RU2067581C1 - Aralkylsubstituted imidazoles showing antihypertensive action, method of their synthesis and pharmaceutical composition showing inhibiting activity with respect to angiotensin ii - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: products: aralkylsubstituted imidazoles of the formula (I)

where R¹-C₂-C₆-alkyl; R² - 1- or 2-naphthyl, 3-, 4- or 5-acenaphthyl, 1-, 2-, 3-, 4- or 9-phenanthrenyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl or 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, C₂-C₁₀-alkenyl. Reagent 1: compound of the formula (II)

where R¹ and R² as indicated above. Reagent 2: compound of the formula (III)

where X¹ - halogen. Reaction conditions: in organic solvent medium, in the presence of the base. Synthesized compounds were used in medicine as antihypertensive agents. ???EFFECT: improved method of synthesis. 4 cl, 8 tbl

Description

 The invention relates to new imidazole derivatives, a method for their preparation and pharmaceutical compositions containing these compounds. The latter can be used both independently and in combination with other formulations, in particular with diuretics and non-steroidal anti-inflammatory drugs.

The compounds described in the present invention suppress the action of the hormone angiotensin and are therefore useful in the treatment of hypertension caused by the formation of angiotensin II (hereinafter AII). The renin enzyme acts on the angiotensinogen α ₂ -globulin in blood plasma, causing the formation of angiotensin I, which then turns into AII under the action of an enzyme specific for angiotensin. Hormone AII is a powerful stimulator of blood pressure increase, which, as you know, is the main cause of blood pressure increase in animals of various species, including rats and dogs, and in humans. The compounds of the present invention inhibit the activity of AII on the corresponding receptors of the target cells and thereby prevent the increase in blood pressure caused by the interaction of this hormone with its receptors. As a result of the administration of the compound of the invention to the said animal mammal suffering from hypertension caused by AII, the blood pressure in the body of these animals can be reduced. In addition, the proposed compounds are useful in the treatment of heart failure due to blockage of blood vessels. When using the latter in combination with a diuretic, such as furosemide or hydrochlorothiazide, both as an independent stage of treatment (when a diuretic is prescribed at the first stage) and as a mixture of these drugs, the antihypertensive effect can be enhanced. Administration of a compound of the invention together with a non-steroidal anti-inflammatory drug (NSAID) can prevent renal failure, often resulting from the administration of NSAIDs.

In the literature, an octapeptide (sac ¹ , ala ⁸ ) analogue of AII is described, named as saralazine, which is the most effective means of combating the harmful effects of AII. However, the analogue itself, like most peptide antagonists, also causes side effects.

 So, it was shown that saralazine 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, N 29, p. 673). However, given the peptide nature of Saralizin in the case when AII is not responsible for the increase in pressure, it itself plays the role of a stimulator of pressure increase. The action of saralazine is relatively short-lived and appears only upon injection; when administered orally, it is ineffective. The main purpose of this compound as a pharmaceutical standard in research.

 Some known non-peptide antihypertensive agents suppress an enzyme called the angiotensin conversion enzyme (EPA), which is responsible for the conversion of angiotensin I to AII. Therefore, these agents are inhibitors of EPA or inhibitors of the conversion enzyme (IEP). IEPs such as captopril and enalapril are commercially available. Experiments and clinical practice show that in 40% of cases an organism susceptible to hypertension is immune to treatment with drugs such as IEP. Only in conjunction with a diuretic, such as furosemide or hydrochlorothiazide, IEP can effectively normalize blood pressure in most cases of diseases. Treatment with a diuretic translates a pathological state of blood pressure regulation, independent of renin, into a normal state regulated by renin. Although the imidazoles proposed in the invention act by a different mechanism, namely, by blocking the AII receptor rather than by suppressing the enzyme responsible for the conversion of angiotensin, nevertheless both of these processes are associated with the renin-angiotensin cascade. However, non-steroidal anti-inflammatory drugs (NSAIDs) cause renal failure in patients with renal subperfusion and high plasma AII levels. The administration of the AII blocking compound of the present invention in combination with NSAIDs (either by sequential administration at different stages of treatment or as a mixture) can prevent the mentioned renal failure (see Dunn MJ Hospital Practical, 1984, v.19, p. 99 )

 PCT application N 0253310, published on 01.20.88, describes aralkyl-substituted imidazoles that block the action of AII and, therefore, are useful for alleviating the course of hypertension caused by angiotensin, as well as for treating heart failure due to vascular obstruction. These compounds differ from the proposed compounds with substituents in the imidazole ring.

 The aim of the invention is the search for new derivatives of imidazole with antihypertensive activity with a wide spectrum of action, the development of a method for their preparation and pharmaceutical compositions based on these compounds that have an inhibitory effect against angiotensin II.

где R¹ С₂-C₆-алкил, R² 1 или 2-нафтил, 3-, 4- или 5-аценафтил, 1-, 2-, 3-, 4- или 9-фенантренил, 2-, 3-, 4-, 5-, 6- или 7-бензофурил или 2-, 3-, 4-, 5-, 6- или 7-бензотиенил; при этом каждая из указанных групп может быть замещена одним или двумя заместителями, выбранными из группы: атом галогена, С₁-С₅-алкоксил или С₂-C₆-алкенил, замещенный замещенной или незамещенной группой полициклического арила, указанного выше, проявляющие противогипертоническую активность.The present invention provides aralkyl-substituted imidazoles of the general formula I

where R ¹ C ₂ -C ₆ -alkyl, R ² 1 or 2-naphthyl, 3-, 4- or 5-acenaphthyl, 1-, 2-, 3-, 4- or 9-phenanthrenyl, 2-, 3- 4-, 5-, 6- or 7-benzofuryl or 2-, 3-, 4-, 5-, 6- or 7-benzothienyl; each of these groups may be substituted by one or two substituents selected from the group: a halogen atom, C ₁ -C ₅ alkoxy or C ₂ -C ₆ alkenyl, substituted by a substituted or unsubstituted polycyclic aryl group indicated above, exhibiting antihypertensive activity.

подвергают взаимодействию с производным бензила общей формулы:

где R¹, R² имеют вышеуказанные значения, R³ - остаток формулы

или R¹-R³ защищены или являются промежуточными группами, х атом галогена, n толуолсульфонилокси- или метилсульфонилоксигруппа, в среде растворителя в присутствии основания при температуре от 20^oС до температуры отгонки растворителя в течение 1-10 ч, с последующим выделением целевого продукта или, в случае необходимости, превращением соединений с промежуточными или защищенными радикалами в целевые соединения.Another object of the invention is a method for producing compounds I, which consists in the fact that the imidazole derivative of formula II

subjected to interaction with a benzyl derivative of the General formula:

where R ¹ , R ² have the above meanings, R ³ is the remainder of the formula

or R ¹ -R ³ are protected or are intermediate groups, x is a halogen atom, n is a toluenesulfonyloxy or methylsulfonyloxy group, in a solvent medium in the presence of a base at a temperature of from 20 ^{° C.} to a temperature for distilling off the solvent for 1-10 hours, followed by isolation of the target product or, if necessary, the conversion of compounds with intermediate or protected radicals to the target compounds.

 The specified method can be carried out using a two-phase solvent system of methylene chloride-water in the presence of a phase transfer catalyst of tricaprylmethylammonium chloride.

 As the base in the process, various bases selected from the group can be used: hydride metal of the formula MH, metal alkoxide of the formula MOR, sodium or potassium carbonate, triethylamine or pyridine, in a dipolar aprotic solvent. If the base is a metal alkoxide MOR, then the solvent may be ROH alcohol, where R is methyl, ethyl, tert-butyl, M is lithium, sodium, potassium.

 A subject of the invention is also a pharmaceutical composition having inhibitory activity against angiotensin II, containing an active principle and a pharmaceutically acceptable carrier.

 The difference between the proposed composition from a previously known composition of the same purpose is the use as an active principle of the compounds of formula I in an effective amount.

The composition may further comprise a diuretic in the following components:
the compound of formula I 1-100 mg per daily dose
diuretic 25-100 mg per daily dose,
and may also optionally contain a non-steroidal anti-inflammatory drug with the following components:
the compound of formula I 1-500 mg per dose,
non-steroidal anti-inflammatory drug 1-500 mg per dose.

 DETAILED DESCRIPTION OF THE INVENTION

 Synthesis. A new compound of formula I can be prepared using the reactions and techniques described in this section. These reactions are carried out in a solvent medium suitable for the reagents and substances used, namely, suitable for carrying out the necessary chemical transformations. Specialists in the field of organic synthesis are well aware that the functionality "carried" by imidazole and other parts of the molecule of the compound must correspond to the intended chemical transformations. As with other synthesis processes, it is often necessary to make decisions about what protective groups are needed, conditions for deprotection, methods of activating a position in the ring of benzyl capable of “crosslinking” with nitrogen in the imidazole nucleus. Not all compounds of formula I mentioned in the text of this section and related to a given class can be obtained by all the methods given for this class. Substituting groups in the starting materials may be incompatible with certain reaction conditions that are required in the case of individual of the above methods. The restriction placed on substituting groups in terms of their compatibility with the reaction conditions is obvious for one of the alternative methods also described in this section.

In general, the compounds of the invention are readily prepared by direct alkylation of imidazole with a suitably protected benzyl halide, tosylate or mesylate in the presence of a base. It is better if an imidazole salt is prepared by reacting imidazole I with a proton acceptor, such as MH, where M is lithium, sodium or potassium, in a solvent such as dimethylformamide (DMF), or by reacting an imidazole of formula I with a metal alkoxide of formula MOR, where R is methyl, ethyl, tert-butyl in an alcohol solvent (ethyl or tert-butyl alcohol), or in a dipolar aprotic solvent such as dimethylformamide. The imidazole salt is dissolved in an inert aprotic solvent, such as DMF, and treated with the above alkylating agent. Alternatively, imidazole can be alkylated with benzyl halide (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 dimethyl sulfoxide (DMSO), at temperatures from 20 ^o C to a temperature of distillation of the solvent for 1-10 hours

 Preferred methods for producing tetrazoles are shown in Scheme 1 by equations a and b. Compounds A can be prepared by the 1,3-dipolar cycloaddition of azides of trialkyltin or triphenyltin to the corresponding nitrile B, as represented by equation a. "Alkyl" means normal alkyl with 1-6 carbon atoms. An example of such a technology was described by Cosima et al. (Kozima S. et al. Organic Chemistry, 1971, p. 337). The necessary trialkyl or triaryl tin azides are synthesized from commercially available trialkyl and triaryl tin chlorides and sodium azide. The trialkyl or triaryl tin group is removed by acid or basic hydrolysis, and tetrazole can be protected by the trityl group by reaction with trityl chloride and triethylamine to give compound C. Subsequent bromination with N-bromosuccinimide and dibenzoyl peroxide gives compound D. Alkylation of compound E with the corresponding substituted benzyl halide D base, followed by removal of the protecting group of trityl by hydrolysis gives compound 1, in which R tetrazole. Instead of the trityl group, other protective groups such as para-nitrobenzyl and I-ethoxyethyl can be used to protect the tetrazole part of the molecule. These groups, as well as the trityl group, can be introduced and removed according to the method described in Green's guide “Protective Groups in Organic Synthesis” (Green Protective Groups in Organic Synthesis, Wiley Interscience, 1980) (see Scheme 1).

The compounds of formula I, where R ² arylalkenyl, and R ³ represents CH ₂ OH, CHO or COOH, can be obtained as shown in scheme 2.

 2-alkylimidazole-4,5-dicarboxylic acid A, obtained by the method developed by Farger and Paymen (Farger RG of Pymen FZJ Chem. Soc. 1991, v. 115, p. 217), can be converted into their corresponding diesters distillation of the alcoholic solvent in the presence of an acid, such as hydrochloric acid, or one of many other methods well known to one skilled in the art.

основанием в подходящем растворителе, таком как ДМФА, в присутствии акцептора кислоты, такого как карбонат калия или натрия.Further, ester B can be converted into its metal salt by reaction with methoxide, ethoxide or sodium hydride or other

a base in a suitable solvent, such as DMF, in the presence of an acid acceptor, such as potassium or sodium carbonate.

Complex diester C can be reduced with lithium aluminum hydride in an inert solvent such as tetrahydrofuran to the corresponding dialkol D. Selective oxidation of dialcohol D with manganese dioxide in an inert solvent such as tetrahydrofuran gives mainly aldehyde G with a small amount of dialdehyde E. Crystallization or chromatographic separation of compounds E and G followed by the reaction of yttig of compound G with a suitably substituted aralkylidene triphenylphosphorane in An excipient, such as tetrahydrofuran, gives 4-arylalkenyl-5-hydroxymethylimidazole F. as a product. Further oxidation of compound F with a periodide, as proposed by Dess Martin, see J. Org. Chem. 1983, v. 48, p. 4155, as well as manganese dioxide, pyridinium chlorochromate, barium manganate or other oxidizing agents well known to one skilled in the art in an inert solvent such as tetrahydrofuran or methylene chloride, followed by removal (if necessary) of the protective groups from any of the radicals R ¹ , R ² or R ³ gives 4-arylalkenylimidazole-5-carboxaldehyde Q as the product (see Scheme 2).

 Compounds of the present invention and methods for their preparation will be better understood by considering the following examples, which, however, do not limit the present invention. Degrees are indicated on the Celsius scale, and shares and percentages are in mass units.

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

 Example 1. Part A: preparation of 5-hydroxymethyl-4-iodo-2-n-propylimidazole.

A solution of 31.5 g of 4 (5) -hydroxymethyl-2-n-propylimidazole and 50.6 g of N-iodosuccinimide in 560 ml of 1,4-dioxane and 480 ml of 2-methoxyethanol was stirred at 45 ^{° C.} for 2 hours. Next solvents are removed in vacuo. The resulting solids are washed with distilled water and then dried to obtain 54.6 g of the product as a solid with a melting point of 169-170 ^{° C.} and NMR (dimethyl sulfoxide-d ₆ ) δ 12.06 (br, s, 1H); 5.08 (t, 1H); 4.27 (d, 2H); 2.50 (t, 2H); 1.59 (sext, 2H); 0.84 (t, 3H).

 Part B: Preparation of 4-iodo-2-n-propylimidazole-5-carboxaldehyde.

To a solution of 35.8 g of 5-hydroxymethyl-4-iodo-2n-propylimidazole in 325 ml of glacial acetic acid was added dropwise at 20 ^{° C.} over 1 hour 290 ml of a 1.0 l aqueous solution of cerium ammonium nitrate. The resulting mixture was stirred at 20 ^o C for 1 h. Then the reaction mixture was diluted with water, adjusting the pH to 5-6 with an aqueous solution of sodium hydroxide and extracted with chloroform. The combined organic phases are washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude solid was recrystallized from 1-chlorobutane to give 29.9 g of the product as a pale yellow solid with a melting point of 141-142 ^° C. NMR data (CDCl ₃ ): d 11.51 (br, s, 1H ); 9.43 (s, 1H); 2.81 (t, 2H); 1.81 (sext, 2H); 0.97 (t, 3H)
Part C: Preparation of 4- (naphth-1-yl) -2-n-propylimidazole-5-carboxaldehyde.

A solution containing 2.64 g (0.01 mol) of 4-iodo-2-n-propylimidazole-5-carboxaldehyde, 40 ml of toluene and 0.33 g (0.00029 mol) of palladium tetrakistriphenylphosphine (O) was stirred at room temperature in nitrogen, and a solution of 3.44 g (0.022 mol) of 1-naphthylboronic acid in 50 ml of ethyl alcohol is slowly added thereto. The reagents are stirred for 5 minutes, after which 12 ml of 2M sodium carbonate are slowly added. Upon completion of the addition, the reaction is carried out by boiling the solvent for 48 hours, after which it is cooled. The reaction products are filtered, the filtrate is distilled off under vacuum, and the precipitate formed is dissolved in 300 ml of methylene chloride, washed twice with 300 ml of 10% hydrochloric acid. The hydrochloric acid precipitate is treated with 50% sodium hydroxide until the pH reaches 10. The resulting aqueous basic layer is extracted three times with 300 ml of methylene chloride, then the methylene chloride layer is dried over sodium sulfate and evaporated in vacuo. The yield is 0.90 g of product (0.0034 M, 34%). NMR Characteristics (CDCl ₃ ): d 11.45 (m, 1H); 9.42 (s, 1H); 7.28 (m, 7H); 2.82 (t, 2H); 1.85 (m, 2H); 1.01 (t, 3H).

Part D: Preparation of 4-methyl-2 ¹ - [N-triphenylmethyl- (1H-tetrazol-5-yl)] biphenyl.

4 ^1- Methylbiphenyl-2-nitrile is mixed (its preparation is described in PCT application 0253310 published on 01.20.88) in an amount of 10.00 g (51.7 mmol, 1 eq.), Tri-n-butyltin chloride in an amount of 14, 0 ml (51.7 mmol, 1 equiv.), Sodium azide in an amount of 3.4 g (51.7 mmol, 1 equiv.) And xylene in an amount of 50 ml. The reaction mixture was exposed to distillation of the solvent for 64 hours, after which it was cooled to room temperature. Then add 10, He NaOH in an amount of 5.10 ml (0.061 mm, 1.2 equiv.) And trityl chloride in an amount of 14.99 g (53.8 mm, 1.04 equiv.), Then these substances are stirred for 24 h, after which 39 ml of water and 100 ml of heptane are added to the mixture. The resulting mixture was stirred at 0 ^{° C.} for 1.5 hours. The resulting solids were filtered off, washed twice with 55 ml portions of water and once with a mixture of heptane with toluene taken in an amount of 55 ml, after which dehydration was carried out overnight under high vacuum to obtain 19.97 g of the product in the form of a light yellow powder with a melting point of 148.0-155.0 ^o C (decomp.). The resulting solid was suspended in 75 ml of ethyl acetate and filtered to give 15.0 g of the product as a pale yellow powder with a melting point of 164.0-165.5 ^{° C.} (decomp.). NMR characteristics (CDCl ₃ : d 7.91 (d, 1H, J = 0 Hz); 7.53-7.18 (m, 13H); 7.02-6.84 (m, 9H); 2.25 (s, 3H).

 Part E: Preparation of 4-bromomethyl-2 '- [N-triphenylmethyl (1H-tetrazol-5-yl)] biphenyl; indicative procedure.

4-Methyl-2 '- [N-triphenylmethyl (1H-tetrazol-5-yl)] biphenyl (for its preparation see Example 22B) in an amount of 52.07 mg (109 mmol, 1 equiv.), 19.4 are mixed. g of N-bromosuccinimide (109 mM, 1 equiv.), 1.0 g of benzoyl peroxide, as well as 300 ml of carbon tetrachloride. The mixture was kept under solvent distillation for 2.5 hours, then cooled to room temperature and succinimide was filtered off. Then the filtrate is concentrated, and the precipitate is triturated with ether and 36.0 g of substance with a melting point of 129.5-133.0 ^° C (decomp.) Are obtained as the first removal product. NMR Characteristics (CDCl ₃ ): d 4.37 (CH ₃ Br). The resulting substance is suitable for further transformations.

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

A suspension of 4- (naphth-1-yl) -2-n-propylimidazole-5-carboxaldehyde in an amount of 0.90 g (39.7 mmol, 1 equiv.), 4-bromomethyl-2 '- [N-triphenylmethyl- ( 1H-tetrazol-5-yl)] biphenyl in an amount of 2.03 g (43.7 mmol, 1 equiv.), 20 ml of anhydrous dimethylformamide and 3.0 g of potassium carbonate were stirred at room temperature for 18 hours. Next, the reaction mixture filtered, the precipitate is washed with methylene chloride and chromatographed in a mixture of methylene chloride with ethyl acetate at a ratio of components 98: 2 on silica gel to obtain a yellow foam. The yield was 1.50 g. NMR characteristics (CDCl ₃ : d 9.45 (s, 1H); 7.85 (m, 1H); 6.86-7.45 (m, 29H); 5.55 ( s, 2H); 2.60 (t, 2); 1.80 (m, 2H); 0.95 (t, 3H).

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

4- (naphth-1-yl) -2-n-propyl-1 - [(2 '- [N-triphenylmethyl- (1H-tetrazol-5-yl)] biphenyl-4-yl) methyl] imidazol-5- carboxaldehyde in an amount of 1.50 g, 80 ml of tetrahydrofuran and 10% hydrochloric acid are stirred at room temperature. After 8 hours, this mixture was poured into a mixture of ice with 5% NaOH and the pH was adjusted to 10. The resulting material was filtered off, and the pH of the filtrate was adjusted to 4-5 with 10% hydrochloric acid. The turbid solution was extracted with a mixture of methylene chloride with isopropyl alcohol at a component ratio of 80:20 in three doses using 100 ml of the mixture, after which the organic phase was dried over sodium sulfate and evaporated in vacuo to obtain 0.51 g of a white glassy substance. NMR Characteristics (CDCl ₃ ): d 9.35 (s, 1H); 7.78 (m, 1H); 7.60-7.38 (m, 2H); 7.35-6.96 (m, 12H); 5.62 (s, 1H); 2.60 (m, 2H); 1.85 (m, 2H); 0.90 (t, 3H).

 According to the method described in example 1 (part C), the following intermediate compounds can be obtained (table. 1).

 The compounds shown in table. 2 can be synthesized according to the procedure described in example 1, or by the methods described in PCT application 0253310.

 The compounds of examples 2-21, are presented in table. 3 and 4, can be obtained by the methods described in example 1, as well as by the methods described in PCT application 0253310, published on 01.20.88.

 Example 22

 Part A: Preparation of 2-n-propyl-4,5-dicarbomethoxy-imidazole.

2-n-propylimidazole-4,5-dicarboxylic acid obtained by the method of Farger and Paymen (Farger RG Pyman FZJ Chem. Soc.v.115, p. 217), with a melting point of 257 ^o C (decomp.), Taken in the amount of 17 , 14 g (86.6 mmol, 1 equiv.), 400 ml of methyl alcohol and 38.1 ml of acetyl chloride (534 mmol, 6 equiv.) Are mixed under the necessary precautions (adding acetyl chloride to methyl alcohol is a highly exothermic process) and boiled for throughout the night. The solvent was removed in vacuo, after which 100 ml of water and 10 N NaOH were added until pH = 7. The aqueous mixture was extracted three times with ethyl acetate, the organic layers were combined, dried with magnesium sulfate and the solvent was removed in vacuo 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 (yield 58%) with a melting point of 162.0-164.5 ^o C.

NMR Characteristics (CDCl ₃ ): d 3.95 (s, 6H); 2.78 (t, 2H); 1.83 (t of t 2H; J = 7.7 Hz); 0.97 (t, 3H, J = 7 Hz). IR Absorption Data (for undiluted): 1735 cm ^-1 . Elemental analysis calculated for the formula C ₁₀ H ₁₄ N ₂ O ₄ H ₂ O: 52.06 C; 6.28 N; 12.14 N.

 Received: 52.06 C; 6.17 N; 12.49 N.

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

4-methylbiphenyl-2'-nitrile (the method of preparation of which is described in PCT application 0253310 published on 01.20.88) in an amount of 10.00 g (51.7 mmol, 1 equiv.), 14.0 ml of tri-n-butyl chloride -tin (51.7 mmol, 1 equiv.), 3.4 sodium azide (51.7 mmol, 1 equiv.) and 50 silt of xylene are stirred and the solvent is distilled off for 64 hours, after which the reaction mixture is cooled to room temperature. Then add 6.10 ml of 10.0 n NaOH (0.06 mm, 1.2 equiv.) And 14.99 g of trityl chloride (53.8 mm, 1.04 equiv.), After which the mixture is stirred for 24 hours and then 30 ml of water and 100 ml of heptane are added to it. The resulting slip is stirred at 0 ^{° C.} for 1.5 hours. The resulting solids are filtered off, washed with two 55 ml portions of water and 55 ml of a mixture of heptane with toluene once in a ratio of 3: 2, and then dehydrated overnight under vacuum to obtain 19.97 g of a light yellow powder with a temperature of 148-155 ^o C (decomp.). The solid precipitate is suspended in 75 ml of ethyl acetate, filtered to obtain 15.0 g of a light yellow powder with a melting point of 164.0-165.5 ^o C (decomp.). NMR Characteristics (CDCl ₃ ): d 7.91 (d, 1H, J = 9 Hz); 7.53-7.18 (m, 13H); 7.02-6.84 (m, 9H); 2.25 (s, 3H).

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

4-methyl-2 '- [N-triphenylmethyl- (1H-tetrazol-5-yl)] biphenyl in an amount of 52.07 g (109 mm, 1 equiv.), N-bromosuccinimide in an amount of 19.4 g (109 mm , 1 equiv.), 1.0 g of benzoyl peroxide and 300 ml of carbon tetrachloride are mixed, boiled and the solvent for 2.5 hours. Next, the reaction products are cooled to room temperature and succinimide is filtered off. The filtrate is concentrated, and the residue is triturated with ether until the first removal in the amount of 36.0 g of a substance with a melting point of 129.5-133.0 ^o C (decomp.). NMR Characteristics (CDCl ₃ ) d 4.37 (CHBr). This substance is suitable for further transformations.

 Part D: Preparation of 4,5-dicarbomethoxy-2-n-propyl-1- [2 '- (N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] imidazole.

Sodium hydride was added to a solution of 10.00 g of 4,5-dicarbomethoxy-2-n-propylimidazole (44.2 mmol, 1 equiv.) In dimethylformamide in the amount of 1.06 g (44.2 mmol, 1 equiv.) At room temperature. In this case, foaming and evolution of gaseous products is observed. Then, the temperature is increased to 60 ^{° C.} over 15 minutes in order to completely dissolve the sodium hydride. Then, gas evolution ceases and the mixture is cooled to room temperature. To this mixture was added a solution of 2- (N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4-yl) methyl bromide in dimethylformamide, taken in an amount of 24.64 g (44.2 mmol, 1 equiv.) . After 24 hours, the solvent was removed in vacuo and the residue was subjected to thin-layer chromatography in a mixture of hexane and ethyl acetate (at a ratio of 75:25) to 100% ethyl acetate on silica gel to obtain 25.78 g (51% yield) of a white glassy substance suitable for subsequent transformations.

Recrystallization from ethanol gives a sample for analysis in the form of white crystals with a melting point of 124.0-125.5 ^° C. NMR characteristics (CDCl ₃ : d 7.91 (d from d 1H, J = 3.9 Hz); 7 , 59-7.20 (m, 12H); 7.09 (d, 2H, J = 9 Hz); 6.94 (m, 6H); 6.76 (d, 2H, J = 9 Hz); 5 , 30 (s, 2H); 3.89 (s, 3H); 2.50 (t, 2H, J = 7 Hz); 1.67 (t of t, 2H; J = 7.7 Hz); 0 85 (9t, 3H, J = 8 Hz). IR absorption (for undilution): 1718 cm ^-1 . Calculated for the formula C ₄₃ H ₃₈ N ₆ O ₄ : 73.49 C; 5.45 N; 11, 96 N. Found 73.23 C; 5.48 N; 12.22 N.

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

4,5-dicarbomethoxy-2-n-propyl-1 - [(2 '- (N-triphenylmethyl (1H-tetrazol-5-yl -)) biphenyl-4-yl) methyl] imidazole in an amount of 9.88 g ( 14.1 mmol, 1 equiv.) Are dissolved in a minimum amount of tetrahydrofuran. To this solution, 1, OM solution of lithium aluminum hydride in tetrahydrofuran was slowly added dropwise in an amount of 15.48 ml (15.48 mmol, 1.1 eq.). The mixture was stirred overnight at room temperature and then rapidly cooled by the Steinhardt method, see Fieser of Fieserr VI, p. 584, as follows: 0.66 ml of water was carefully added to the reaction mixture first, then 0.66 ml of 15% NaOH and then another 1.97 water. After stirring for 72 hours, a very fine precipitate is obtained, which is slowly filtered off on a Celite ^™ brand zeolite filter. The filtrate was dried using magnesium sulfate, and the solvent was removed in vacuo. The result is 8.83 g of a yellow vitreous substance incapable of recrystallization. This intermediate is suitable for subsequent conversions. NMR characteristics (dimethyl sulfoxide d ₆ ): d 7.82 (d, 1H, J = 9 Hz); 7.68-7.28 (m, 12H); 7.05 (d, 2H, J = Hz); 6.78 (d, 6H, J = 9 Hz); 5.16 (s, 2H); 4.94 (t, 1H, J = 7 Hz); 4.66 (t, 1H, J = 7 Hz); 4.37 (d, 2H, J = 7 Hz); 4.32 (d, 2H, J = 7 Hz); 2.34 (t, 2H, J = 7 Hz); 1.52 (t of q, 2H, J = 7 Hz); 0.77 (t, 3H, J = 7 Hz); IR absorption (for undiluted): 3300 br; 3061; 1027; 1006; 909; 732; 699 cm ^-1 . Calculated for formula C ₄₁ H ₃₈ N ₆ O ₂ H ₂ O: 74.07 C; 6.06 N; 12.64 N. Found 74.06 C; 5.95 N; 11.86 N.

 Part F: Preparation of 5-hydroxymethyl-2-n-propyl-1 - [(2 '(N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] imidazole-4-carboxaldehyde and 2 n-propyl-1 - [(2'-N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] imidazole-4,5-dicarboxaldehyde.

4,5-dihydroxymethyl-2-n-propyl-1 - [(2- (N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] imidazole in an amount of 8.56 g (13 , 2 mM, 1 equiv.) Are dissolved in a minimum amount of tetrahydrofuran and a suspension is added containing 11.14 g of manganese dioxide 128.1 mm, 9.7 equiv.) In 100 ml of tetrahydrofuran and having room temperature. After 24 hours, the contents of the reaction vessel were filtered through a Celite ^™ brand cell filter. The residue was subjected to thin-layer chromatography in a mixture of hexane with ethyl acetate (at a ratio of 1:10) to 100% ethyl acetate on silica gel to obtain dialdehyde, which was washed first, as well as 1.25 g of a vitreous substance (yield 15%). NMR characteristics (dimethyl sulfoxide d ₆ ): d 10.27 (s, 1H); 10.17 (s, 1H); 7.81 (d, 1H, J = 7 Hz); 7.68 (m, 2H); 7.50-7.23 (m, 10H); 7.09 (d, 25, J = 9 Hz); 6.96 (d, 2H, J = 9 Hz); 6.86 (m, 6H); 5.59 (s, 2H); 2.52 (t, 2H, J = 7 Hz); 1.58 (t of q, 2H, J = 7 Hz); 0.77 (t, 3H, J = 7 Hz). IR absorption (for undiluted) 1697, 1672 cm ^-1 . Calculated for the formula C ₄₁ H ₃₆ N ₆ O ₂ : 76.62 C; 5.33 N; 13.07 N. Found: 76.46 C; 5.54 N; 12.94 N.

The product of subsequent washing was 4-hydroxymethylimidazole-5-carboxaldehyde, which is a light yellow solid with a melting point of 164.5-166.0 ^° C. NMR characteristics (dimethyl sulfoxide d ₆ ) d 9.86 (s, 1H); 7.80 (d, 1H, J = 9 Hz); 7.63 (t, 1H, J = 9 Hz); 7.53 (t, 1H, J = 7 Hz); 7.50-7.25 (m, 10H); 7.07 (d, 2H, J = 9 Hz); 6.97-6.80 (m, 8H); 5.47 (t, 1H, J = 7 Hz); 5.29 (s, 2H); 4.63 (d, 2H, J = 7 Hz); 2.37 (t, 2H, J = 7 Hz); 1.49 (t of q, 2H, J = 7.7 Hz); 0.73 (t, 3H, J = 7 Hz). IR absorption (required) 1688 cm ^-1 . Calculated for the formula C ₄₁ H ₃₆ N ₆ O ₂ (H ₂ O) _0.1 : 76.16 C; 5.64 N; 12.84 N. Found: 76.02 C; 5.36 N; 12.84 N.

 Part G: Preparation of 5-hydroxymethyl-4- [cis- (naphth-1-yl) ethenyl] -2-n-propyl-1 - [(2 '- (N-triphenylmethyl - (1H-tetrazol-5-yl) ) biphenyl-4-yl) methyl] imidazole.

A suspension of 6.82 g of 1-naphthylmethylphenylphosphonium chloride (0.0155 M, 2 equiv.) In 90 ml of tetrahydrofuran is prepared, into which 20.68 ml of potassium salt of bis (trimethylsilyl) amide (0.0155 M, 2 equiv) is added dropwise. .) taken in the form of a 0.75 M solution in toluene. The resulting red solution was heated at 45 ^{° C.} for 0.5 hours. Then, 5.00 g of 5-hydroxymethyl-2-n-propyl-1 - [(2 '- (N-triphenylmethyl- (1H-tetrazole) -5-yl)) biphenyl-4-yl) methyl] imidazole-4-carboxaldehyde (7.75 mmol, 1 eq.), Dissolved in a minimum amount of tetrahydrofuran, after which the solution was stirred overnight. 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 with magnesium sulfate, and the solvent is removed under vacuum to obtain 9.29 g of a yellow glassy substance. As a result of thin-layer chromatography with a mixture of pentane with ethyl acetate (at a ratio of 1: 1) to 100% ethyl acetate, 7.95 g of a yellow vitreous substance are obtained. NMR characteristics (dimethyl sulfoxide d ₆ ): d 8.20-7.20 (m, 20H); 7.10-6.60 (m, 12H); 5.10 (s, 2H); 4.97 (t, 1H, J = 7 Hz); 4.00 (m, 2H); 2.20 (t, 2H, J = 7 Hz); 0.62 (t, 3H, J = 7 Hz). Calculated for the formula C ₅₂ H ₄₄ N ₆ O (triphenylphosphine oxide) _1.6 (H ₂ O): 78.76 C; 5.73 N; 6.82 N. Found: 78.69 C; 5.67 N; 6.90 N.

 Part H: Preparation of 4- [cis- (naphth-1-yl) ethynyl] -2-n-propyl-1- [2 '- (N-triphenylmethyl) - (1H-tetrazol-5-yl)) biphenyl-4 -yl) methyl] imidazole-5-carboxaldehyde.

7.86 g of 5-hydroxymethyl-4- [cis- (naphth-1-yl) -2-n-propyl-1- [2 '- (N-triphenylmethyl - (1H-tetrazol-5-yl)) biphenyl is mixed -4-yl) methyl] imidazole (10.2 mM, 1 equiv.), 4.44 g of manganese dioxide (51.1 mm, 5 equiv.) And 25 ml of methylene chloride. The mixture is boiled overnight in a solvent in a nitrogen medium N ₂ overnight. Manganese dioxide is filtered off on a Celite ^™ zeolite filter, and the cake on the filter is washed with methylene chloride. Next, the filtrate was evaporated from the cake, and the residue was subjected to thin-layer chromatography with a mixture of pentane and ethyl acetate at a ratio of 75:25 to 50:50 to obtain 3.78 g of an orange glassy substance. NMR Characteristics (CDCl ₃ ): 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, 16H); 7.10-6.70 (m, 10H); 6.53 (d, 2H, J = 8 Hz); 5.30 (s, 2H); 2.38 (t, 2H, J = 7 Hz); 1.56 (t of q, 2H, J = 7.7 Hz); 0.77 (t, 3H, J = 7 Hz). Calculated for the formula C ₅₂ H ₄₂ N ₆ O (H ₂ O) _0.7 : 80.12 C; 5.61 H; 10.78 N. Found: 80.24 C; 5.91 N; 10.46 N.

 Part I: Preparation of 4- [cis- (naphth-1-yl) ethenyl] -2-n-propyl-1-yl - [(2 '- (1n-tetrazol-5-yl)) biphenyl-4-yl) methyl] imidazole-5-carboxaldehyde.

A mixture of 3.50 g of 4- [cis- (naphth-1-yl) ethenyl] -2-n-propyl-1-yl - [(2 '- (N-triphenylmethyl- (1H-tetrazol-5-yl)) is prepared ) biphenyl-4-yl) methyl] imidazole-5-carboxaldehyde, 12 ml of trifluoroacetic acid, 12 ml of water and 40 ml of tetrahydrofuran, which was stirred at room temperature. After 2 hours, the pH of this mixture was adjusted using 10 N NaOH to pH 12, after which the organic solvent was evaporated. Then add 100 ml of water and a rubbery solid is precipitated. 50 ml of ethyl alcohol are added to dissolve the solid precipitates. After separation of the layers, the aqueous layer was extracted with two 50 ml portions of ethyl ether. The aqueous layer is then acidified with concentrated hydrochloric acid to pH 2, whereupon a rubbery solid precipitates again. To dissolve it, add 100 ml of ethyl acetate, after which again the separation of the layers occurs. The aqueous layer was extracted with two 100 ml portions of ethyl acetate. The ethyl acetate layers are collected together and dehydrated with magnesium sulfate. The solvent was removed in vacuo and the residue was dissolved in methyl alcohol. Water is added and the pH is adjusted to 2 with concentrated hydrochloric acid. The solvent was removed in vacuo and the residue was partitioned between 100 ml of ethyl acetate and 100 ml of water. The layers are separated, and the aqueous layers are extracted with two 100 ml portions of ethyl acetate. The ethyl acetate layers were collected together, dried with magnesium sulfate, the solvent was removed in vacuo, and the residue was crystallized from ethyl acetate to obtain 1.48 g of a white solid with a melting point of 192.5-193.5 ^° C. NMR characteristics (dimethyl sulfoxide d ₆ ) d 9.53 (s, 1H); 8.10-7.30 (m, 1H); 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); 2.42 (t, 2H, J = 7 Hz); 1.34 (t of q, 2H, J = 7.7 Hz); 0.67 (t, 3H, J = 7 Hz). Calculated for formula C ₃₃ H ₂₈ N ₆ O (H ₂ O): 74.53 C; 5.46 N; 15.80 N. Found: 74.48 C; 5.35 H; 15.65 N.

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

 The usefulness of the invention.

The angiotensin II (II) hormone causes various biological reactions, for example, vascular contraction, due to the stimulation of the receptors of this hormone on the cell membranes. In order to identify compounds such as AII antagonists capable of interacting with the AII receptor, a ligand-receptor binding method was tested with the initial approach. This approach was carried out according to the technique described by Glossman et al. (Glossman et al. J. Biol. Chem. 1974, v. 249, p. 825), with only some modifications. The reaction mixture contains adrenal cortical microsomes (source of AII receptors) in Tris buffer solution containing 2 nM ³ H-AII or 0.05 nM ¹²⁵ J-AII in the presence or absence of a potential AII antagonist. The mixture is ripened for 1 h at room temperature, and immediately after the completion of the reaction, accelerated filtration and washing through a glass-fiber filter are carried out. The hormone ³ H-AII or ¹²⁵ J-AII bound to the receptor trapped on the filter is quantified by scintillation counts (flashes). The inhibitory concentration of IC _{50 of the} potential antagonist of the hormone AII, which characterizes the 50% substitution of all specifically linked ³ H-AII or ¹²⁵ J-AII groups, is a measure of the affinity of these compounds for the AII receptor. Compounds corresponding to the present invention, tested by binding method, showed values (IC _{50 of the} order of 10 M or less (table. 6).

 The potential antihypertensive effect of the compounds of the present invention can be demonstrated by administering these compounds to awake rats prone to hypertension by ligating their left renal artery, see Kanjano et al. (Cangiano et al. J. Pharmacol. Exp. Ther 1979, v. 208, p. 310). Such an operation increases blood pressure due to an increase in renin production, which is accompanied by the administration of compounds orally at doses of 30 mg / kg or through a tube inserted into the jugular vein at a dosage of 3 mg / kg. In this case, a direct measurement of blood pressure is continuously carried out, and a pressure sensor and a multi-position recorder are used to record data. The blood pressure levels before the experiment are compared with the corresponding levels before treatment to establish the antihypertensive effect of the tested compounds. Some compounds of the present invention show intravenous activity at a dose of 3 mg / kg, and some activity upon oral administration at a dose of 30 mg / kg (Table 6).

 Forms of application. Compounds of the present invention can be prescribed for the treatment of hypertension in accordance with the present invention in any way, if the active ingredient (compound) is contacted with the exposure zone in a warm-blooded animal. For example, the appointment can be realized by injection, namely, subcutaneously, intravenously, intramuscularly or by injection into the abdominal cavity. As a supplement or an exception, the drug can also be prescribed orally (through the oral cavity).

 Taking the drug can be prescribed by any conventional method suitable for use in combination with other drugs, which are both independent drugs and combinations of drugs. The drugs can be prescribed in pure form, but, as a rule, together with a pharmaceutical carrier selected on the basis of a particular method of administration in accordance with normal pharmaceutical practice.

 As for the object of application of all of the above, such is a warm-blooded animal belonging to those representatives of the animal world that have a homeostatic mechanism: this includes mammals and birds.

 The prescribed dosage will depend on the age, state of health and weight of the treated animal, taking into account the frequency of the nature of the desired effect. Typically, the daily dose of the active ingredient (compound) is 1-500 mg / sut. As a rule, 10-100 mg / day is enough to achieve the desired results (once or several times a day). These dosages are effective both in the treatment of hypertension and in the treatment of heart failure associated with clogging of blood vessels.

 The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets or powders, or in liquid dosage forms, such as elixirs, medicines and suspensions. This ingredient can also be administered by injection in sterile liquid dosages.

 Gelatin capsules contain the active ingredient and powder carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar fillers can be used in the manufacture of compressed tablets. Tablets and capsules can be made in the form of slow-acting forms to ensure the continuous flow of drugs into the bloodstream over a period of time, measured in hours. Compressed tablets may be coated with a layer of sugar or a film to mask an unpleasant taste and protect the tablet from atmospheric factors. Alternatively, the tablets may have internal film septa providing selective separation of the tablet into parts in the digestive tract.

 Liquid dosages for oral administration may contain coloring or flavoring agents to make them more attractive to the animal being treated.

 For injection, etc. for external solutions, carriers such as water, a suitable oil, brine, water-soluble dextrose (glucose) and appropriate sugar solutions, as well as glycols such as propylene glycol or polyethylene glycol, are suitable. Solutions for administration by injection preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, buffers. Suitable stabilizing agents are antioxidant agents, such as sodium bisulfite or sodium sulfite, or ascorbic acid, taken individually or in combination. In addition, citric acid and its salts are used, and the injections may contain preserving additives, such as benzalkonium chloride, methyl or propyl paraben, chlorobutanol.

 Suitable pharmaceutical carriers are described in the Remington's Pharmaceutical Sciens, A. Osol, a commonly accepted guide in the art.

 The pharmaceutical dosages used to administer the compounds of the invention are given below.

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

 Soft gelatin capsules. A mixture of the active ingredient is prepared with easily digestible oil, such as soybean, cottonseed or olive oil, which is injected into gelatin using a special tool to produce soft gelatin capsules containing 100 ml of the active ingredient. These capsules were washed and dried.

 Tablets. Many types of tablets are prepared according to the usual technology, when the dosage consists of 100 mg of the active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Suitable tablet coatings may be used to improve palatability and ease assimilation.

 Injection fluids. A composition for administration by injection is prepared by stirring 1.5% (mass fraction) of the active ingredient in a 10% (volume fraction) aqueous propylene glycol solution. When increasing the volume of the label, use special water for injection. The finished solution is sterilized.

 Suspensions For oral administration, an aqueous suspension is prepared in each 5 ml of which 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, USP, as well as 0.025 ml vanillin.

 The same types of dosages that are listed above can be used when prescribing the compounds of the invention at any stage of treatment in combination with other drugs. If two drugs are prescribed in their physical combination, then the type of dosage and method of administration must be selected taking into account the compatibility of both drugs. Suitable dosages, varieties of dosage forms and methods of administration are listed below in table. 7 and 8.

 When used with NSAIDs, the doses of AII blockers are usually the same as with the independent use of the AII hormone blocker: 1-500 mg / day, usually 10-100 mg / day in one or several doses. When used in conjunction with diuretics, the initial dose of AII blocker may be less: 1-100 mg / day, and in the case of more active compounds, it is 1-10 mg / day.

 Compounds of the invention are also expected to be useful in the treatment of chronic renal failure.

Claims (5)

1. Aralkyl-substituted imidazoles of the general formula I

where R ¹ means C ₂ C ₆ alkyl;
R ² means 1- or 2-naphthyl, 3-, 4- or 5-acenaphthyl, 1-, 2-, 3- 4- or 9-phenanthrenyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl or 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, wherein any of the above groups may be substituted with one or two substituents selected from the group: halogen or C ₁ - C ₅ alkoxyl; or C ₂ C _{1 0} alkenyl substituted with a substituted or unsubstituted polycyclic aryl group as defined above having antihypertensive effects.  2. A pharmaceutical composition having inhibitory activity against angiotensin II, containing an active principle and a pharmaceutically acceptable carrier, characterized in that it contains as an active principle an aralkyl-substituted imidazole of formula I according to claim 1 in an effective amount. 3. The composition according to claim 2, characterized in that it additionally contains a diuretic in the following components, per daily dose:
The compound according to claim 1 1 100
Diuretic 25 100
4. The composition according to claim 2, characterized in that it additionally contains a non-steroidal anti-inflammatory drug with the following components, mg per daily dose:
The compound according to claim 1 1 500
Nonsteroidal anti-inflammatory drug 1,500
5. The method of obtaining aralkyl-substituted imidazoles of the general formula I according to claim 1, characterized in that the imidazole derivative of the general formula

reacted with a benzyl derivative of the general formula

where R ¹ , R ² have the meanings indicated above;
R ³ group

or R ¹ R ³ are protected or are intermediate groups,
X ¹ halogen, paratoluenesulfonyloxy or methylsulfonyloxy,
in a solvent medium in the presence of a base at a temperature of from 20 ^o C to a temperature of distillation of the solvent for 1 to 10 hours, followed by isolation of the target product or, if necessary, conversion of compounds with intermediate or protected forms of radicals into target compounds.  6. The method according to p. 5, characterized in that the process is conducted in the presence of a base selected from the group consisting of a metal hydride of the formula MH, a metal alkoxide of the formula MOR, sodium or potassium carbonate, triethylamine or pyridine, in a dipolar aprotic solvent or, if the base is a metal alkoxide MOR, the solvent may be alcohol R OH, where R is methyl, ethyl or tert-butyl, M-lithium, sodium or potassium.  7. The method according to claim 5, characterized in that a two-phase solvent system methylene chloride water is used and the process is carried out in the presence of a phase transfer catalyst of tricaprylmethylammonium chloride.

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