so pl. 139-141,5. NMR (200 MHz, CDCl3CD3OD, TMC) : being 9.61 (singlet, 1H), 2,66 (triplet, J=7.5 Hz, 2H), 1,83-1,67 (multiplet, 2H), and 0.98 (triplet, J=7 Hz, 3H).

Part of the Century.

Obtain 2-propyl-4-chloro-1[(2' -(1-triphenylmethanol-5-yl)biphenyl-4-ilma - til]imidazol-5-carboxaldehyde. To a mixture of 2-propyl-4-chloroimidazo-5-carboxamide guide (15.0 g, 86,9 mmole) and potassium carbonate (13,2 g, 95,6 mmole) in N,N-dimethylformamide (800 ml) was added 4' -methyl bromide-2-(1-triphenylmethanol-5-yl)biphenyl (received under part b of example 38 (53,3 g, 4 95,6 mmole). The mixture was heated to 75-80aboutC for 4-18 h, cooled to room temperature and was poured into a separating funnel containing 1 l of water and 1 l of ethyl acetate. The aqueous phase was twice extracted with ethyl acetate (250 ml) the combined organic phase was washed with water (I ml) and saturated aqueous sodium chloride (500 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacume with obtaining a crude product.

In the cleaning method of the instant chromatography on silica gel (1 kg, 10-20% EtOAc (hexane) received 27.5 g (49%) of target compound as a pale yellow solid, so pl. 55-62, = 7.5 Hz, 2H), 1,75-1,64 (multiplet, 2H), 0,89 (triplet, J=7 Hz, 3H).

Part C.

Obtain 2-propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl/emida-evil-5-carb of Hexaldehyde

To slammy 2-propyl-4-chloro-1-[(2' -(1-triphenylmethanol-5-yl)biphenyl-4-yl)me - til] imidazol-5-carboxaldehyde (26,5 g of 40.8 mmole) in water (100 ml) was added dropwise within 15 minutes of a 50% aqueous solution triperoxonane acid (V/V, 200 ml). Even after 15 min the mixture was podslushivaet 4 N. NaOH solution (350 ml). The resulting mixture was extracted with ether (CH ml) and the aqueous phase was acidified to pH 4-5 4 N. HCl solution and the precipitate was extracted with ethyl acetate (CH ml). United an ethyl acetate layers were dried over anhydrous magnesium sulfate and then filtered and concentrated in vacuum to obtain 16 g of crude product.

In the cleaning method of the instant chromatography on silica gel (100 g, 50% EtOAc (hexane) was received of 13.7 g (83%) of purified target compound, so pl. 165-167 about.

NMR (200 MHz, CDCl3, TMS) : 9,65 (singlet, 1H), 7.95 is-of 6.96 (multiplet, 8H), 5,51 (singlet, 2H), 2,59 (triplet, J=7.5 Hz, 2H), 1.70 to 1,63 (multiplet, 2H), 0,92 (triplet, J=7 Hz, 3H).

P R I m e R 37. This example illustrates the method of obtaining the substance of example 4, frequent the CLASS="ptx2">

Preparation of 1-[(2'-(trimethylsilylmethyl-5-yl)diphenyl-4-yl)methyl] -2-butyl-4 - chloro-5-hydroxymethylimidazole

1-[(2' -Cyanobiphenyl-4-yl)methyl] -2-butyl-4-chloro-5-gidroksietilimino (766 g), azide trimethylurea (766 g) and of 7.90 l of xylene are placed in a 12-liter round-bottom flask equipped with a mechanical stirrer, a refrigerator with the introduction of nitrogen and a thermometer and enclosed by a heating jacket. The suspension is heated to 115aboutWith and get a clear solution, which was incubated for 41 hours the Resulting suspension is cooled to room temperature and the crude product is produce by vacuum filtration, washed his toluene (800 ml) and dried in vacuum at about 50aboutWith during the night. The crude product (1202) is loaded into a 12-liter round bottom flask and suspended him with 105aboutWith in toluene (7.0 l). This suspension is cooled to 50aboutWith and allocate product by vacuum filtration, washed with one liter of toluene and dried in vacuum at 50aboutWith during the night.

Output 1071, 94%

So pl. 211-214aboutC.

Part of the Century.

Preparation of 1-[(2' -(triphenylmethanol-5-yl)-diphenyl-4-yl)methyl] -2-butyl-4-chloro-5-hydroxym of ethylimidazole.

1-[(2' -(Trimet l) tetrahydrofuran (0,85 l) and 10 N. a solution of sodium hydroxide (192 ml) is placed in a 12-liter round bottom flask equipped with a mechanical stirrer, a refrigerator with the introduction of nitrogen and a thermometer. After stirring for 5 min at room temperature add chloride triphenylmethyl (0,530 kg) and the mixture is stirred for 3 hours Add 20 ml of 10 n sodium hydroxide solution and an additional amount (50 g) chloride triphenylmethyl and the mixture is stirred over night. Add 3,70 l of deionized water and 30 ml of 10 n sodium hydroxide solution and allow to separate the phases. The organic phase is twice probyvat 2.0-liter portions of water, dried with sodium sulfate (100 g) and filtered in a 12-liter round bottom flask equipped for distillation. Distilled to about 2.0 liters methylene chloride. Heat stop and add in 5.0 l of heptane. The resulting suspension is stirred at room temperature (approximately 68 hours). The mixture is cooled to about 5aboutWith the product, isolated by vacuum filtration, probyvat heptane (1.0 l), dried for 48 h in vacuum at 40-50aboutC.

Output 959,5 g, 80%

So pl. 167-169aboutC. the Purity 99.8% according to liquid chromatography high pressure.

Part C.

Cooked is-yl)diphenyl-4-yl)methyl] -2-butyl-4-chloro-5 - hydroxymethylimidazole (920 g) and 2.10 l of methanol is placed in a 12-liter round bottom flask, equipped with a mechanical stirrer, a refrigerator with the introduction of nitrogen and a thermometer. The suspension is cooled to approximately 10aboutWith and add 700 ml of 3.4 G. hydrochloric acid (for 10 min). After stirring 2 h at 10-20aboutWith thick suspension is diluted with methanol (500 ml) and heated to 30aboutC.

After 1 h at 30aboutWith the reaction mixture is neutralized to pH 13 with 10 n sodium hydroxide solution (420 ml). The solvent (mostly methanol 2.3 liters) distilled at new 2.3 liter deionized water. Heat stop and add 700 ml of deionized water and 1.40 l of toluene. After cooling to about 30aboutWith the organic phase removed. The aqueous phase is re-extracted with toluene (700 ml). Into the flask containing the aqueous phase, add 1,20 l of ethyl acetate. After stirring 10 min add 130 ml of acetic acid. The mixture is stirred for 1 h, then left to Mature overnight. Resume stirring and the mixture is cooled to about 5aboutC. the Product produce by vacuum filtration, re-suspended in a 1.50 l of deionized water and sucked the water up to a moist condition. The wet cake was placed in a 12 liter round bottom flask and re-suspended in 0.5 h pritate and dried in vacuum overnight at 50aboutC.

The output 518 g, 88.5% of So pl. 184-185aboutC.

Purity according to liquid chromatography high pressure: 98,8%

An NMR spectrum (200 MHz, perdeuteromethoxy): b-multiplet (chem. shift) to 7.61 (m, 4H), 7,05 (m, 4H), of 5.24 (s, 2H), 4,32 (singlet, 2H), 3,35 (Shir. singlet, 1H), 2,46 (triplet, 2H, J=7.8 Hz), 1,44 (multiplet, 2H), 1,23 (multiplet, 2H), 0,79 (triplet, 3H, J=7.2 Hz).

Part D.

Preparation of potassium salt of 2-butyl-4-chloro-5-gidroksimetil-1-[(2'-(1H-Tetra - Zol-5-yl)diphenyl-4-yl)methyl]imidazole.

The product from part C (11,00 g) and 30 ml of isopropyl alcohol is loaded into a 100-ml round bottom flask, equipped with magnetic stirrer, thermometer and a trap Dean-stark in nitrogen atmosphere. The suspension is heated to 40aboutC. Add a solution of 87% potassium hydroxide (2.00 g) (isopropanol/20 ml), water (1.0 ml) to pH 11 (18.5 ml). Most of the water is removed by azeotropic distillation with isopropanol (Argonauts 20 ml). Add 25 ml of heptane and the suspension is cooled to room temperature. Add an additional number (15 ml) of heptane and the mixture is stirred for 1/2 hour allocate Product by vacuum filtration, washed 1 time with heptane (20 ml) and dried over night at 60aboutWith the vacuum.

the capacity of the method of obtaining the substance of example 7, part E.

Part A.

Preparation of 2-(triphenylmethanol-5-yl)-4' -methylbiphenyl.

2-(para-Tolyl)benzonitrile (9.00 g), sodium azide (3.00 g), toluene (35 ml) and the presence of TBT chloride (16.4 g) are loaded into a 250-ml round bottom flask equipped with a mechanical stirrer, a refrigerator with the introduction of nitrogen and a thermometer in the heating jacket. This mixture is heated to 110aboutC and maintained for 70 hours the Mixture is diluted with 35 ml of toluene and cooled to room temperature. Add 5.5 ml of 10 n sodium hydroxide solution and 13.5 g of triphenylmethylchloride and the mixture is stirred for 3 h at room temperature. Add 35 ml of deionized water and 70 ml of heptane and the resulting suspension is cooled in an ice bath for 0.5-1 h the Mixture is filtered under vacuum, washed 2 times with water (50 ml) and once with 50 ml of a mixture (3:2 by volume) heptane/toluene and dried in vacuum overnight at 40aboutC. the Yield of crude substances equal 18,32 g (82% ). The crude product is dissolved in methylene chloride (200 ml) and washed with 1 time of 0.4 N. the solution of sodium hydroxide (52 ml). The organic phase is filtered under gravity, evaporated on a rotary evaporator and the product re-suspended in heptane (100 ml), filtered and dried in Vacu the effect of 4' -methyl bromide-2-(triphenylmethanol-5-yl)diphenyl.

In a round bottom flask with a capacity of 100 ml equipped with a thermometer, refrigerator, in an atmosphere of nitrogen injected 9.0 g of [2-((-triphenylmethanol-5-yl))-4' -methyl-1,1' -diphenyl (18,8 mmol), 4.0 g of N-bromosuccinimide are (22.5 mmol) of 0.1 g of azo(piezomechanical) (0.61 mmol) and 40 ml of carbon tetrachloride. The reaction mass is then cooled to room temperature, diluted with methylene chloride (30 ml) and washed with water (30 ml). The aqueous phase is discarded.

Part C.

Preparation of 2-n-butyl-4-chloroimidazo-5-carboxaldehyde.

2-n-Butyl-4-chloro-5-hydroxymethylene - Gasol (50.0 g, 265 mmol. 1 EQ.) dissolved in glacial acetic acid (150 ml). Then to mix the solution of imidazole are added dropwise 1 n solution of cerium (IV) ammonium nitrate (575 ml, 595 mmol, of 2.25 equiv.) maintaining the temperature of the mixture at 20-30aboutC. After complete addition, yet add 10 ml of 1 n solution of suryamaninagar, so that the mixture remained orange. After 3 h the reaction mixture was cooled on ice and add 50% sodium hydroxide solution (210 ml) to neutralize the acetic acid.

The product precipitates. The pH is brought to 6 and the solid is filtered, washed with water (3 x 500 ml) and dried eurohorror), ; 11,83 (multiplet, 1H), for 9.64 (singlet, 1H), 2,85 (triplet 2H, J=7 Hz), 1,78 (triplet of triplets, 2H, J= 7,7 Hz), 1,38 (triplet of quartets, 2H, J=7,7 Hz) 0,93 (triplet, 3H, J=7 Hz).

Calculated With 51,48; N 5,94; Cl 19,00; N 15,01.

WITH8H11ClN2O

Found, Won With 51.75; H Of 5.82; Cl 18,73; N 14,87.

Part D.

Preparation of 1-[(2' -(triphenylmethanol-5-yl)-diphenyl-4-yl)methyl] -butyl-4-chloro-5-hydroxymethylimidazole

The organic phase is loaded into a round bottom flask with a capacity of 100 ml, equipped with a fridge, a thermometer under nitrogen atmosphere. In addition flask is charged of 2.56 g of 2-butyl-4-chloroimidazo-5-carboxaldehyde (13.7 mmol), and 9.5 ml of water, and 2.8 ml of 10 n sodium hydroxide solution and 1.2 ml of aliquot 336, this two-phase system is stirred over night at room temperature. This reaction mass is added to 0.48 g of sodium borohydride (12.7 mmol) and the reaction mass is again stirred overnight at room temperature. Upon completion of the reaction mass is washed with 30 ml of water and the aqueous phase discarded.

The organic phase is introduced into a round bottom flask with a capacity of 100 ml equipped with a thermometer, a condenser phlegmy, collection and addition funnel. Methylene chloride and carbon tetrachloride is distilled off and reactio/SUP>C. the Reaction mass is then cooled to approximately 40aboutC and then diluted with 15 ml of ethyl acetate and 20 ml of n-heptane. Add the seed crystal and the reaction mass is additionally cooled to 0-10aboutC and stirred for 1.0 to 2.0 hours, the Suspension is filtered through a Buchner funnel and the solid washed with a small amount of cold mixture of toluene and ethyl acetate. The solid is dried in a vacuum Cabinet during the night, getting 5,91, the Output of 51.7% based on 2-butyl-4-chloro-imidazole-5-carboxaldehyde or to 47.2% (based on 2-(triphenylmethanol-5-yl)-4' -methylbiphenyl).

The crude material is subjected to recrystallization from 30 ml of toluene, receiving of 4.57 g of the product (emphasis on 77,33%) with a melting point 161-162,5aboutC.

Part E.

Preparation of 2-butyl-4-chloro-5-hydroxymethyl-1-[(2' -(1H-tetrazol-5-yl)-diphenyl-4-yl)methyl]imidazole and its potassium salt.

The product of part C in turn specified in the procurement of a connection and its potassium salt by the method of example 37, part C, and D.

P R I m e R 39.

Part A.

Preparation of 2-butyl-4-chloro-1[(2' -N-triphenylmethyl-(1H-tetrazol-5-yl) diphenyl-4-yl)methyl]imidazole-5-carboxaldehyde.

2-n-Butyl-4-chlorimide (80,0 g, 143 mmol, 1 EQ.) (extracted from example 38, part b) by a known method.

After chromatography was carried out and recrystallization from a mixture of hexane-tetrahydrofuran one-third of the crude material was obtained quintiles these figures were 19.63 g of a white powder with so pl. 86,0-88,0aboutC.

An NMR spectrum (portaterraferma): 9,76 (singlet, 1H), of 7.96 (doublet, 1H, J=8 Hz), 7,56-6,80 (multiplet, 22N), 5,47 (singlet, 2H), 2,53 (triplet, 2H), 1,65 (triplet of triplets, 2H, J=7,7 Hz), 1,30 (triplet of quartets, 2H, J= 7,7 Hz), 0.83 (triplet, 3H, J=7 Hz).

Calculated With 73,5; N. Of 5.89; N 11,43.

WITH41H35ClN6O.

Found, 73,32; N 5,88; N 11,84.

P R I m e R 40. Part A.

Preparation of 4-carbomethoxy-5-hydroxymethyl-2-n-propyl-1-[(2' -N-triphenylmethyl(1H-tetrazol-5-yl)diphenyl-4-yl)me - til]imidazole.

4,5-Dicarboxy-2-n-propyl-1-[(2' -N-triphenylmethyl(1H-tetrazol-5-yl)WPPT-Neil-4-yl)methyl] imidazole (see example 59) (10.0 g, 14.0 mmol, 1 EQ) is dissolved in 50 ml of tetrahydrofuran and there, add a solution of tri-tert-butoxycarbonylamino lithium in tetrahydrofuran (7.2 g, 28,0 mmol/,2 EQ). After 24 h, add another 0.5 EQ. the reducing agent. After another 24 h the reaction is interrupted by adding 10 ml of methanol, and the solvent is removed in vacuum. When chromatogr which According to NMR data, it is a 6:1 regioisomers at 4.5 the provisions of imidazole.

An NMR spectrum (in deuterium chloroform, main isomer) : of 7.96 (multiplet, 1H), 7,80 (multiplet, 2H), 7,39-7,18 (multiplet, 10H), 7,13 (doublet, 2H, J= 9 Hz), 6,95 (multiplet, 6N), of 6.71 (doublet, 2H, J=9 Hz) 5,08 (singlet, 2H), 4,57 (doublet, 2H, J=6 Hz), 3,95 (singlet, 3H), 3,50 (multiplet, 1H), 2,55 (triplet, 2H, J=7 Hz), 1,65 (triple. quart. 2H, J=7,7 Hz), 1,62 (water) to 0.89 (triplet, 3H), J=7 Hz). Key peaks of impurity isomer (NMR) : the 5.45 (singlet, 2H), 4,84 (multiplet, 2H), 3,84 (multiplet, 1H), 3.72 points (singlet, 3H).

Calculated With 73,77; N 5,74; N 12,29.

WITH42H38N6ABOUT3(H2O)0,5< / BR>
Found, With 73,54; N 5,76; N 12,59.

Part of the Century.

Preparation of 4-carbomethoxy-5-hydroxymethyl-2-n-propyl-1-[(2' -(1H-tetrazol-5-yl)diphenyl)methyl]imidazole.

The product from part 4 is subjected to demethylation by the method of example 59 and receive a glassy mass. The crystallization is carried out by stirring in ethyl acetate. So pl. 113-210about(Observed decomposition). An NMR spectrum (perdeuteromethoxy) : 7,54 (multiplet, 1H), 7,43-7,28 (multiplet, 3H), 7,08 (doublet, 2H, J=9 Hz), 6,88 (doublet, 2H, J=9 Hz), and 5.30 (singlet, 2H), 4.72 in (singlet, 2H), of 3.73 (singlet, 3H), 2,48 (triplet, 2H, J= 7 Hz), and 1.56 (triplet, quart.2H, J=7,7 Hz), 0,87 (triplet, 2H, J=7 Hz).

IR-spectrum (in notkola), 3206 (lat.) 1B>O)3,5< / BR>
Found, With 55,83; N 5,71; N 16,86.

P R I m e R 41.

Getting 5-hydroxymethyl-2-n-propyl-1-[(2' -(1H-tetrazol-5-yl)diphenyl)methyl]imidazole-4-carboxylic acid.

The product from example 40, part a, is subjected to the interaction with triperoxonane acid as described in example 36, part C. After acidification of the aqueous phase with hydrochloric acid formed adhesive material is stirred in an aqueous mixture, to which was added ethyl acetate. A white crystalline product which is insoluble in both phases. This product is filtered and dried. So pl. 250about(Darkening above 275aboutC). An NMR spectrum (perdeuteromethoxy),

7,73-7,47 (multiplet, 4H), 7,07 (doublet, 2H, J=9 Hz), 6,98 (doublet 2H, J= 9 Hz), and 5.30 (singlet, 2H), 4.72 in (singlet, 2H), 3,5 (water) 2,44 (triplet, 2H, J=7 Hz), 1,52 (triplet, square 2H, J=7,7 Hz) of 0.85 (3H triplet, J=7 Hz).

Calculated With 62,47; N Are 5.36; N 19,87.

WITH22H22N6O3(H2O)of 0.25< / BR>
Found, 62,63; N A 5.25; N 19,51.

P R I m e R 42. Getting 2-butyl-1-[(2' (1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-4-three - pharmatramadol-5-carboxylic acid.

A mixture of 4.00 g 2 util-5-hydroxymethyl-4 - trifluoromethyl-1-[(2'-triphenylmethanol-5-yl)-biphenyl - 4-yl) methyl them is 24 h the reaction mixture was added to 2.00 g of manganese dioxide. After 100 h, the reaction mixture was filtered using methylene chloride. Then, the solids were washed with methanol and the methanol filtrate was concentrated. The residue was dissolved in water. The resulting aqueous solution was brought to pH 3 with 10% hydrochloric acid and then was extracted with a mixture of chloroform/isopropanol. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. In the cleaning method of column chromatography (elution with a mixture of chloroform/methanol/acetic acid in the ratio 95:5: 0.5) is received 0.25 g of 2-butyl-1-[(2' -(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl] -4-triptoreline - evil-5-carboxylic acid as an amorphous solid.

NMR (200 MHz, DMCO-d6) : 7,70-of 7.48 (multiplet, 4H), 7,00 (A2IN2, 4H), 5,58 (singlet, 2H), 2,59 (triplet, 2H) and 1.51 (quintet, 2H), 125 (sextet, 2H), 0,79 (triplet, 3H).

A. NMR (200 MHz, CDCl3CD3OD, TMS/ 7,88-6,90 (multiplet, 8H), 5,52 (singlet, 2H), 2.63 in (triplet, J=7.5 Hz, 2H), 1.77 in-1,66 (multiplet, 2H), 0.95 (triplet, J=7 Hz, 3H).

b. NMR (200 MHz, DMCO-d6) : 7,46-7,63 (multiplet, 4H), 7,05 (doublet, 2H, J= 8 Hz), 6,93 (doublet, 2H, J=8 Hz), 5.56mm (singlet, 2H), 4.1 (singlet, N), 2,55 O-d6) : 7,71-7,50 (multiplet, 4H), 7,02 (A2IN2, 4H), ceiling of 5.60 (singlet, 2H), 2,59 (triplet, 2H), 1.57 in (sextet, 2H), 0.84 (triplet, 3H).

d. NMR (200 MHz, DMCO-d6) : 7,74-7,52 (multiplet, 4H), 7,05 (A2IN2, 4H), 5,58 (singlet, 2H), 2,62 (triplet, 2H) and 1.51 (quintet, 2H), 1,25 (sextet, 2H), 0,80 (triplet, 3H).

E. NMR (200 MHz, DMCO-d6) : 7,73-7,53 (multiplet, 4H),? 7.04 baby mortality (A2IN2,4H), 5,58 (singlet, 2H), 2,60 (triplet, 2H), and 1.56 (sextet, 2H), 0.84 (triplet, 3H).

f. NMR (200 MHz, DMCO-d6) : 13,78 (sh.with. 1H), 12,82 (sh.with. 1H), 7,75 (doublet, 1H), to 7.59 (triplet, 1H), 7,47 (triplet, 1H), 7,35 (multiplet, 3H), 7,08 (doublet, 2H), 5,63 (singlet, 2H), 2,66 (triplet, 2H), 1,61 (sextet, 2H), 0,86 (triplet 3H).

g. NMR (200 MHz, DMCO-d6): : 13,73 (sh.with. 1H), 12,80 (sh.with. 1H), 7,74 (doublet, 1H), to 7.59 (triplet, 1H), 7,46 (triplet, 1H), 7,33 (multiplet, 3H), 7,07 (doublet, 2H), 5,65 (singlet, 2H), 2,65 (triplet, 2H), 1,62 (sextet, 2H), 0,85 (triplet, 3H).

Substances of examples in table. 5 were obtained using the methods described in example 42.

Also received compound 1, where R1R2-n-butyl, R3-Cl and R4-CH2OH (example No. 50).

P R I m e R 51. Part A.

Preparation of 4(5)-methyl-2-propylimidazol.

In a well-mixed mixture 72,0 ml of butyric aldehyde and 240 g of monohydrate Azem the mixture is heated to 80-100aboutC for 0.5 hours After the mix is allowed to cool down, the resulting gray-green precipitate allocate by filtering.

A suspension of this solid in water at 80aboutWith bubbled gaseous hydrogen for 0.5 h Then filtered while hot to remove the solid sulfide copper (I). After cooling to 25aboutThe mixture is extracted with methylene chloride. Then the combined organic phases are washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, obtaining of 26.4 g of 4(5)-methyl-2-propylimidazol in the form of a viscous orange oil.

NMR spectrum (200 MHz, portaterraferma) : 10,15 (sh.with. 1H), 6,61 (singlet, 1H), 2,64 (triplet, 2H), 2,20 (singlet, 3H), 1,72 (sextet, 2H), 0,92 (triplet, 3H).

Part of the Century.

Preparation of 4(5)-hydroxymethyl-5(4)-methyl-2-propylimidazol.

The solution to 21.0 g of 4(5)-methyl-2-propylimidazol, 14.0 g of 37% aqueous formaldehyde, 76,0 g of concentrated hydrochloric acid and 100 ml of water is refluxed for 62 hours After cooling, the mixture is diluted with water. The resulting aqueous solution is alkalinized to pH 10 with 10% aqueous sodium hydroxide solution and then extracted with a mixture of 4: 1 chlorine is, filter and concentrate. After chromatography was carried out on a column (elution with a mixture of 10% methanol) chloroform 0.2% concentrated ammonia) followed by recrystallization from ethyl acetate gives a 13.9 g of 4(5)-hydroxymethyl-5(4)-methyl-2-propylimidazol with a melting point 138,5-139,5aboutC.

NMR spectrum (200 MHz, perdeuteromethoxy) : 11,30 (sh.with. 1H), 4,68 (sh.with. 1H), 4.26 deaths (singlet, 2H), 2,46 (triplet, 2H), 2.06 to (singlet, 3H), 1,60 (sextet, 2H), from 0.88 (triplet, 3H).

Part C.

Preparation of 4(5)-methyl-2-propylimidazol-5(4)-carboxaldehyde.

To a solution of 12.1 g of 4(5)-hydroxymethyl-5(4)-methyl-2-propylimidazol in 200 ml of acetic acid at 25aboutTo add 170 ml of a 1.0 normal solution of cereomony nitrate in water is added dropwise within 1 h the Resulting solution is stirred for one hour at 25aboutC and then poured into water. This solution is brought to pH 4 using 10% aqueous sodium hydroxide solution and then extracted with chloroform.

The combined organic phases are washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product is subjected to recrystallization, getting to 9.66 g of 4(5)-methyl-2-propylimidazol-5(4)-carboxyl is nget, 1H), 253 (triplet, 2H), 2,38 (singlet, 3H), of 1.65 (sextet, 2H), 0,87 (triplet, 3H).

Part D.

Preparation of 1-[(2'-tert-butoxycarbonylmethyl-4-yl)methyl] -4-methyl-2-propylimidazol-2-carboxaldehyde.

A solution of 3.60 g of 4(5)-methyl-2-propylimidazol-5(4)-carboxaldehyde, 8,64 g of tert-butyl-4' -bromomethylbiphenyl-2-carboxylate, is 6.54 g of anhydrous potassium carbonate and 60 ml of dimethylformamide is stirred for 18 h at 25aboutC. the Reaction mixture was filtered, and the filtrate is diluted with water and then extracted with ethyl acetate. The combined organic extracts are filtered and concentrated. After chromatographic purification on a column, eluruumi a mixture of ethyl acetate/benzene, get of 6.31 g of 1-[(2'-tert-butoxycarbonylmethyl-4-yl)methyl] -4-methyl-2-propylimidazol-5-carboxaldehyde.

NMR spectrum (200 MHz, portaterraferma) : 9,77 (singlet, 1H), 7,78 (doublet, 1H), 7,51-7,35 (multiplet, 2H), 7,27 (multiplet, 3H), 7,05 (doublet, 2H), 5,59 (singlet, 2H), 2,64 (triplet, 2H), 2,50 (singlet, 3H), 1,78 (sextet, 2H), 1,20 (singlet, N), 0,97 (triplet, 3H).

Part E.

Preparation of 1-[(2' -carboxyphenyl-4-yl)methyl]-4-methyl-2-Propylamine - evil-5-carboxaldehyde.

This substance receive in accordance with the procedure described in example 9, part C, is'-carboxyphenyl-4-yl)-methyl)-4-methyl-2-propylimidazol-5-carboxaldehyde with so pl. 243-245aboutC.

NMR spectrum (200 MHz, perdeuteromethoxy), 12,77 (sh.with. 1H), 9,75 (singlet, 1H), 7,71 (doublet, 2H), 7,55 (triplet, 1H), 7,43 (triplet, 1H), was 7.36-7,27 (multiplet, 3H), 7,06 (doublet, 2H), 5,59 (singlet, 2H), 2,60 (triplet, 2H), 2,41 (singlet, 3H), 1,62 (sextet, 2H), 0,86 (triplet, 3H).

P R I m e R 52. Part A.

Preparation of 1-[(2'-tert-butoxycarbonylmethyl-4-yl)-methyl] -5-hydroxymethyl-4-methyl-2-propylimidazol.

To a solution of 3.43 g -[(2'-tert-butoxycarbonylmethyl-4-yl)-methyl] -4-methyl-2-propylimidazol-5-carboxaldehyde (from example 51, part D) in 22 ml of methanol and 22 ml of tetrahydrofuran at 25aboutWith added in several portions to 3.09 g of sodium borohydride. The reaction mixture was stirred at 25aboutC for 1.5 h and then poured into dilute aqueous sodium hydroxide solution. After stirring for 0.2 h at 25aboutWith this solution extracted with chloroform. The combined organic phases are washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The chromatography was carried out on a column, eluruumi a mixture of ethyl acetate/benzene, provides of 3.32 g of 1-[(2' -tert-butoxycarbonylmethyl-4-yl)-methyl] -5-hydroxymethyl-4-methyl-2-propylimidazol.

NMR spectrum (200 MHz, the(triplet, 2H), 2,21 (singlet, 3H), 1,71 (sextet, 2H), 1,25 (singlet, M), 0.95 (triplet, 3H).

Part of the Century.

Preparation of 1-[(2'-carboxyphenyl-4-yl)methyl] -5-hydroxymethyl-4-methyl-2-propylimidazol hydrochloride.

A solution of 3.32 g of 1-[(2'-tert-butoxycarbonylmethyl-4-yl)-methyl] -5-hydroxymethyl-4-methyl-2-propylimidazol in 100 ml of 10% aqueous hydrochloric acid is stirred for 16 h at 25aboutC. Then the solvent and excess hydrochloric acid is removed in vacuum, obtaining 2,22 g of 1-[(2' -carboxyphenyl-4-yl)methyl]-5-hydroxymethyl-4-methyl-2-Pro - eliminator hydrochloride with so pl. 208-210aboutC. (decomposes).

NMR spectrum (200 MHz, perdeuteromethoxy) : 12,92 (sh.with. 1H), 7,74 (doublet, 1H), 7,58 (triplet, 1H), 7,47 (triplet, 1H), 7,34 (multiplet, 3H), 7,26 (doublet, 2H), 5,67 (sh.with. 1H), of 5.53 (singlet, 2H), 4,42 (singlet, 2H), 2,86 (triplet, 2H), 2,30 (singlet, 3H), and 1.54 (sextet, 2H), 0.83 (triplet, 3H).

Substance table. 5 have been obtained or can be obtained according to the methods of examples 51-52.

P R I m e R 55.

Part A.

Preparation of 2-n-propyl-4,5-descarboethoxyloratadine-2-n-propylimidazol-4,5-dicarboxylic acid.

So pl. 257aboutC (with decomp.) (17,14 g, 86,6 mmol, 1 EQ.) 400 ml of methanol and acetyl chloride (38,1 ml, 534 millimole, 6 EQ.) careful what dildocam during the night. The solvent is removed in vacuum and add 100 ml of water and 10 n sodium hydroxide solution to establish a pH of 7. The aqueous mixture is extracted three times with ethyl acetate, the organic layers combined, dried with magnesium sulfate and the solvent is removed in vacuum, obtaining 12 00 g of a white solid. Upon recrystallization from a mixture of hexane/ethyl acetate receive 11,41 g of a white solid. So pl. 162-164,5aboutC.

NMR-spectrum (in portaterraferma) 3,95 (singlet, 6N), 2,78 (triplet, 2H), 1,83 (triplet triple. 2H, J=7,7 Hz) of 0.87 (3H triplet, J=7 Hz).

Calculated With 52,06; N 6,28; N 12,14.

WITH10H14N2ABOUT4(H2O)of 0.25< / BR>
Found, With 52,06; N 6,17; N 12,49.

Part of the Century.

Preparation of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl] -4,5-dicarboxy-2-n-propylimidazol. 2-n-Propyl-4,5-dicarbonitriles (2.00 g, 8,8 mmol, 1 EQ.) alkylate 4' -methyl bromide-2-carbomethoxybiphenyl (2.70 g, 8,8 mmol, 1 EQ.) by well-known methods.

Get a 3.87 g of a yellow oil, which is suitable for further transformation.

NMR-spectrum (in perdeuteromethoxy) : 7,84-7,22 (multiplet, 4H), 7,22 (doublet, 2H, J=9 Hz), 7,13 (doublet, 2H, J=9 Hz), 5,50 (singlet, 2H), of 3.77 (singlet, 3H), of 3.75 (singlet, 3H), 3,55 (singlet, 3H), 2,67 (the of 1-[(2' -carboxyphenyl-4-yl)methyl]-imidazole-4,5-dicarbon-howl acid.

Triavir part In amyraut by well-known methods.

The resulting glassy mass crystallized from chloroform. So pl. 143about(Shrinkage) to 152.0aboutC (decomposition).

NMR-spectrum (in perdeuteromethoxy) : 12,74 (multiplet, 1H), 7,72 (doublet, 1H, J=9 Hz), 7,56 (triplet, 1H, J=9 Hz), 7,46 (triplet, 1H), J=9 Hz), was 7.36 (doublet, 1H, J=9 Hz), 7,30 (doublet, 2H, J=9 Hz), 7,20 (doublet, 2H, J=9 Hz), 5,99 (singlet, 2H), 2,89 (triplet, 2H, J=7 Hz), 1,48 (triplet, quart. 2H, J=7,7 Hz), 0,80 (triplet, 3H, J=7 Hz).

Calculated With 60,68; N 5,32; N To 6.43.

WITH22H20N2ABOUT6(H2O)1,5< / BR>
Found, With 60,99; N 5,71; N 6,50.

Substance table. 7 can be obtained by the method described in example 55.

P R I m e R 59. Preparation of 4,5-dicarboxy-2-n-propyl-1-[(2' -(1H-tetrazol-5-yl)diphenyl-4-yl)methyl] imidazole. 4,5-Dicarboxy-2-n-propyl-1-[(2'-N-triphenylmethyl(1H-tetrazol-5-yl)WPPT - Neil-4-yl)methyl]imidazole prepared according to the method of example 55. Part of the Century. so pl. 124-125,5aboutWith, from 4' -methyl bromide-2-(N-triphenylmethyl(1H-tetrazol-5-yl)diphenyl) (3.00 g) are mixed and refluxed in 50 ml of methanol for 4 hours the Solvent is removed in vacuo, and the residue is immediately subjected to flash chromatographicaliy on silica gel in a mixture 1: the ether, that gives 0,92 g of a white solid substance with so pl. 100about(Slow decomposition).

NMR-spectrum (in perdeuteromethoxy) to 7.68-7,43 (multiplet, 4H), 7,08 (doublet, 2H, J=9 Hz), of 6.96 (doublet, 2H, J=9 Hz), 5,41 (singlet, 2H), 3,80 (singlet, 3H), 3,74 (singlet, 3H), 2.63 in (triplet, 2H, J=7 Hz), 1,62 (triplet quart. 2H, J=7,7 Hz) to 0.88 (triplet, 3H, J=7 Hz).

Calculated C $ 59.13 USD; N To 5.58; N 17,23.

WITH24H24N6ABOUT4(H2O)1,5.< / BR>
Found, C 59,27; N 5,31; N 17.11 Per Bbl.

Utility.

Hormonal angiotensin P ( AP) produces numerous biological responses (e.g., compression of blood vessels by stimulating its receptors on cell membranes. To identify compounds, such as antagonists AP, which can interact with the receptor, AP, for the initial screening test was used for ligand-receptor binding. This test was carried out according to the method described Glassmanor al. but with some changes. The reaction mixture contained adrenal-cortical microsome assay rats (source receptor A11) in a buffer solution of Tris and 2 nanomole 3H-up with potential AP antagonist or without him. This mixture was stirred for 1 h at room temperature, and the reaction popcorn associated 3H-up captured on the filter was quantified using a scintillation counter. Inhibitory concentration (IC50potential AP antagonist which gives 50% replacement of the total specifically bound 3H-up presented as a measure of the affinity of such compound for the up-receptor (see table 7).

Potential protivogipertonicheskoe effects of the compounds of this invention can be demonstrated by introducing compounds awake rats made hypertensive by linking the left renal artery. According to this method, the blood pressure increases due to increased production of renin with a subsequent increase in the level of AP. The substance was administered orally at a dose of 100 mg/kg and/or intravenously, through a hollow tube into the jugular vein at a dose of 10 mg/kg Arterial blood pressure was continuously measured directly through the hollow tube of the carotid artery and recorded using a pressure transducer and a multichannel recorder. The level of blood pressure after administration of the substance were compared with the level before the introduction to determine protivogipertonicheskoe effect substances (see table. 8).

Although many of the tested substances were not akinaga reduce blood pressure with intravenous dose of 10 mg/kg, but was slightly reduced pressure at this dose, and therefore it can be expected that they will be active intravenously in high doses, for example, 30 mg/kg

NT not tested.

Substances listed in the table. 9, were tested in the same manner as described for table. 8, except that when tested in protivogipertonicheskoe action in the kidney of hypertensive rats substance was administered orally at a dose of 30 mg/kg or intravenously at a dose of 3 mg/kg

In table. 10 given the values of the ED30for some compounds. Values IR50and/or the ED30most compounds exceed the corresponding values of known compounds obtained in examples 7 and 20.

Thus, the compounds of formula I have a high activity as antagonists to the receptors of angiotensin II and protivogipertonicheskoe activity and can be used in medicine.

IMIDAZOLE DERIVATIVES of General formula

< / BR>
where R1CO2H or a group

,< / BR>
R2n-propyl or n-butyl;

R3-Cl, -CF3, -C2F5, phenyl or CO2H;

R4-CO2H, -CHO or-CH2OH,

provided that: (a) when R4-CH2OH, then R2-n-propyl, R3-C2F5and R4-CO2H, R1< / BR>
group

< / BR>
Priority signs:

07.01.88 when R1CO2H or a group

< / BR>
R2H-propyl or n-butyl,

R3-Cl, -CF3or-C2F5,

R4-CO2H, -CHO or-CH2OH;

06.12.88 when R3-CO2H or phenyl.

R1, R2and R4have the specified values.

 

Same patents:

The invention relates to 7-examinerlawrence heterocyclic Amida - analogues of prostaglandins, which are receptor antagonists AND thromboxane a2(THA2or combined receptor antagonists AND thromboxane a2(thromboxane synthetase inhibitors, and are used, for example, in the treatment of thrombotic disease and/or vascular spasm: have a long duration of action

The invention relates to new chemical compounds in a series of benzimidazole, namely periodical benzimidazole General formula 1

where R is H, CH3; R1= CH3H

provided that 1A R - H, R1- H (N 65 in the work log); 1B, R = CH3, R1= H (N 66 in the work log); 1B, R = CH3, R1= CH3(N 71 in the work log);

possessing antibacterial action

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 ex

FIELD: organic chemistry and pharmaceutical compositions.

SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.

EFFECT: new effective kinase p38 inhibitors.

23 cl, 6 dwg, 1 tbl, 1 ex

FIELD: veterinary science.

SUBSTANCE: a dog should be introduced with 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-il]benzene sulfonamide or its pharmaceutically acceptable salt at daily dosage ranged about 0.1-10 mg/kg body weight.

EFFECT: higher efficiency of therapy.

4 cl,262 ex, 12 tbl

FIELD: medicine, gynecology, anesthesiology.

SUBSTANCE: invention concerns to a method for carrying out the anesthesiology assistance for woman in childbirth with accompanying bronchial asthma. Method involves administration of atropine, dimedrol, analgin and clophelin. Method involves additional intravenous administration of transamine for 5-7 min. Transamine is administrated in doses 12-14 and 15-17 mg/kg in woman in childbirth with body mass 75 kg and above and 74 kg and less, respectively. Method provides enhancing quality and safety of anesthesia in this class of woman in childbirth.

EFFECT: improved assistance method.

7 tbl, 4 ex

FIELD: medicine, dermatology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to an antifungal gel pharmaceutical composition based on ketoconazole and clotrimazole that are derivatives of imidazole. The composition comprises ketoconazole or clotrimazole as an active component, polyethylene glycol-400 (PEG-400) as a solvent, carboxyvinyl polymer as a gel-forming agent, polyethylene glycol as a gel stabilizing agent, organic amine or inorganic bas as a regulator of pH and water taken in the definite ratio of components. The composition is prepared by dissolving active component in PEG-400, dispersing carboxyvinyl polymer in water, successive addition to dispersion propylene glycol as a stabilizing agent and regulator of pH and combination of prepared solution and gel followed by stirring the mixture up to preparing the gel composition with pH 5-7. Invention provides preparing antifungal composition with reduced adverse effect.

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

2 cl, 1 tbl, 11 ex

FIELD: veterinary science.

SUBSTANCE: the present innovation deals with applying selector as a selenium-containing organic preparation to be introduced for cows and calves monthly intramuscularly at the dosage of 10 mcg/kg body weight. The method provides decreased fodder expenses for the synthesis of the production obtained.

EFFECT: higher productivity in cattle.

2 ex, 7 tbl

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

SUBSTANCE: invention relates to a method for treatment of patient suffering with allergic disease. Method involves administration to patient the therapeutically effective dose of pharmaceutical composition comprising compound of the formula (I)

. The compound elicits high effectiveness in treatment of allergy and shows low toxicity also.

EFFECT: improved method for treatment.

9 cl, 2 tbl, 2 dwg, 40 ex

FIELD: veterinary science.

SUBSTANCE: one should apply a selenium-containing preparation named selecor: it should be introduced on the 80-90th d of swine gestation twice at 10-15-d-long interval parenterally at the dosage of 20 mg/kg animal body weight. Application of low-toxic antioxidant as selecor enables to improve functional properties of cell membranes of placental system and endometrium and increase inspecific immune resistance in sows. It, also, enables to increase fertility in sows, values of uncomplicated deliveries and puerperal period.

EFFECT: higher viability of off-spring.

2 ex, 3 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of adamantine, in particular, to a new method for preparing adamant-1-yl-containing azoles of the general formula I-VIII: wherein R1 means ; R2 means ; R3 means ; R4 means ; R5 means ; R6 means ; R7 means , and R8 means . Indicated derivatives of adamantine are semifinished products used in synthesis of biologically active substances. Proposed method for preparing these compounds involves using a new method for synthesis of adamant-1-yl-containing azoles that includes the addition reaction of azoles: 2-methylimidazole, 3(5)-methylpyrazole and 4-methylpyrazole, 3,4-dinitropyrazole, 1,2,4-triazole, 3-methylpyrazole, 3-nitro-1,2,4-triazole and 5-methyltetrazole to 1,3-dehydroadamantane in the mole ratio of 1,3-dehydroadamantane to azole = 1:1 in diethyl ether medium at temperature 100°C for 4-5 h.

EFFECT: improved preparing method.

8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using phenylethenyl- or phenylethynyl-derivatives as antagonists of glutamates receptors. Invention describes using compound of the general formula (I):

wherein each among R1, R2, R3, R4 and R5 means independently of one another hydrogen atom, (C1-C6)-alkyl, -(CH2)n-halogen, (C1-C6)-alkoxy-group, -(CH2)n-NRR', -(CH2)n-N(R)-C(O)-C1-C6)-alkyl, phenyl or pyrrolyl that can be unsubstituted or substituted with one or more (C1-C6)-alkyl; each among R, R' and R'' means independently of one another hydrogen atom or (C1-C6)-alkyl; A means -CH=CH- or C≡C; B means ,, , , or wherein R6 means hydrogen atom, (C1-C)-alkyl, -(CH2)n-C(O)OR, or halogen atom; R7 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-C(O)OR', halogen atom, nitro-group or oxodiazolyl group that can be unsubstituted or substituted with (C1-C6)-alkyl or cycloalkyl; R8 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-OH, -(CH2)n-C(O)OR'' or phenyl; R9 means (C1-C6)-alkyl; R10 and R11 mean hydrogen atom; R12 means -(CH2)n-N(R)-C(O)-(C1-C6)-alkyl; R13 means hydrogen atom; each R14, R15, R16 and R17 independently of one another means hydrogen atom or (C1-C6)-alkoxy-group; each R18, R19 and R20 independently of one another means hydrogen atom; R21 means hydrogen atom or (C1-C6)-alkyl; R22 means hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkyl comprising one or more substitutes chosen from groups hydroxy- or halogen atom; R23 means hydrogen atom, (C1-C6)-alkanoyl or nitro-group; each among R24, R25 and R26 independently of one another means hydrogen atom or (C1-C6)-alkyl; n = 0, 1, 2, 3, 4, 5 or 6; X means -O- or -S-; Y means -CH= or -N=, and its pharmaceutically acceptable salts used in preparing medicinal agents designates for treatment or prophylaxis of disorders mediated by mGluR5-receptors. Also, invention describes compounds of the formula (I-A), compound of the formula (I-B-1) given in the invention description, and a medicinal agent used in treatment or prophylaxis of disorders mediated by mGluR5-receptors.

EFFECT: valuable medicinal properties of compounds.

44 cl, 1 tbl, 44 ex

FIELD: chemistry of organophosphorus compounds, chemical technology.

SUBSTANCE: invention describes a method for synthesis of monohydroperfluoroalkanes, bis-(perfluoroalkyl)phosphinates and perfluoroalkylphosphonates. Method involves treatment of at least one perfluoroalkylphosphorane with at least one base wherein base(s) are chosen from group consisting of alkali-earth metal hydroxides, metalloorganic compound in useful solvent or at least one organic base and an acid in useful reaction medium. Also, invention describes novel perfluoroalkylphosphonates and bis-(perfluoroalkyl)phosphinates, using novel perfluoroalkylphosphonates and bis-(perfluoroalyl)phosphinates as ionic liquids, catalysts of phase transfer or surfactants.

EFFECT: improved method of synthesis.

18 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new displaced heterocyclic derivatives that can be used in treatment of diabetes and to reduce the content of cholesterol. In formula m is 1; n is 1; Q is C; A is -(CH2)x2-0-(CH2)x3-, where x2 varies from 1 to 3 and x3 is 0; B is a bond or it is (CH2)x4, where x4 varies from 1 to 2; X represents CH or N; X2, X3, X4, X5, X6 represent C, N, O; provided that one from X2 X3 X4 X5 and X6 represents N; and at least one of X2, X3, X4, X5, and X6 represents C; R1 represents H or C1-C6alkyl; R2 is H; R2a, R2b and R2c can be equal or different and selected from H, C1-C6alkyl, C1-C6alkoxy, halogen or thyano; R3 is selected from phenyloxycarbonile, C1-C6alkyloxycarbonile, phenylcarbinol, phenyl, alkoxy; Y represents CO2R4 (where R4 represents H or C1-C6alkyl); (CH2)m can be not necessarily displaced by 1 substitute.

EFFECT: produced are pharmaceutical composition for treatment of diabetes and to reduce the content of cholesterol.

13 cl, 2 tbl, 22 dwg, 88 ex

FIELD: chemistry.

SUBSTANCE: invention refers to synthesis of [18F]fluororganic compounds ensured by reaction of [18F]fluoride and relevant halogenide or sulphonate with alcoholic vehicle of formula 1 where R1, R2 and R3 represent hydrogen atom or C1-C18 alkyl.

EFFECT: possibility for mild process with low reaction time and high yield.

21 cl, 2 tbl, 27 ex

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