Aralkylamines the imidazoles with protivogipertonicheskoe action, the retrieval method and the pharmaceutical composition having inhibitory activity against angiotensin ii

 

(57) Abstract:

Usage: in medicine as protivogipertonicheskoe funds. The inventive products: aralkylamines the imidazoles f-ly I, where R1- C2-C6- alkyl, R2- 1 - or 2-naphthyl, 3-, 4 - or 5-acenaphthyl, 1-, 2-, 3-, 4- or 9-phenanthrene, 2-, 3-, 4-, 5-, 6- or 7-benzofuran or 2-, 3-, 4-, 5-, 6- or 7-benzothiazyl,2-C10alkenyl. Reagent 1. Connection f-crystals 2, where R1and R2have the above values. Reagent 2: compound f-crystals 3, where X1- halogen. Reaction conditions: in a medium of an organic solvent in the presence of a base. 3 N. p. F.-ly, 8 PL.

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The invention relates to new imidazole derivative, method for their production and pharmaceutical compositions containing these compounds. The latter can be used both independently and in combination with other compounds, especially with diuretics and nonsteroidal anti-inflammatory drugs.

Compounds described in this invention inhibit the action of harmoneerimisega and is therefore useful in the treatment of hypertension caused by the formation of angiotensin II (hereinafter AII). The enzyme renin acts on angiotensinogen

The literature describes oktapeptid (sac1ala8) similar AII, named as saralasin, which is the most effective means of combating the harmful effects of AII. However, the very similar, like most peptide antagonists, also causes side effects.

Thus, it was shown that saralasin lowers blood pressure in mammals and humans when high blood pressure depends on the circulation of AII in the blood (see Pals at al. Ciradation Renarch, 1971, No. 29, R. 673). However, given the peptide nature saralasin in the case, when the pressure increase is not responsible AII, he plays the role of a stimulator of pressure increase. The effect of saralasin relatively short and is only a problem when injection; when staticheskom introduction it is inefficient. The main purpose of this compound as a pharmaceutical standard in research.

Some famous ones protivogipertonicheskoe agents inhibit the enzyme, called enzyme converting angiotensin (EPA), responsible for the conversion of angiotensin I to AII. Therefore, these agents are inhibitors EPA or inhibitors of the enzyme transformations (INRM). Available commercially such INRM, as captopren, immune to treatment type EPI. Only in conjunction with a diuretic, such as furosemide or hydrochlorothiazide, INRM allows you to effectively normalize blood pressure in most cases. Treatment with diuretic translates to a pathological state regulation of blood pressure, independent of renin in normal conditions, regulated by renin. Although the imidazoles proposed in the invention, operate on a different mechanism, namely, probably by blocking receptor AII, rather than by suppressing the enzyme responsible for conversion of angiotensin, yet both of these processes are connected with the cascade of the renin-angiotensin". However, non-steroidal anti-inflammatory drugs (spit) cause renal failure in patients with renal pompertuzat and high levels of AII in the blood plasma. The assignment meets the present invention, compounds that block AII, in combination with spit (either by serial reception at different stages of treatment, either in the form of a mixture) capable of preventing referred to renal insufficiency (see Dunn M. J. Hospital Practic, 1984, v.19, p. 99).

In PCT application N 0253310 published 20.01.88, describes aralkylamines the imidazoles, Blo is nom, and also for the treatment of heart failure, caused by blockage of blood vessels. These compounds differ from the proposed compounds with substituents in the imidazole ring.

The aim of the invention is the finding of new derivatives of imidazole with protivogipertonicheskoe activity with a broad spectrum of action, development of a method of production thereof and pharmaceutical compositions based on these compounds with inhibitory activity against angiotensin II.

According to the present invention proposed aralkylamines the imidazoles of General formula I

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where R1WITH2-C6-alkyl, R21 or 2-naphthyl, 3-, 4 - or 5-acenaphthyl, 1-, 2-, 3-, 4- or 9-phenanthrene, 2-, 3-, 4-, 5-, 6- or 7-benzofuran or 2-, 3-, 4-, 5-, 6- or 7-benzothiazyl; each of these groups may be substituted by one or two substituents selected from the group: halogen atom, a C1-C5-alkoxyl or2-C6alkenyl, replaced by a substituted or unsubstituted group polycyclic aryl, above, showing protivogipertonicheskoe activity.

Another object of the invention is a method of obtaining the compounds of the first, namely, that carried the
where R1, R2have the above values, R3- residue formula

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or R1-R3protected or are an intermediate group, x a halogen atom, n toluensulfonate or methylsulfonylamino, in the environment of a solvent in the presence of a base at a temperature of 20oWith temperatures of distillation of the solvent for 1 to 10 h, followed by separation of the target product or, if necessary, the conversion of compounds with intermediate or protected by radicals in the target connection.

This method can be performed using a two-phase solvent system methylene chloride-water in the presence of phase transfer catalyst transfer tricaprylmethyl ammonium chloride.

As a Foundation in the process you can use different base selected from the group of hydridotris formula MN, the metal alkoxide of the formula R, sodium carbonate or potassium hydroxide, triethylamine or pyridine, in a dipolar aprotic solvent. If the base is a metal alkoxide OR, the solvent can be an alcohol ROH, where R is methyl, ethyl, tert.butyl, M is lithium, sodium, potassium.

The object of the invention is also a pharmaceutical composition having ing Eitel.

The difference of the composition from the previously known compositions of the same assignment is used as active principle compounds of formula I in an effective amount.

The composition may further contain a diuretic in the following components:

the compound of formula I, 1-100 mg daily dose

diuretic 25-100 mg per daily dose,

and can additionally include non-steroidal anti-inflammatory drug in the following components:

the compound of formula I 1-500 mg per dose,

nonsteroidal anti-inflammatory drug 1-500 mg per dose.

Detailed description of the invention.

The synthesis. The new compound of the formula I can be obtained using the reactions and techniques described in this section. These reactions are conducted in the environment of a solvent suitable for the used reagents and substances, namely, suitable for implementation of the necessary chemical reactions. Specialists in the field of organic synthesis well known that functionality, "carried" by imidazole and other parts of the molecule compounds must comply with the proposed chemical transformations. As well as in the implementation via unprotect, methods of activating position in the ring of the benzyl able to "stitch" with nitrogen in the imidazole nucleus. Not all compounds of formula I, referred to in the text of this section and attributable to a specific class, you can get all the methods described for this class. Replaced the group's original substances may not be compatible with certain reaction conditions that are required in the case of some of the mentioned methods. The limitation imposed on the replaced group in respect of their compatibility with the reaction conditions, it is obvious for one of the alternative methods described in this section.

Basically proposed connection easy to get direct alkylation of imidazole is protected adequately by benzylchloride, tosylate or mesilate in the presence of a base. Better if you get salt imidazole reaction of imidazole I with a proton acceptor, such as MN, where M is lithium, sodium or potassium, in a solvent such as dimethylformamide (DMF), or by conducting the reaction of the imidazole of formula I with a metal alkoxide of the formula MOR, where R is methyl, ethyl, tert-butyl alcohol solvent (ethanol or tert-butyl alcohol), or in the dipolar proton the com as DMF, and the above process almyroudis agent. In another case, the imidazole can be alkilirovanii antilogarithm (bromide or chloride) in the presence of a base such as sodium carbonate, potassium carbonate, triethylamine or pyridine. The reaction is carried out in an inert solvent, such as DMF or dimethylsulfoxide (DMSO) at temperatures between 20oWith temperatures of distillation of the solvent for 1 to 10 hours

Preferred ways of getting tetrazolo shown in scheme 1 by equations a and b. Compounds And can be obtained 1,3-dipolar-cyclopentadiene of azides triamcinolone or triphenylamine to the corresponding nitrile In, as represented by the equation. "Alkyl" means a normal alkyl with 1-6 carbon atoms. An example of such technology described Cosima al. (S. Kozima et al. Organic Chemistry, 1971, p. 337). Required azides trialkyl or triarylamine synthesized from the commercially available chloride trialkyl and tiarella and sodium azide. The group trialkyl or Triaryl-tin remove acidic or basic hydrolysis, and tetrazol you can protect a group of trityl carrying out the reaction with Fritillaria and triethylamine getting connection With. Subsequent bromination with N-bromosuccinimide and dibenzofuran the tvii Foundation, with the subsequent removal of the protecting group of trityl by hydrolysis gives compound 1, in which R tetrazol. To protect tetrazoles part of the molecule instead of a group of trityl you can use other protective groups, such as para-nitrobenzyl and I-ethoxyethyl. These groups, as well as a group of trityl, can be inserted and removed according to the methods described in Greene, "Protective groups in organic synthesis" (Green, Protective Groups in Organic Synthesis, Wiley Interscience, 1980) (see scheme 1).

The compounds of formula I, where R2arylalkyl, and R3represents CH2OH, Cho, or COOH, can be obtained as shown in scheme 2.

2-alkylimidazole-4,5-dicarboxylic acid And obtained by the method, which was developed Farger and Pimen (Farger R. G. of Pymen F. Z. J. Chem. Soc. 1991, v. 115, p. 217), can be translated into their corresponding complex diesters In a simple distillation of the alcoholic solvent in the presence of acid, such as hydrochloric, or one of many other methods, well known specialist in this field.

Next, the ester can be converted into its metal salt by conducting the reaction with methoxide, ethoxide or sodium hydride or other

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base in a suitable solvent, such as DMF, in the Pris shall be lithium hydride and aluminum in an inert solvent, such as tetrahydrofuran, to the appropriate dialcohol D. Selective oxidation of dialcohol D manganese dioxide in an inert solvent, such as tetrahydrofuran, gives as a product mainly aldehyde G with a small amount of dialdehyde that is, Crystallization or chromatographic separation of compounds E and G followed by conducting the reaction of ittia connection G with the appropriately substituted uralelectrosetstroy in an inert solvent, such as tetrahydrofuran, gives the quality of the product 4-arylalkyl-5-hydroxymethylimidazole F. Further oxidation compounds F periodical proposed dess-Martin, see J. Org. Chem. 1983, v.48, p. 4155, as well as manganese dioxide, chlorbromuron pyridinium, manganates barium or other oxidizing agents well known to the person skilled in the art, in an inert solvent, such as tetrahydrofuran or methylene chloride, followed by removal (if necessary), protective groups with any of the radicals R1, R2or R3gives the quality of the product 4-arylalkylamines-5-carboxaldehyde Q (cm. scheme 2).

Connections matching the present invention, and methods of obtaining them will become more clear when considering nizes the Oli and interest in mass units.

Throughout the text it must be borne in mind that, if mentioned alkyl substituent, it is assumed the normal structure of alkyl, namely, "butyl" means "n-butyl", unless otherwise specified.

Example 1. Part a: getting 5-hydroxymethyl-4-iodine-2-n-propylimidazol.

A solution of 31.5 g of 4(5)-hydroxymethyl-2-n-propylimidazol and 50.6 g of N-jodatime in 560 ml of 1,4-dioxane and 480 ml of 2-methoxyethanol stirred at 45oC for 2 h Then the solvent removed under vacuum. The resulting solids washed with distilled water and then dried to obtain 54.6 g of product in the form of a solid substance with a melting point 169-170oAnd indicators NMR (dimethylsulfoxide-d6) 12,06 (br, s, 1H); to 5.08 (t, 1H); 4,27 (d, 2H); 2.50 each (t, 2H); 1,59 (sext, 2H); from 0.84 (t, 3H).

Part b: getting 4-iodine-2-n-propylimidazol-5-carboxaldehyde.

In the solution to 35.8 g of 5-hydroxymethyl-4-iodine-2H-propylimidazol in 325 ml of glacial acetic acid is added dropwise at 20oC for 1 h 290 ml 1.0 l of an aqueous solution of suryamaninagar. The resulting mixture was stirred at 20oC for 1 h Then the reaction mixture is diluted with water, adjusting the pH to 5-6 with an aqueous solution of sodium hydroxide and extragroup sodium, filter and concentrate. The obtained crude solid substance is subjected to recrystallization from 1-chlorobutane with the receipt of 29.9 g of the product as a pale yellow solid with a melting point 141-142oC. Data NMR (CDCl3): d 11,51 (br, s, 1H); 9,43 (s, 1H); of 2.81 (t, 2H); 1,81 (sext, 2H); to 0.97 (t, 3H)

Part C: getting 4-(naphthas-1-yl)-2-n-propylimidazol-5-carboxaldehyde.

The solution containing 2.64 g (0,01 mol) 4-iodine-2-n-propylimidazol-5-carboxaldehyde, 40 ml of toluene and 0.33 g (0,00029 mole) of tetranitroaniline palladium (O) was stirred at room temperature in a nitrogen atmosphere, and there slowly introducing the solution 3,44 g (0,022 mol) 1-afterborn acid in 50 ml of ethanol. The reagents are stirred for 5 min, then slowly add 12 ml of 2M sodium carbonate. After the addition was finished the reaction is carried out at boiling solvent for 48 h, then cooled. The products of the reaction is filtered, the filtrate is distilled off under vacuum and the resulting residue is dissolved in 300 ml of methylene chloride, washed twice with 300 ml of 10% hydrochloric acid. Hydrochloric acid residue is treated with 50% sodium hydroxide to until the pH reaches 10. The resulting aqueous basic layer extracted three times with 300 ml of methylene chloride, the 0 g (0,0034 M, 34%). Characteristics of the YOKES (CDCl3): of 11.45 d (m, 1H); 9,42 (s, 1H); 7,28 (m, 7H); 2,82 (t, 2H); of 1.85 (m, 2H); of 1.01 (t, 3H).

Part D: Getting 4-methyl-21-[N-triphenylmethyl-(1H-tetrazol-5-yl)]biphenyl.

Mix 41-methylbiphenyl-2-nitrile (receipt described in PCT application 0253310 published 20.01.88) in the amount of 10.00 g (51.7 mm, 1 equiv.) chloride tri-n-butyanova in the amount of 14.0 ml (51.7 mm, 1 equiv.) sodium azide in the amount of 3.4 g (51.7 mm, 1 equiv.) and xylene in a quantity of 50 ml of the Reaction mixture is subjected to exposure with a Stripping solvent for 64 h, then cooled to room temperature. Then add 10,He NaOH in the amount of 5,10 ml (0,061 mm, 1.2 EQ.) and trailhead in the number 14,99 g (53,8 mm, 1.04 equiv.) then these substances are stirred for 24 h, after which the mixture was added 39 ml of water and 100 ml of heptane. The resulting mixture was stirred at 0oWith over 1,5 hours the Formed solid is filtered off, washed twice with portions of water 55 ml and once with a mixture of heptane to toluene, taken up in 55 ml, then for nights dehydration under high vacuum to obtain 19,97 g of the product as a pale yellow powder with a melting point 148,0-155,0oC (with decomp.). The obtained solid substance suspen melting 164,0-165,5oC (with decomp.). Characteristics NMR (CDCl3: d to $ 7.91 (d, 1H, J=0 Hz); 7,53-to 7.18 (m, 13H); 7,02-6,84 (m, N); of 2.25 (s, 3H).

Part E: Obtain 4-methyl bromide-2'-[N-triphenylmethyl(1H-tetrazol-5-yl)]biphenyl; a demonstration of the procedure.

Mix 4-methyl-2'-[N-triphenylmethyl(1H-tetrazol-5-yl)] biphenyl (on receipt see example 22B) in the amount of 52,07 mg (109 mm, 1 equiv.) with 19.4 g of N-bromosuccinimide (109 mm, 1 equiv.) 1.0 g of benzoyl peroxide and 300 ml of carbon tetrachloride. The mixture was kept under the conditions of distillation solvent for 2.5 h, then cooled to room temperature and filtered succinimide. Then, the filtrate concentrated, and the residue is ground to powder with simple ether and obtained as a product of the first pickup to 36.0 g of a substance with a melting point of 129.5-133,0oC (with decomp.). Characteristics NMR (DCl3): d 4,37 (CH3Br). The resulting material is suitable for further transformations.

Part F: Obtain 4-(naphthas-1-yl)-2-n-propyl-1-[2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)]biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde.

A suspension of 4-(naphthas-1-yl)-2-n-propylimidazol-5-carboxaldehyde in the number of 0.90 g (39,7 mm, 1 equiv.) 4-methyl bromide-2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)]biphenyl in the number 2,03 g (43,7 mm, 1 equiv.) 20 ml betweenyou the mixture is filtered, the precipitate is washed with methylene chloride and chromatographic in a mixture of methylene chloride with ethyl acetate in the ratio 98:2 on silica gel to obtain a yellow foam. The yield of product amounted to $ 1,50, Characteristics NMR (DCl3: d of 9.45 (s, 1H); a 7.85 (m, 1H); 6,86 was 7.45 (m, 29H); of 5.55 (s, 2H); 2,60 (t, 2); of 1.80 (m, 2H); of 0.95 (t, 3H).

Part G: Obtain 4-(naphthas-1-yl)-2-n-propyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde.

4-(naphthas-1-yl)-2-n-propyl-1-[(2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)] biphenyl-4-yl)methyl] imidazole-5-carboxaldehyde in the amount of 1.50 g, 80 ml of tetrahydrofuran and 10% hydrochloric acid is stirred at room temperature. After 8 h the mixture was poured into a mixture of ice with 5% NaOH and adjust the pH to 10. The resulting material is filtered off and the pH of the filtrate is set to 4-5 10% hydrochloric acid. A cloudy solution is extracted with a mixture of methylene chloride with isopropyl alcohol in the ratio 80:20 in three steps, using 100 ml of the mixture, after which the organic phase is dehydrated over sodium sulfate and evaporated under vacuum to obtain 0.51 g of white vitreous substance. Characteristics NMR (CDCl3): d a 9.35 (s, 1H); for 7.78 (m, 1H); 7,60-7,38 (m, 2H); 7,35-of 6.96 (m, N); 5,62 (s, 1H); 2,60 (m, 2H); of 1.85 (m, 2H); from 0.90 (t, 3H).

On medicinenet, are given in table. 2 can be synthesized according to the method described in example 1, or by the methods described in PCT application 0253310.

Compounds of examples 2-21 presented in table. 3 and 4, can be obtained according to the methods described in example 1, and the methods described in PCT application 0253310 published 20.01.88.

Example 22.

Part a: Getting 2-n-propyl-4,5-dicarboxy-imidazole.

2-n-propylimidazol-4,5-dicarboxylic acid obtained by the method of Porgera and Pimen (Farger R. G. Pyman F. Z. J. Chem. Soc.v.115, p. 217), with a melting point of 257oC (decomp), taken in an amount 17,14 g (86,6 mm, 1 equiv.) 400 ml of methyl alcohol and 38,1 ml acetylchloride (534 mm, 6 EQ.) mix while observing the necessary precautions (add acetylchloride to methyl alcohol is strongly exothermic process) and boil over night. The solvent is removed under vacuum, and then add 100 ml of water and 10 n NaOH to pH=7. The aqueous mixture is extracted three times with ethyl acetate, the organic layers are combined to dehydrate magnesium sulfate and remove the solvent under vacuum to obtain 12.0 g of a white solid. Recrystallization from a mixture of hexane with ethyl acetate gives 11,41 g of a white solid substance (in the,83 (t of t, 2H; J=7,7 Hz); of 0.97 (t, 3H, J=7 Hz). These IR absorption (nerdball.): 1735 cm-1. Elemental analysis calculated for the formula C10H14N2O4H2O: 52,06; 6,28 N; 12,14 n

Received: 52,06; 6,17 N; 12,49 n

Part b: Getting 4-methyl-2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)]biphenyl.

4-methylbiphenyl-2'-nitrile (method of obtaining of which is described in PCT application 0253310 published 20.01.88) in the amount of 10.00 g (51.7 mm, 1 equiv.) 14,0 ml chloride tri-n-butyl-tin (51.7 mm, 1 equiv.) 3,4 of sodium azide (51.7 mm, 1 equiv.) and 50 Il of xylene is stirred and the solvent is distilled off over a period of 64 hours, then the reaction mixture is cooled to room temperature. Then add 6,10 ml 10.0 n NaOH (0.06 mmol, 1.2 EQ.) and 14,99 g Fritillaria (53,8 mm, 1.04 equiv.) then the mixture is stirred for 24 h, and then there was added 30 ml of water and 100 ml of heptane. The resulting slurry was stirred at 0oWith for 1.5 hours resulting solids filtered off, washed with two portions of water 55 ml and once with 55 ml of a mixture of heptane to toluene in the ratio 3:2, followed by dehydration during the night under vacuum to obtain 19,97 g light yellow powder with temperature 148-155oC (decomp.). Solid asado what I 164,0-165,5oC (decomp.). Characteristics NMR (CDCl3): d to $ 7.91 (d, 1H, J=9 Hz); 7,53-to 7.18 (m, 13H); 7,02-6,84 (m, 9H); of 2.25 (s, 3H).

Part C: Getting 4-bromomethyl-2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl bromide: a demonstration of the procedure.

4-methyl-2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)] biphenyl in the number 52,07 g (109 mm, 1 equiv.) N-bromosuccinimide in the amount of 19.4 g (109 mm, 1 EQ. ), 1.0 g of benzoyl peroxide and 300 ml of carbon tetrachloride is mixed boiled and solvent for 2.5 hours Then the reaction products are cooled to room temperature and filtered succinimide. The filtrate is concentrated and the residue triturated with simple ether to obtain the first pickup in the number 36,0 g of substance with a melting point of 129.5-133,0oC (decomp.). Characteristics NMR (CDCl3d 4,37 (ADHD). This substance is suitable for further transformations.

Part D: Getting a 4.5-dicarboxy-2-n-propyl-1-[2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]imidazole.

In a solution of 10.00 g of 4,5-dicarboxy-2-n-propylimidazol (44,2 mm, 1 EQ. ) in dimethylformamide injected sodium hydride in an amount of 1.06 g (44,2 mm, 1 equiv.) at room temperature. There foaming and separation of gaseous products. Next, the temperature in tecia and the mixture is cooled to room temperature. To this mixture add a solution of 2-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)-methyl bromide in dimethylformamide, taken in an amount 24,64 g (44,2 mm, 1 equiv.). After 24 h the solvent is removed in vacuo, and the residue is subjected to thin-layer chromatography in a mixture of hexane with ethyl acetate (75:25 ratio), 100% ethyl acetate on silica gel to obtain 25,78 g (51% yield) of a white glassy substance, suitable for subsequent transformations.

By recrystallization from ethyl alcohol to obtain a sample for analysis in the form of white crystals with a melting point 124,0 output reached 125.5oC. Characteristics NMR (DCl3: d to $ 7.91 (d of d, 1H, J=3,9 Hz); to 7.59-7,20 (m, N); to 7.09 (d, 2H, J= 9 Hz); 6,94 (m, 6N); 6,76 (d, 2H, J=9 Hz); and 5.30 (s, 2H); to 3.89 (s, 3H); 2.50 each (t, 2H, J=7 Hz); rate of 1.67 (t of t, 2H, J=7,7 Hz); 0,85 (9t, 3H, J=8 Hz). IR absorption (nerdball. ): 1718 cm-1. Calculated for formula C43H38N6O4: 73,49 With; The 5.45 N; 11,96 N. Found 73,23; 5,48 N; 12,22 n

Part E: Obtaining 4,5-dihydroxymethyl-2-n-propyl-1-[(2'-(N-triphenylmethyl(1H-tetrazol-5-yl -) biphenyl-4-yl)methyl]imidazole.

4,5-dicarboxy-2-n-propyl-1-[(2'-(N-triphenylmethyl(1H-tetrazol-5-yl -) biphenyl-4-yl)methyl]imidazole in the number of 9.88 g (14,1 mm, 1 equiv.) dissolve in a minimum amount of tetrahydrofuran. In this RA 1.1 EQ.). The mixture is stirred over night at room temperature, and then cooled rapidly by the method Steinhardt (Steinhardt), see Federowski manual (Fieser of Fieserr VI, p. 584) as follows: the reaction mixture gently add to 0.66 ml of water, then of 0.66 ml of 15% NaOH, and then 1,97 water. After stirring for 72 h are very fine precipitate, which slowly sucked zeolite filter brand CeliteTM. The filtrate is dehydrated with magnesium sulfate, and the solvent is removed in vacuum. The result 8,83 g yellow glassy substance, incapable of recrystallization. This is an intermediate substance suitable for subsequent transformations. Characteristics NMR (dimethylsulfoxide d6): d of 7.82 (d, 1H, J=9 Hz); 7.68 per-7,28 (m, N); 7,05 (d, 2H, J= Hz); is 6.78 (d, 6N, J=9 Hz); 5,16 (s, 2H); 4,94 (t, 1H, J= 7 Hz); of 4.66 (t, 1H, J=7 Hz); 4,37 (d, 2H, J=7 Hz); 4,32 (d, 2H, J=7 Hz); of 2.34 (t, 2H, J=7 Hz); 1,52 (t of q, 2H, J=7 Hz); of 0.77 (t, 3H, J=7 Hz); infrared absorption (nerdball. ): 3300 br; 3061; 1027; 1006; 909; 732; 699 cm-1. Calculated for formula C41H38N6O2H2O: 74,07; 6,06 N; 12,64 N. Found 74,06; 5,95 N; up 11,86 n

Part F: Obtain 5-hydroxymethyl-2-n-propyl-1-[(2'(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl] imidazole-4-carboxaldehyde the P> 4,5-dihydroxymethyl-2-n-propyl-1-[(2-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]imidazole in the number 8,56 g (13.2 mm, 1 equiv.) dissolve in a minimum amount of tetrahydrofuran and added dropwise to the suspension containing 11,14 g of manganese dioxide 128,1 mm, 9.7 EQ.) in 100 ml of tetrahydrofuran and having a room temperature. After 24 h, the contents of the reaction vessel is filtered through zelany filter brand CeliteTM. The residue is subjected to thin-layer chromatography in a mixture of hexane with ethyl acetate (at a ratio 1:10) to 100% ethyl acetate on silica gel to obtain the dialdehyde, washed first, and also to 1.25 g of a glassy substance (yield 15%). Characteristics NMR (dimethylsulfoxide d6): d 10,27 (s, 1H); 10,17 (s, 1H); 7,81 (d, 1H, J= 7 Hz); to 7.68 (m, 2H); 7,50-of 7.23 (m, 10H); to 7.09 (d, 25, J=9 Hz); of 6.96 (d, 2H, J=9 Hz); 6,86 (m, 6N); 5,59 (s, 2H); 2,52 (t, 2H, J=7 Hz); 1,58 (t of q, 2H, J= 7 Hz); of 0.77 (t, 3H, J=7 Hz). IR absorption (nerdball.) 1697, 1672 cm-1. Calculated for formula C41H36N6O2: 76,62; 5,33 N; 13,07 N. Found: 76,46; 5,54 N; 12,94 n

Product subsequent leaching was 4-hydroxymethylimidazole-5-carboxaldehyde representing a light-yellow solid with a melting point 164,5-166,0oC. Characteristics NMR (dimethylsulfoxide d6) d 9(d, 2H, J=7 Hz); is 2.37 (t, 2H, J=7 Hz); 1,49 (t of q, 2H, J= 7,7 Hz); to 0.73 (t, 3H, J=7 Hz). IR absorption (nujol.) 1688 cm-1. Calculated for formula C41H36N6O2(H2O)a 0.1: 76,16; 5,64 N; 12,84 N. Found: 76,02 With; Are 5.36 N; 12,84 n

Part G: Obtain 5-hydroxymethyl-4-[CIS-(naphthas-1-yl)ethynyl]-2-n-propyl-1-[(2'-(N-triphenylmethyl -(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]imidazole.

Preparing a suspension 6,82 g chloride 1-naphthylethylenediamine (0,0155 M, 2 EQ.) in 90 ml of tetrahydrofuran to which is added dropwise at room temperature is injected 20.68 ml of the potassium salt of bis(trimethylsilyl)amide (0,0155 M, 2 equiv.) taken in the form of a 0.75 M solution in toluene. The resulting red solution is heated at 45oC for 0.5 hours Then added to 5.00 g of 5-hydroxymethyl-2-n-propyl-1-[(2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl] imidazole-4-carboxaldehyde (7,75 mm, 1 equiv.) dissolved in a minimum amount of tetrahydrofuran, and the solution was stirred over night. The reaction is completed by adding 300 ml of ethyl acetate and 200 ml of water. After separation of the layers the organic layer is dehydrated by magnesium sulfate, and the solvent is removed under vacuum to obtain 9,29 g yellow glassy substance. In the thin-layer chromatog the CSOs substances. Characteristics NMR (dimethylsulfoxide d6): d 8,20-7,20 (m, 20N); 7,10-6,60 (m, 12H); 5,10 (s, 2H); equal to 4.97 (t, 1H, J=7 Hz); 4,00 (m, 2H); of 2.20 (t, 2H, J=7 Hz); 0,62 (t, 3H, J=7 Hz). Calculated for formula C52H44N6O (triphenylphosphine)1,6(H2O): 78,76; 5,73 N; 6,82 N. Found: 78,69; 5,67 N; 6,90 n

Part H: preparation of 4-[CIS-(naphthas-1-yl)ethinyl]-2-n-propyl-1-[2'-(N-triphenylmethyl)-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl] imidazole-5-carboxaldehyde.

Mix 7,86 g of 5-hydroxymethyl-4-[CIS-(naphthas-1-yl)-2-n-propyl-1-[2'-(N-triphenylmethyl -(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]imidazole (10,2 mm, 1 equiv.) 4.44 g of manganese dioxide (51,1 mm, 5 EQ.) and 25 ml of methylene chloride. From the mixture during the night boil in a solvent in a nitrogen atmosphere, N2. Manganese dioxide is filtered off on a zeolite filter CeliteTMand the cake on the filter is washed with methylene chloride. Next, the filtrate is evaporated out of the crust, and the residue is subjected to thin-layer chromatography with a mixture of pentane with ethyl acetate at a ratio of 75:25 to 50:50 to obtain of 3.78 g of an orange glassy substance. Characteristics NMR (CDCl3): d 9,37 (s, 1H); 8,04 (m, 1H); 7,92 (d, 1H, J= 8 Hz); 7,80 (m, 1H); 7,72 (m, 1H); 7,60-7,10 (m, N); 7,10-6,70 (m, 10H); 6,53 (d, 2H, J=8 Hz); and 5.30 (s, 2H); of 2.38 (t, 2H, J=7 Hz); 1,56 (t of q, 2H, J= 7,7 Hz); of 0.77 (t, 3H, J=7 Hz). Calculated for formula C52NS-(naphthas-1-yl)ethynyl]-2-n-propyl-1-yl-[(2'-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde.

Prepare a mixture of 3.50 g of 4-[CIS-(naphthas-1-yl)ethynyl]-2-n-propyl-1-yl-[(2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl] imidazole-5-carboxaldehyde, 12 ml triperoxonane acid, 12 ml of water and 40 ml of tetrahydrofuran, which was stirred at room temperature. After 2 h, the pH of this mixture was adjusted with 10 n NaOH to pH 12, and then is evaporated organic solvent. Then add 100 ml of water and precipitated kauchukopodobnoe solid. For dissolution of solid precipitation add 50 ml of ethanol. After separation of the layers the aqueous layer was extracted with two portions of ethyl ether in 50 ml. Then the aqueous layer was acidified with concentrated hydrochloric acid to pH 2, resulting again deposited kauchukopodobnoe solid. For its dissolution was added 100 ml of ethyl acetate, then again there is a separation of the layers. The aqueous layer was extracted with two portions of ethyl acetate, 100 ml of an ethyl acetate layers together and dehydrated with magnesium sulfate. The solvent is removed in vacuo, and the residue is dissolved in methyl alcohol. Next add water and the pH adjusted to 2 with concentrated hydrochloric acid. The solvent is removed in vacuum and the residue is distributed between 100 ml of an ethyl acetate layers together, dehydrated with magnesium sulfate, the solvent is removed in vacuum and the residue is crystallized from ethyl acetate to obtain 1.48 g of a white solid with a melting point of 192.5 kg-of 193.5oC. Characteristics NMR (dimethylsulfoxide d6): d at 9.53 (s, 1H); 8,10-7,30 (m, 1H); to 7.84 (d, 1H, J=7 Hz); 7,10 (d, 1H, J=11 Hz); 7,01 (d, 2H, J= 8 Hz); 6,76 (d, 1H, J=8 Hz), 5,46 (s, 2H); to 2.42 (t, 2H, J=7 Hz); 1,34 (t of q, 2H, J=7,7 Hz); of 0.67 (t, 3H, J=7 Hz). Calculated for formula C33H28N6O (H2O): 74,53; 5,46 N; 15,80 N. Found: 74,48 C; 5,35 H; 15,65 n

The compounds listed in the table. 5, can be obtained by the method of example 22.

The usefulness of the invention.

The hormone angiotensin II (AII) is causing various biological responses, such as compression of the vessels by stimulating existing on the cell membrane receptors for this hormone. To identify such compounds as AII antagonists capable of interacting with the receptor AII, when the initial approach was tested method of ligand-receptor binding. This approach was carried out according to the method, which was described by Glassman al. (Glossman et al. J. Biol. Chem. 1974, v. 249, p. 825), with some changes. The reaction mixture contains adrenal cortical microsome assay (source receptor AII) in Tris-buff without it. The mixture was subjected to ripening for 1 h at room temperature, and immediately upon completion of the reaction carried out rapid filtration and washing through teclmically filter. Hormone3H-AII or125J-AII associated with the receptor, caught on the filter, quantify the counting of scintillations (flashes). Inhibitory concentration IC50potential antagonist hormone AII characterizing 50% replacement of all specifically related groups3H-AII or125J-AII, is a measure of the affinity of these compounds in relation to the AII receptor. Connections matching the present invention, a proven method of binding, showed values (IC50about 10 M or less (table. 6).

Potential protivogipertonicheskoe action of compounds that meet present invention, it is possible to demonstrate by assigning these compounds awake rats exposed to hypertension by dressing they left renal artery, see Cangiano al. (Cangiano et al. J. Pharmacol. Exp. Ther 1979, v. 208, p. 310). This operation increases the blood pressure due to increased production of renin, accompanied with the introduction of compounds tematicheskie made direct measurement of arterial blood pressure, and to write data to apply pressure sensor and multi-chart recorder. Levels of blood pressure before the experiment is compared with the corresponding levels before treatment to establish protivogipertonicheskoe action of the tested compounds. Some compounds that meet present invention, intravenous show activity at the dose of 3 mg/kg, and some activity at staticheskom introduction at the dose of 30 mg/kg (table.6).

Forms of application. Connections matching the present invention, can be prescribed to treat hypertension, in accordance with the present invention in any way, if there is a contact of the active ingredient (compound) impact zone in the body of warm-blooded animal. For example, the assignment can be realized by injection, namely, subcutaneously, intravenously, intramuscularly, or intraperitoneally. In order additions or exceptions, the drug can also assign tematicheskie (through the mouth).

The drug can assign any conventional method suitable for use in combination with other drugs, representing as self-medication, and Elam, selected on the basis of one or another method of appointment in accordance with conventional pharmaceutical practice.

With regard to the object of application of the above, it is a warm-blooded animal, related to the animal world, which possess homeostatic mechanisms: these include mammals and birds.

Prescribed dosage will depend on the age, health and weight of the treated animal with regard to the frequency assignments of the nature of the desired effect. The usual daily dose of the active ingredient (compound) is 1-500 mg/day. Typically, to achieve the desired results rather 10-100 mg/day (receiving one or more times per day). These dosage effective for the treatment of hypertension and in the treatment of heart failure associated with plugging of vessels.

The active ingredient can be assigned tematicheskie in the form of solid dosage forms such as capsules, tablets or powders, or in liquid dosage forms, such as elixirs, potions, and suspension. This ingredient can also be administered by injection as a sterile liquid dosage.

Gelatin capsules contain the active ing the acid, etc. Similar fillers can be used in the manufacture of compressed tablets. Tablets and capsules can be manufactured in the form of slower-acting forms to ensure a continuous flow in the blood medications over time, measured in hours. Molded tablets may be coated with a layer of sugar or film to mask the unpleasant taste and protect the tablet from the influence of atmospheric factors. Or tablets may have an internal membranous septum, providing electoral division pills in the digestive tract.

Liquid dosage for appointment tematicheskie may contain colouring or flavouring agents with the purpose of more attractive for treatable animal.

For the preparation of injection, etc. of solutions imposed from outside, suitable devices such as water, a suitable oil, brine, water-soluble dextrose (glucose) and the corresponding solutions of sugars and glycols, such as propylene glycol or polyethylene glycol. Solutions to assignment by injection, preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if the necessity is the bisulfite or sodium sulfite, or ascorbic acid alone or in combination. In addition, the use of citric acid and its salts, and injections can contain preserving additives, such as benzalkonium chloride, methyl - or propylparaben, chlorobutanol.

Suitable pharmaceutical carriers are described in "Ringtonescom pharmaceutical Handbook", edited by Ozola (Remington's Pharmacentical Sciens, A. Osol), which is the generally accepted guidance in this area.

Used in the pharmaceutical dosage for appointment of compounds conforming to the invention, below.

The capsule. A large number of sealed packages are prepared by filling standard two-part capsules of hard gelatin, placing each part of 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Capsules soft gelatin. Prepare a mixture of the active ingredient with a digestible oil such as soybean, cottonseed or olive, which with the help of a special device was injectively in gelatin, getting soft gelatin capsules containing 100 ml of the active ingredient. These capsules are washed and dried.

The tablets. Many types of tablets goth is silicon, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98,8 mg of lactose. To enhance taste and easy digestion, you can use a suitable coating of tablets.

Liquid for injection. The composition for the purpose by injection is prepared by stirring 1.5% of (wt. the proportion of active ingredient in 10% (vol. share) aqueous solution of propylene glycol. When you bring the volume label use special water for injection. The finished solution is sterilized.

Suspension. For purposes tematicheskie (through the mouth) to prepare such aqueous suspension, in each 5 ml contains 100 mg of finely dispersed active ingredient, 100 mg of sodium salt of carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, u.s.p., and of 0.025 ml of vanillin.

The same kinds of dosages listed above can be used in the appointment of compounds conforming to the invention, at any stages of treatment in combination with other drugs. If two medicines are prescribed in their physical combination, the dosage form and method of appointment should be selected taking into account the coexistence of both drugs. Suitable dosages, types of dosage forms of the lockers AII usually the same, what and when used alone blockers hormone AII: 1-500 mg/day, usually 10-100 mg/day in one or several stages. When used in conjunction with diuretics initial dose of AII blockers may be less: 1-100 mg/day, and in the case of more active compounds it is 1-10 mg/day.

It is expected that the compounds conforming to the invention will also be useful in the treatment of chronic renal failure.

1. Aralkylamines the imidazoles of General formula I

< / BR>
where R1means2WITH6alkyl;

R2mean 1 - or 2-naphthyl, 3-, 4 - or 5-acenaphthyl, 1-, 2-, 3- 4- or 9 - phenanthrene, 2-, 3-, 4-, 5-, 6- or 7-benzofuran or 2-, 3-, 4-, 5-, 6- or 7 - benzothiazyl with any of the above groups may be substituted by one or two substituents selected from the group: halogen or1- C5alkoxyl; or (C2WITH10alkenyl, replaced by a substituted or unsubstituted group polycyclic aryl, above, with protivogipertonicheskoe action.

2. The pharmaceutical composition having inhibitory activity against angiotensin II, containing the active principle and a pharmaceutically acceptable carrier, characterized in that it cos="ptx2">

3. The composition according to p. 2, characterized in that it additionally contains a diuretic in the following components, at a daily dose of:

Connection on p. 1 1 100

Diuretic 25 100

4. The composition according to p. 2, characterized in that it further comprises a non-steroidal anti-inflammatory drug with the following content of components, mg per daily dose:

Connection on p. 1 1 500

Nonsteroidal anti-inflammatory drug 1 500

5. The method of obtaining aralkylamines of imidazoles of General formula I on p. 1, wherein the imidazole derivative of General formula

< / BR>
subjected to interaction with a derivative of benzyl General formula

< / BR>
where R1, R2have the values specified above;

R3group

< / BR>
or R1R3protected or are intermediate groups

X1halogen, paratoluenesulfonyl or methylsulfonylamino,

in the environment of a solvent in the presence of a base at a temperature of 20oWith temperatures of distillation of the solvent for 1 to 10 hours, followed by separation of the target product or, if necessary, the conversion of compounds with intermediate or protected form radicals in the target connection.

7. The method according to p. 5, characterized in that use two-phase solvent system methylene chloride and water, the process is conducted in the presence of a catalyst phase transfer of chloride tricaprylate.

 

Same patents:

The invention relates to new 2-imidazolin-2-yl)thieno - foroperational compounds, to intermediates used to obtain these compounds, and the way of dealing with these compounds with unwanted annual and perennial plants, namely 6-(2-imidazolin-2-yl)thieno - and furo[2,3-b] and 5-(2-imidazolin-2-yl)thieno - and furo[3,2-b]the pyridine compounds and the corresponding 2,3-dihydrothieno and 2,3-dihydropyrimidine with structural formulas (Ia) and (Ib):

< / BR>
whererepresents a single or double bond; R1represents a C1-C4alkyl; R2represents a C1-C4alkyl or C3-C6cycloalkyl; R1and R2together with the carbon atom to which they are joined, can form WITH3-C6cycloalkyl, optionally substituted stands; And represents СООR3CHO, CH2OH, COCH2HE, CONHCH2CH2OH, CONHOH or

R3hydrogen, C1-C12alkyl, which can be broken od is alkoxy, halogen, hydroxyl, C3-C6cycloalkyl, benzyloxy, fullam, phenyl, furfuryl, galopera, lower alkylphenyl, lower alkoxyphenyl, nitrophenyl, carboxyla, lower alkoxycarbonyl, cyano, C1-C4alkylthio or three (lower) alkylammonium; C3-C6alkenyl, optionally substituted by one of the following groups:1-C3alkoxy, phenyl, halogen or two WITH1-C3alkoxygroup or two halogen groups; C3-C6cyclooctyl, optionally substituted by one or two1-C3alkyl groups; C3-C10quinil, optionally substituted by phenyl, halogen or CH2IT; or the cation of an alkali metal or alkaline-earth metal (CA, BA) manganese, copper, iron, ammonium, or organic ammonium; RWITHand RDrepresent N or CH3; Represents N; COR4or SO2R5provided that when a represents a COR4or SO2R5and is a СOOR3the radical R3cannot be hydrogen or a salt-forming cation; R4represents a C1-C11alkyl, chloromethyl or phenyl, optionally substituted A5 alkyl or phenyl, optionally substituted one metalno, chloro - or nitro-group; W represents 0 or S; X represents 0, S or whenis a single bond, the group S 0; Y and Y', Z and Z' represent hydrogen, halogen, C1-C6alkyl, C1-C4hydroxy (lower) alkyl, C1-C6alkoxy, C1-C6acyloxy, benzoyloxy, optionally substituted by one or two1-C4alkyl, C1-C4alkoxygroup or halogen; C1-C4alkylthio, phenoxy,1-C4haloalkyl,1-C4haloalkoxy, nitro, cyano, C1-C4alkylamino,1-C4dialkylamino,1-C4alkylsulfonyl or phenyl, optionally substituted by one or more1-C4the alkyl, C1-C4alkoxy, halogen, or any combination of these two groups, where Y and Z are the same provided that Y and Z represent hydrogen, halogen, alkyl or alkoxy, and when Y and Y' or Z and Z' are the same group they are hydrogen or alkyl; and taken together, Y and Z form a ring in which YZ has the structural formula -(CH2)n- where n являе/www.fips.ru/fullimg/rupat2/19962/004.dwl/2058313-8t.gif" ALIGN="ABSMIDDLE">-=where L, M, Q, and R7each represent hydrogen, halogen, nitro, C1-C4lower alkyl, C1-C4lower alkoxy, methoxy, phenyl, phenoxy, provided that only one of the radicals L, M, Q or R7may have a value different from hydrogen, halogen, C1-C4the alkyl or C1-C4alkoxy; or a pyridine-N-oxides, when W represents oxygen or sulfur and a is COOR3; and when R1and R2not the same, the optical isomers of these compounds, except for the case when R3represents a salt-forming cation, their salts kislotoustoichivam

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to new chemical compound, particularly to a 10-methoxy-5-methyl-6-(1', 1'-dioxido-2' -meta-chlorvinyls-3'-hydroxy-4' -methoxy-benzo[b] thiophene-7-yl)-5H-3,4,6,7-tetrahydro[4,3,2-Q]-[3]benzazocine formula

(I) with an antidepressant

The invention relates to new derivatives of benzopyran that have protivogipertenzin activity and can be used in the treatment and prevention of cardiovascular diseases

The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

-CH=CH-CH=N (a-5) or

-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

-Alk - R5(b-1),

-Alk - Y - R6(b - 2),

-Alk - Z1- C(=X) - Z2- R7(b-3), or

-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)

Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

The invention relates to indole derivative of General formula (l):

(I)

where R and R1such that:

or R and R1the same or different hydrogen atom, a straight or branched lower alkyl, cycloalkyl to 6 carbon atoms;

or R and R1together with the nitrogen atom to which they are bound, form a piperazinil, substituted lower alkyl,

A -:

or chain /CH2/n, where n can take the values 2 or 3,

or circuit< / BR>
X and Y or each a hydrogen atom,

or one hydrogen atom and the other is a hydroxy radical or1-C4-alkyl,

or X and Y together form an oxo radical, a radical alkyltin with 1-4 carbon atoms or a radical N-OR5where R5a hydrogen atom or an alkyl radical with 1-4 carbon atoms, the substituents a, b, c, d such that:

either each hydrogen atom,

or a and b together form a function oxo and C and d are each a hydrogen atom;

Z -:

or a hydrogen atom,

or a moiety of the lower alkyl or the group aminoalkyl formula:

R2NH2,

where R2lowest alkylen;

moreover, these compounds of formula (I) can nachtergaele or organic acids

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

The invention relates to new imidazole derivative of General formula I

where R1-COOH or the group< / BR>
R2=H-C3H7or n-C4H9;

R3-Cl, CF3C2F5C6H5or 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 the groupwhich inhibit the action of the hormone angiotensin and can be used in medicine

The invention relates to novel condensed heterocyclic compounds or their salts, and their intermediate compounds, method of their production and the fungicide on their basis for the processing of agricultural and horticultural crops

The invention relates to new derivatives of 1-phenylimidazole formula 1

CFN< / BR>
where R represents a hydrogen atom or methyl;

x represents a fluorine atom, a chlorine atom or a nitro-group;

y represents a fluorine atom or a chlorine atom;

z represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, a process for the preparation of these compounds and insecticides containing as active components of these compounds

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

Ionic liquids ii // 2272043

FIELD: organic chemistry.

SUBSTANCE: invention relates to new ionic liquids designated for using in electrochemical cells and in organic synthesis. Invention describes ionic liquids of the general formula: K+A- (I) wherein K+ represents one of cations of the group consisting of the following formulae: wherein R1-R5 can be similar or different and can be bound to one another by a simple or double bond also, and each of them separately or in common can represent the following values: hydrogen atom (H), halogen atom, (C1-C8)-alkyl radical that can be partially or completely substituted with the following groups but preferably with fluorine atom (F), chlorine atom (Cl), N-[CnF(2n+1-x)Hx]2, O-[CnF(2n+1-x)Hx], SO2-[CnF(2n+1-x)Hx] or CnF(2n+1-x)Hx wherein 1 < n < 6 and 0 < x < 2n+1; A- means anion taken among the group consisting of [PFx(CyF(2y+1-z)Hz)6-x]- wherein 1 ≤ x ≤ 6, 1 ≤ y ≤ 8 and 0 ≤ z ≤ 2y+1. Invention provides the development of ionic liquids showing broad range of liquid state, high thermal resistance and low corrosive activity.

EFFECT: improved and valuable properties of ionic liquids.

3 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to benzamide derivatives possessing with inhibitory activity with respect to tyrosine kinase Flt-1-receptors VEGF that can be used in treatment of neoplastic disease. Invention describes a pharmaceutical substance comprising compounds of the group 2-[(4-pyridyl)methyl]-amino-N-[R1]-benzamide wherein R1 means 4-chlorophenyl, 4-methylphenyl, 4-chloro-3-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl possessing with the inhibitory activity with respect to tyrosine kinase Flt5-2-receptors VEGF associated with neoplastic disease and angiogenesis. Also, invention describes novel compounds of the group 2-[(nitrogen-containing heterocycle)methyl]-amino-N-[R1]-benzamide wherein nitrogen-containing heterocycle is represented by 4-pyrodyl, 4- or 5-quinolinyl, 2-imidazolyl, and a method for their synthesis. Also, invention describes a pharmaceutical composition comprising abovementioned compounds possessing the inhibitory activity with respect to tyrosine kinase VEGF receptors used in treatment of neoplastic disease.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 74 ex

FIELD: bioorganic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel aspartyl derivatives of histamine of the general formula (I): , wherein R means hydrogen atom (H), or , or that are able to modulate activity of enzymes of antioxidant protection - superoxide dismutase (SOD) and catalase. Also, invention relates to using the known compounds of the general formula (I) for the same designation wherein at the same values of X the value R represents acetyl group, and to their pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition possessing capacity to modulate activity of SOD and catalase and comprising the effective amount of compound of the general formula (I), and to a method for synthesis of compounds of the general formula (I). Method involves interaction of pentafluorophenyl ester Nα-Z-, β- or α-benzyl ester of aspartic acid with histamine followed by hydrogenolysis without isolation of intermediated protected derivatives of aspartyl histamine.

EFFECT: improved method of synthesis, valuable biochemical properties of derivatives.

12 cl, 3 tbl, 2 sch, 2 dwg, 8 ex

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

SUBSTANCE: invention relates to novel 2-(2,6-dichlorophenyl)diarylimidazoles of the general formula (I): possessing inhibitory effect on activity of protein-tyrosine kinase and first of all c-met kinase, and can be used in treatment of oncological diseases. In the compound of the general formula (I) X means hydrogen atom, -OR1, -SR2, -(SO2)R2 or group A1-Q wherein A1 means (C1-C3)-alkylene group; Q means -OR1, -NR3R4, -NHCH2CH2NR3R4; R1 is chosen from group comprising hydrogen atom, (C1-C)-alkyl, dimethylphosphonylmethyl, (R)-2,3-dihydroxy-1-propyl, (S)-2,3-dihydroxy-1-propyl, 1,3-dihydroxy-2-propyl, 3-hydroxy-2-hydroxymethyl-1-propyl, 2-methoxyethoxymethyl, 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or group A1-Q1 wherein Q1 means (C1-C2)-alkoxy, cyano group, carboxyl, (C1-C6)-alkoxycarbonyl, and if A1 means 1,2-ethylene- or 1,3-propylene group then Q1 means hydroxy group; R2 means (C1-C6)-alkyl or A1-Q; R3 and R4 are chosen independently from group comprising hydrogen atom, (C1-C6)-alkyl, or form in common 6-membered saturated cycle comprising two heteroatoms chosen from nitrogen (N) or oxygen (O) atoms; Y means hydrogen atom or group A2-R wherein A2 means (C1-C5)-alkylene optionally substituted with (C1-C6)-alkyl, phenyl or hydroxy group; R means hydroxy group, linear or branched (C1-C6)-alkoxy, amino, dimethylamino, diethylamino, tert.-butyloxycarbonylamino group, carboxyl, (C1-C6)-alkoxycarbonyl, triazolyl, 1-pyrrolidinyl, morpholino group, 4-methylpiperazin-1-yl, O-A1-NR3R4, S-A1-NR3R4, 4-carboxyphenyl, furan-3-yl, thiophen-2-yl or 3-methylthiophen-2-yl; Z means one or two substitutes chosen independently from group comprising halogen atom, hydroxy, allyloxy group, methyl, (C1-C5)-alkoxy, methoxymethoxy, (2-methoxyethocy)methyloxy, methylthio, ethoxymethoxy group, ethynyl and benzyloxy group optionally substituted with halogen atom, methoxy, cyano, ethoxy group, and its pharmaceutically acceptable salts. Also, invention elates to novel intermediate compounds and synthesis of compounds, and to their using for preparing drugs and pharmaceutical composition.

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

13 cl, 97 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to substituted ω-azolylalkane anilides. Invention describes substituted ω-(1H-azol-1-yl)-N-phenylalkaneamides of the general formula (I): wherein Z and Y mean nitrogen atom of CH-group, or they represent the chain -C-CH=CH-CH=CH-C- simultaneously and forming in common an anellated ring; n means a whole number from 1 to 3; Rm are similar or different and mean hydrogen, halogen atom, alkyl group with number of carbon atoms from 1 to 4, alkoxy group, alkylenedioxy group, benzyloxy group, perfluoroalkyl group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group, carboxyl group, halogenphenylthio group, halogenbenzoyl group; m means a whole number from 0 to 5, their salts with acids. Also, invention describes methods for synthesis of compounds of the formula (I) and their using as anti-aggregative preparations. Invention provides synthesis of novel compounds possessing the useful biological properties.

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

8 tbl, 11 ex

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